US20170074857A1 - Medication adherence monitoring device - Google Patents

Medication adherence monitoring device Download PDF

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US20170074857A1
US20170074857A1 US15/123,424 US201515123424A US2017074857A1 US 20170074857 A1 US20170074857 A1 US 20170074857A1 US 201515123424 A US201515123424 A US 201515123424A US 2017074857 A1 US2017074857 A1 US 2017074857A1
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breath
medication
aem
subject
smart
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Donn Dennis
Matthew Booth
Scott WASDO
Chris Batich
Hank WHOLTJEN
Douglas Crumb
Mark Tanner
Susan BAUMGARTNER
Poonam Kaul
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University of Florida Research Foundation Inc
Xhale Inc
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University of Florida Research Foundation Inc
Xhale Inc
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Assigned to UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. reassignment UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BATICH, CHRIS, BOOTH, MATTHEW, DENNIS, DONN, WASDO, Scott
Assigned to XHALE, INC. reassignment XHALE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAUL, POONAM, BAUMGARTNER, Susan, CRUMB, DOUGLAS, TANNER, MARK, WOHLTJEN, Hank
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/083—Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
    • A61B5/0836—Measuring rate of CO2 production
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/097—Devices for facilitating collection of breath or for directing breath into or through measuring devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4833—Assessment of subject's compliance to treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • G01N33/4975—Physical analysis of biological material of gaseous biological material, e.g. breath other than oxygen, carbon dioxide or alcohol, e.g. organic vapours
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B2010/0083—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements for taking gas samples
    • A61B2010/0087—Breath samples
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/08—Measuring devices for evaluating the respiratory organs
    • A61B5/087—Measuring breath flow
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/025—Gas chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors
    • G01N2030/743—FTIR
    • G01N2033/4975—

Definitions

  • MAMS Medication Adherence Monitoring System
  • SMART® an acronym for Self Monitoring and Reporting Therapeutics
  • Xhale, Inc. is a medical device development company which, for the last several years, has been developing, improving and perfecting a state of the art Medication Adherence Monitoring System (MAMS).
  • MAMS Medication Adherence Monitoring System
  • SMART® an acronym for Self Monitoring and Reporting Therapeutics
  • the improved SMART® system according to this invention provides an integrated series of solutions to meet the long-felt need for a reliable, gold-standard system to enable automated confirmation of subject adherence to a wide range of medication dosage regimens and contexts.
  • the present patent disclosure for the provides an integrated system capable of providing definitive medication adherence assessments and monitoring, both on an acute (dose-to-dose) basis, and on the basis of longer time frames, in the case of certain specific embodiments disclosed herein, up to and including over several doses of a given medication, over several days, or both.
  • This is enabled by providing: a highly sophisticated device which includes heretofore unknown features and combinations of features for integrated use in combination with novel medication compositions, thus defining novel methods of utilizing the system to achieve medication adherence monitoring.
  • Each of these elements of the integrated system is taken up in turn in this patent disclosure, with extensive but non-limiting exemplary support, to enable and fully describe the various embodiments and equivalents thereof encompassed by the present system.
  • the present disclosure provides a plethora of select improvements, either in specific components of the SMART® system, as in the device, the compositions of matter for use in combination with the device in particular contexts, in methods of making the device or composition of matter, or, in combination, to the system as a whole.
  • Proteus Biomedical, Inc. (now known as Proteus Digital Health) has taken the approach to medication adherence monitoring, as disclosed, for example, in U.S. Pat. No. 8,258,962, a “Multi-mode communication ingestible event markers (IEMs) and systems, and methods of using the same”, in which an integrated circuit comprising a conductive communication module is ingested to confirm medication adherence by sending out a signal (e.g., an RFID signal) once the circuitry has been ingested by a subject with a medication bearing that circuitry.
  • a signal e.g., an RFID signal
  • AiCure by contrast, is an artificial intelligence company which utilizes facial recognition and motion-sensing technology to monitor medication ingestion using a smartphone camera.
  • the medication adherence monitoring technology described herein is distinguishable from, for example, the implantation of a drug delivery device, such as, for example the osmostic delivery device disclosed in Ayer, U.S. Pat. No. 6,283,953, comprising an implantable reservoir having at least one opening for delivering a beneficial agent contained within an interior of the reservoir to an organ of an animal, an osmotic engine adapted to cause the release of the beneficial agent contained within the reservoir to the animal, and means for noninvasively measuring the release of the beneficial agent from the reservoir from outside, of tissue in which the delivery device is implanted.
  • the Ayer system requires the invasive implantation of a mechanical medication delivery device.
  • Noninvasive monitoring is conducted to ensure correct operation of the implanted device, but once implanted, there is no question of medication adherence—if the device is implanted and is operating as it should, the subject receives medication.
  • the Ayer system is not scalable for a large scale clinical trial, thousands of implantation surgeries would be required to implant the drug delivery device.
  • the system according to the present invention does not require the implantation of a drug delivery device.
  • MAMS components including an optimized SMART® device, improved compositions of matter and methods of making and use thereof, and, in particular, an integrated system in which these components operate together to accommodate a wide range of medication adherence monitoring requirements in varying contexts.
  • the present disclosure therefore, represents a quantum leap forward in that an integrated system is provided herein wherein commercial embodiments of a SMART® device are disclosed in combination with selected embodiments of SMART® compositions of matter and methods of using such embodiments in optimized combinations with each other to provide a gold-standard in the field of acute and chronic medication adherence monitoring.
  • the present invention accommodates a number of aspects of MAMS not heretofore adequately addressed by any known medication adherence monitoring system. Included in these aspects are improved embodiments of the SMART® device, improved embodiments of SMART® composition of matter for use in combination with the improved SMART® device, and improved embodiments of methods of making and using the SMART® device and composition of matter as an integrated system to address different contexts in which medication adherence monitoring is desired.
  • SMART ® DEVICE See section 6 + 8; examples 1-4; FIGS. 1-18 (a) biometric capture concurrent with breath collection; (b) portable GC with 5 ppb sensitivity for select VOCs; (c) catalytic incineration + IR detection; (d) EBM measurement without separation (e) small footprint device; (f) combinations of (a)-(e); SMART ® COMPOSITION OF MATTER: See Section 7 + 8; examples 5-26; FIGS.
  • a further object of the invention is to provide an improved SMART® device.
  • a further object of the invention is to provide an improved SMART® composition of matter.
  • a yet further object of the invention is to provide an improved method of making and using the SMART® system, device, and composition of matter.
  • a further object of the invention is to provide a system for medication adherence monitoring which enables acute medication adherence monitoring (AMAM), intermediate medication adherence monitoring (IMAM), and chronic medication adherence monitoring (CMAM).
  • AMAM acute medication adherence monitoring
  • IMAM intermediate medication adherence monitoring
  • CMAM chronic medication adherence monitoring
  • the inverse of medication adherence monitoring is the detection of drug diversion and/or drug counterfeiting. That is, if a subject is definitively confirmed to be taking their prescribed medication, there cannot be drug diversion or counterfeiting. Conversely, if a subject is thought to be non-adherent, the system and method according to this invention provides a basis for exploration of whether the subject has been prescribed a counterfeit medication or if the subject is diverting their medication to another person or persons. Therefore, it is a further aspect of this invention to provide an improved method, system, and device for detection of drug diversion or counterfeiting.
  • a state of the art device or apparatus configured to identify and/or quantitate volatile compounds in a gas sample.
  • the device includes at least one sensor adapted for identification and/or quantitation of a volatile compound of interest present in the gas sample and at least one capture device which captures volatile compounds in the gas sample.
  • the sensor is selected from any of an array of known sensors, including but not limited to metal oxide sensors (MOS sensors), infrared sensors (IR), Surface Acoustic Wave sensors (SAW sensors) or the like. Combinations of such sensors may be included in the device such that the gas or components of the gas introduced into the device is/are contacted with each such sensor before being released from the device into the atmosphere.
  • MOS sensors metal oxide sensors
  • IR infrared sensors
  • SAW sensors Surface Acoustic Wave sensors
  • the capture device is selective in that, while it is efficient at capture of volatile compounds, especially volatile organic compounds, it either does not capture at all or is inefficient in the capture of moisture, hydrogen, nitrogen, or carbon dioxide, present in the gas sample. These latter components in the gas sample, therefore, merely flow through the capture device and are vented to the atmosphere.
  • the capture device is selected and adapted to further exhibit the property of releasing captured volatile compounds for sensing by the at least one sensor at a time coordinated in the device to coincide with readiness of the at least one sensor to be contacted with released volatile compounds that had been captured.
  • the apparatus is adapted for identifying and/or quantitating volatile compounds present in the exhaled breath of a subject.
  • the adaptations for this purpose include, but are not limited to at least one or a combination of:
  • the apparatus includes at least two sensors with differential sensitivity to a volatile compound of interest in the exhaled breath of a subject.
  • the differential sensitivity or selectivity of the at least two sensors allows information to be derived by manipulation, including by comparison of signals from each such sensor (e.g., addition of one signal to the other, subtraction of one signal from the other and the like) about the presence and optionally the amount of a particular analyte of interest in the exhaled breath sample.
  • the device includes at least one or a combination of:
  • a compound separator such as, in a preferred embodiment, a gas chromatograph that is operatively coupled with an air scrubber that provides a scrubbed air stream which is driven through the gas chromatograph by a pump;
  • thermoly desorbable concentrator column operating as a volatile organic compound capture device in intimate association with a heating element such that, upon heating of the heating element, captured volatile compounds are released from the capture device;
  • a wireless data transceiver comprising at least one or a combination of: a WiFi transceiver; a mobile cellular data transceiver; a Bluetooth® transceiver; or the like;
  • a camera operating as a biometric capture device which captures at least one still image of the subject at the time that the subject exhales into a mouthpiece incorporated into and in operative coupling with the device;
  • the battery is a rechargeable battery
  • the device described above is used in a method for medication adherence monitoring, which comprises contacting the device (e.g., breathing into the device; separately capturing a breath or breaths in a capture device, (e.g., a breath capture bag, a breath capture column which efficiently captures organic compounds in the exhaled breath but which does not efficiently capture moisture, hydrogen, nitrogen or carbon dioxide), and then releasing captured breath or breath components into the device), with an exhaled breath sample of a subject.
  • a capture device e.g., a breath capture bag, a breath capture column which efficiently captures organic compounds in the exhaled breath but which does not efficiently capture moisture, hydrogen, nitrogen or carbon dioxide
  • the device is used by a subject in combination with a medication adapted for provision of a marker which the device is configured to detect in exhaled breath.
  • an Active Pharmaceutical Ingredient is provided with or without a separate Adherence Enabling Marker (AEM).
  • the API, the AEM, or both when taken or administered to a subject generates a sufficient quantity of an Exhaled Breath Marker (EBM) in the exhaled breath of the subject to be detected by the at least one sensor.
  • EBM Exhaled Breath Marker
  • the device is used to detect the EBM within a specified time period after a subject takes or is administered or applies a single dose of the medication.
  • the device and the medication are selected and configured such that the EBM is detectable in the exhaled breath of the subject after the subject takes or is administered or applies multiple doses of the medication, and/or in relatively wide windows of time, or even random times, after a subject has or should have taken one or multiple doses of a medication.
  • the medication formulation options and device feature options are sufficiently malleable that the method can be practiced in any or each of these modes to reliably achieve AMAM, IMAM, CMAM, as needed for a given medication, subject, or set of clinical trial requirements.
  • the method described herein may, in one preferred embodiment, be practiced with an API, an AEM, or both, which includes a non-ordinary isotope.
  • the non-ordinary isotope is preferably selected to exist in the API, AEM or both such that the non-ordinary isotope is included in a resulting EBM, when it appears in the exhaled breath of a subject that takes or applies or is administered such a medication.
  • the non-ordinary isotope appears in the exhaled breath of a subject at a known and/or predictable concentration in the exhaled breath of such a subject at a time after taking such a medication which is convenient, or randomly selected, for the subject to provide an exhaled breath sample to the device.
  • the method according to this aspect of the invention includes embodiments in which:
  • a SMART® (Self Monitoring And Reporting Therapeutic) medication is provided to a subject which enables monitoring of the subject's adherence in taking or administration of at least one Active Pharmaceutical Ingredient (API) included in the medication in which the medication includes: (i) an i-API fraction, that is a known percentage of the total amount of the API delivered, which includes at least one non-ordinary but stable isotope; or (ii) an i-AEM, an Adherence Enabling Marker, which includes at least one non-ordinary but stable isotope; or (iii) both an i-API fraction and an i-AEM; such that, on taking or administration of the medication by or to the subject, an i-EBM, (an Exhaled Breath Marker comprising at least one non-ordinary but stable isotope), is produced in the exhaled breath of the subject; and/or
  • API Active Pharmaceutical Ingredient
  • An i-EBM is detected and/or quantitated in the exhaled breath of a subject utilizing a device which comprises a component element that strips the exhaled breath sample of moisture and carbon dioxide, without impacting (e.g., removing, depleting) the i-EBM.
  • the device used according to this method may further include a catalyst for converting the i-EBM to carbon dioxide and water, such that: (a) the isotope from the i-EBM is included in the water fraction, such that, following catalysis, isotopically labeled water is quantitated in the exhaled breath sample; and/or (b) the isotope from the i-EBM is included in the carbon dioxide fraction, such that, following catalysis, isotopically labeled carbon dioxide is quantitated in the exhaled breath sample.
  • a catalyst for converting the i-EBM to carbon dioxide and water such that: (a) the isotope from the i-EBM is included in the water fraction, such that, following catalysis, isotopically labeled water is quantitated in the exhaled breath sample; and/or (b) the isotope from the i-EBM is included in the carbon dioxide fraction, such that, following catalysis, isotopically labeled carbon dioxide is quantitate
  • the system according to this invention includes a medication comprising an API and an AEM, wherein the AEM is contained in a chemical form or within a barrier adequate to contain loss of the AEM and/or to prevent the AEM from contacting the API prior to being taken or administered by a subject.
  • the chemical form or barrier facilitates rapid release of the AEM and/or API in a subject to permit medication adherence monitoring by measurement of an EBM in the exhaled breath of a subject within a specified time period, either immediately or a short period (up to about an hour), or a longer period, (from about one hour up to and including several days) after a medication is ingested by, taken by, is administered to or applied onto the subject.
  • the barrier in a preferred embodiment comprises a softgel capsule shell which is optionally coated by a barrier, surface coating, or materials which prevent loss of the AEM from the capsule.
  • the AEM is provided in a chemical form that is stable until exposed to the biological environment of the subject, whereupon it quickly forms the AEM in situ and is then expired in the exhaled breath as the EBM.
  • the AEM comprises either or both (a) a non-ordinary isotope; (b) butanol, isopropanol, or both, either or both of which may include a non-ordinary isotope, or other selected secondary alcohols, or other AEMs.
  • the medication includes a surface coating comprising an i-AEM. Given the sensitivity of a D 2 O detector described herein, a low quantity (e.g., 1-10 mg) of a deuterated AEM placed on the surface (partial surface or total surface) of SODFs (solid tablets, capsules) is adequate to permit medication adherence monitoring.
  • the AEM is incorporated into the surface coating of the SODF so that it does not require storage in a blister pack, but rather can be stored in a standard pill bottle.
  • the Adherence Enabling Marker (AEM) composition comprises at least one of:
  • the AEM formulation includes permutations or combinations of the following: the AEM is preferably a secondary alcohol, e.g., 2-butanol, isopropyl alcohol, or both, or other combinations and equivalents of other AEMs as disclosed herein; the bulking agent comprises PEG-400, or any of a wide array of other bulking agents known in the art (fractionated coconut oil; Acconon® surfactant/dispersing agents, e.g., MC-8-2; Phosal® lipids; oleic acid (refined); various grades of PEG; HPC, e.g., Klucel®; povidone; Capmul® emulsifiers; potassium acesulfame); the flavorant, if present, comprises e.g., vanillin, DL-menthol, or both, or other flavorants known in the art.
  • the bulking agent comprises PEG-400, or any of a wide array of other bulking agents known in the art (fractionated coconut oil; Acconon®
  • the formulation consists of: (a) 20 mg 2-butanol+0.7 mg DL-menthol+5 mg vanillin+9.3 mg PEG-400; or (b) 40 mg 2-butanol+1.4 mg DL-menthol+10 mg vanillin+18.6 mg PEG-400; (c) 20 mg of 2-butanol alone; (d) 40 mg of 2-butanol alone; (e) combinations of 2-butanol and isopropyl alcohol, alone or in combination with other excipients.
  • the amount of AEM used may be varied, depending on the concentration of EBM required to be detected in the exhaled breath.
  • the SMART® device can detect either or both AEMs in the exhaled breath, and either or both EBMs generated from the AEMs (e.g., butanone and acetone), and any interferents can thereby be identified if the ratio of AEMs/EBMs is inconsistent with a detected compound which could not have been generated from the AEM in the relative amount detected in exhaled breath.
  • EBMs generated from the AEMs
  • the system for medication adherence monitoring comprises the use of an apparatus as described herein in combination with a medication comprising an API, an AEM, or an API and AEM, wherein the API, the AEM, or both are present in a chemical form or contained within barriers adequate to contain the API, the AEM, or both from loss or contact between the AEM (if present) and the API.
  • the barrier to facilitate rapid release of the AEM, the API or both, in a subject to permit medication adherence monitoring by measurement of an EBM in the exhaled breath of such a subject generated from the AEM, from the API, or both, within a specified time period after the medication is ingested or otherwise administered or applied to or by the subject.
  • the system includes:
  • SMART® drug comprising an API, an AEM, or both which generate a marker or markers, Exhaled Drug Ingestion Marker(s) (EDIMs) that appear(s) in the exhaled breath of humans or other vertebrates, to confirm definitive medication adherence, and
  • EDIMs Exhaled Drug Ingestion Marker
  • SMART® device which accurately measures the EDIMs and optionally provides medication reminder functions, and orchestrates critical adherence information flow between the relevant stakeholders;
  • the SMART® drug comprises an Adherence Enabling Marker (AEM) composition comprising: (i) at least one secondary alcohol which when ingested or otherwise taken or administered to a subject produces an Exhaled Drug Ingestion Marker (EDIM) detectable in the exhaled breath of the subject; (ii) an adequate quantity of flavorant such that greater than 90% of recipients of the AEM composition report little or no adverse taste following ingestion of the AEM composition; and (iii) an adequate quantity of bulking agent to permit reliable filling of soft-gel capsules and stable storage of the AEM composition within a soft-gel capsule.
  • AEM Adherence Enabling Marker
  • EDIM Exhaled Drug Ingestion Marker
  • the SMART® device accurately measures the EDIMs, optionally provides medication reminder functions, and orchestrates critical adherence information flow between the relevant stakeholders.
  • a sensor from the group consisting of miniaturized Gas Chromatography linked to any or a combination of a Metal Oxide Sensor (mGC-MOS), a surface acoustic wave (SAW) sensor, an infrared (IR) sensor, and an ion mobility spectroscopy (IMS) sensor.
  • mGC-MOS Metal Oxide Sensor
  • SAW surface acoustic wave
  • IR infrared
  • IMS ion mobility spectroscopy
  • the present invention provides a method for using an Adherence Enabling Marker, AEM x , (which may include use of an API acting as its own marker), or measuring an Exhaled Drug Ingestion Marker X, EDIM x produced on ingestion of an AEM x comprising characterizing the pharmacokinetics, including concentration-time relationships of appearance and clearance of EDIM x in the exhaled breath of a subject.
  • AEM x Adherence Enabling Marker
  • EDIM x Exhaled Drug Ingestion Marker X
  • AEM x comprises a non-ordinary isotope of an atom which constitutes AEM x such that the non-ordinary isotope is included in EDIM x in the exhaled breath upon dosing of a subject with a medication comprising AEM x .
  • the non-ordinary isotope is deuterium.
  • the Limit of Detection, LOD of the method is only constrained by the lowest concentration of EDIM x that the sensor used in the method is able to reliably measure, thereby providing a lookback period limited only by the LOD of the sensor, and the relationship of steady state concentration EDIM x (related to its half life) and the mass of the AEM delivered to the subject.
  • This method may also be practiced with a combination of AEMs and EDIMs concurrently, (that is AEM x , EDIM x ; AEM A , EDIM A ; AEM B , EDIM A ; AEM C , EDIM C ; AEM N , EDIM N ). See Example 28 herein below for detailed description of this aspect of the invention.
  • An optimized device or system according to this invention is optimized by including in the device:
  • the characterizing data for storage preferably includes measurement data, to within defined confidence limits, of:
  • Such a device is preferably configured to integrate the pharmacokinetic parameters defined above to provide an adherence lookback window, T AdhWindow , defined as the period of time required for the marker (EDIM) concentration in breath of the subject to decay from an initial value (C EDIMo ) to a lower concentration (C EDIM,Limit ):
  • T AdhWindow defined as the period of time required for the marker (EDIM) concentration in breath of the subject to decay from an initial value (C EDIMo ) to a lower concentration (C EDIM,Limit ):
  • T AdhWindow t 1 / 2 ⁇ e 0.693 * ln ⁇ ( C EDIMo C EDIMLimit )
  • C EDIMo original or starting concentration of marker (EDIM) in breath at times equal to or greater than T MAX (i.e., C EDIMo ⁇ C MAX ) of said patient;
  • Such a device preferably exhibits a T AdhWindow between about 1 hour and about 400 hours, and includes a sensor with a LoD for the marker of between 1 part per trillion and 5 parts per billion or, naturally, higher, as the higher the concentration the easier it is to define a sensor with an adequate LOD.
  • the sensor is adapted to distinguish between ordinary and non-ordinary isotopes present in EDIMs and volatile compounds which otherwise would interfere with selective measurement of EDIMs in the exhaled breath.
  • the invention disclosed herein includes an improved system for medication adherence monitoring wherein the system comprises:
  • the improvements in such a system as disclosed herein comprise at least one or a combination of the following elements, with respect to the AEM, the device or both:
  • SMART® Adherence System To support development and facilitate regulatory filings, a number of complementary in vitro (benchtop) and clinical (human) studies have been carried out to characterize the SMART® Adherence System. In terms of human exposure, the system has been safely used to date in 32 human studies (oral, sublingual, and microbicide administration routes), encompassing 1,293 experiments in 303 subjects and 8,474 breath analyses. Of particular note, three recent prospective, blinded, randomized, cross over clinical validation studies (127 subjects with 472 experiments and 2,464 breath analyses) using the SMART® Adherence System designed for oral medications were executed that focused on identifying an optimal adherence-enabling marker (AEM) formulation and carrying out receiver operating characteristic (ROC) curve analyses to make an optimal cutoff determination and assess diagnostic performance.
  • AEM optimal adherence-enabling marker
  • ROC receiver operating characteristic
  • FIG. 1 Provides an illustrative example of how the system and method according to this invention works.
  • Panel A metabolism of the AEM, 2-butanol, by on-alcohol dehydrogenase (ADH) to generate the volatile product, 2-butanone, an Exhaled Drug Ingestion Marker (EDIM)/Exhaled Breath Marker (EBM).
  • Panel B breath concentration-time relationship for the exhalation of 2-butanone (an EDIM) in breath following consumption of 2-butanol at time 0 min. Data shown are mean ⁇ SD.
  • FIGS. 2A and 2B Graphic representations of a Handheld Miniature SMART® Device according to this invention.
  • FIG. 3 SMART® device block diagram showing breath sampling, separation, biometric capture, data and instruction display, data communication, microcontroller and power subsystems.
  • FIG. 4A-E SMART® GC Subsystem Interconnect Block Diagrams.
  • FIG. 5 Graphic representation of a first embodiment of a Mouthpiece (Straw).
  • FIG. 6 Technical Drawing of Disposable Mouthpiece.
  • FIG. 7A-C Mouthpiece Sensor, Breath Flow Sensor and Vapor Inlet in two different embodiments of the SMART® device according to this invention.
  • FIG. 8 Flow Diagram for Breath Collection and component separation in a miniature GC (mGC) embodiment of the SMART® device according to this invention.
  • mGC miniature GC
  • FIG. 9 Exemplary representation of a SMART® mGC chromatographic separation of isoprene, acetone, and 2-butanone in human breath.
  • FIGS. 10A and 10B Photograph of internal architecture of one exemplary embodiment of internal components of the SMART® device.
  • FIG. 11 Photograph of internal architecture of obverse view shown in FIG. 10 in one exemplary embodiment of the SMART® device.
  • FIG. 12 Air flow path for scrubbed carrier air in the SMART® device.
  • FIG. 13 Exemplary representation of one embodiment of a user interface and SMART® device operational flow diagram.
  • FIG. 14 SMART® device logic flow diagram.
  • FIG. 15 SMART® device logic and data flow diagram.
  • FIG. 16 a - g A Prospective Randomized Cross Over Clinical Study in 50 Subjects to Determine the Optimal Configuration of the SMART® Adherence System: Effect of Four Adherence-Enabling Marker Formulations and Validation of the SMART® device operation; 16 a Age; 16 b Gender; 16 c Ethnicity; 16 d Body Mass Index (BMI); 16 e Time From Last Meal; 16 f Alcohol Use; 16 g Tobacco Use; none of these factors appeared to be confounding factors.
  • BMI Body Mass Index
  • FIG. 17 a - j 2-Butanone Breath Concentration-Time Relationship—Effect of Adherence-Enabling Marker (AEM) Formulation, see FIG. 17 a; ⁇ 2-Butanone (Change In Concentration From Baseline Values) Breath Concentration-Time Relationship, see FIG. 17 b ; Effect of Adherence-Enabling Marker (AEM) Formulation on ⁇ 2-Butanone Breath Concentration-Time Relationship: Effect of AEM Formulation; Individual ⁇ 2-Butanone Concentration-Time Curves in 50 Subjects: 20 mg 2-Butanol—See FIG.
  • FIG. 18 a - i Effect of Meal Timing on ⁇ 2-Butanone Concentrations Across AEM Formulations—See FIG. 18 a ; Covariates: Tobacco and Alcohol Use—See FIG. 18 b ; ⁇ T Max : Effect of AEM Formulation see FIG. 18 c ; Cumulative Frequency (%) of Subjects Achieving ⁇ T Max by Time and Formulation—See FIG. 18 d ; ⁇ C Max : Effect of AEM Formulation—See FIG. 18 e ; ⁇ AUC: Effect of AEM Formulation—See FIG. 18 f ; SMART® Device Performance: Full 2-Butanone Concentration Range—See FIG.
  • FIG. 19 Schematic of optional features, permutations and combinations of features for embodiments of the SMART® device (Type II) according to this invention.
  • FIG. 20 Schematic details of a first optional arrangement of Type II SMART® device components.
  • FIG. 21 Schematic details of a second optional arrangement of Type II SMART® device components and output example from analysis of i-EBM.
  • FIG. 22 Schema showing the metabolic fate of selected ordinary isotope and non-ordinary isotope labeled alcohols, aldehydes and carboxylic acids.
  • FIGS. 23-53 Schemes showing particular biochemical conversions of selected molecules to exemplify fate of particular atoms which may act as non-ordinary isotopes for use as i-AEMs/i-EBMs in combination with an embodiment of the SMART® device (Type II) according to this invention.
  • FIG. 54 Breath Concentration-Time Profile from a 30 mg bolus of isopropyl alcohol (IPA; isopropanol; 2-propanol) delivered in a size 0 capsule to a fasting subject, showing IPA induced increase above baseline for acetone in the exhaled breath of the subject. See FIG. 55 for mGC analysis after ingestion of 10 mg IPA.
  • IPA isopropyl alcohol
  • FIGS. 55A and 55B First derivative of the mGC profile for 0, 5, 10, 15, and 30 minutes post ingestion of 10 mg IPA; 55 B shows the ratio of first derivatives for the acetone/isoprene mGC profiles.
  • FIGS. 56-59 GC/MS and OrbiTrap (LC/MS/MS) Analysis.
  • FIGS. 60-61 Real time Analysis of Acetone Breath Kinetics following Ingestion of 3 mg d8-Isopropanol Using the OrbiTrap LC/MS.
  • FIG. 62 Real time Analysis of Acetone Breath Kinetics following two repeated ingestions of 10 mg d8-Isopropanol and 10 mg Isopropanol Using the OrbiTrap LC/MS.
  • FIG. 63 Breath kinetics of exhaled 2-butanol and 2-butanone following the concurrent ingestion of 2-butanol and ethanol;
  • B Mass spectrum of a single breath sample taken 5 min after the ingestion of 2-butanol and ethanol. Ethanol, 2-butanone and acetone are now present as prominent peaks, but 2-butanol is barely detectable above baseline;
  • C Mass spectrum of a single breath sample taken 5 min after the ingestion of 2-butanol and ethanol.
  • the electrospray interface on the orbitrap was modified to allow a subject to blow exhaled breath samples directly into the source while the mass spectra were being collected.
  • the rapid clearance of the breath samples from the source allowed us to capture and characterize mass spectra from exhaled breath samples in real time.
  • FIG. 64 Breath kinetics of exhaled 2-butanol and 2-butanone following the concurrent ingestion of 2-butanol and ethanol;
  • A Plotting the peak height of each compound of interest as a function of time yields the breath kinetics for each potential breath marker. Even with a reasonable dose of ethanol present in the stomach, the kinetics of 2-butanone appears unaffected (or at least very similar to a typical response following the ingestion of just 2-butanol) and no significant 2-butanol was detected;
  • B Breath kinetics of 2-butanone and d6-acetone following ingestion of neat 2-butanol (40 mg) and d8-isopropanol after lunch.
  • FIG. 65 FTIR Analysis of Acetone and Isopropyl Alcohol along with their perdeuterated isotopologues; 65 A tracing showing the infrared spectrum from a NIST Webbook Gas Phase IR Spectrum of 2-Propanol; 65 B there is provided a spectrum obtained by the inventors using a Thermo Nicolet 6700 FTIR Gas Phase IR Spectrum of 2-Propanol.
  • FIG. 66 66 A tracing of the FTIR analysis of acetone and d6-acetone showing clear areas where these spectra are distinguishable from each other; 66 A′ shows an expanded portion of the tracing from FIG. 66 a in which this is very clearly shown; 66 B tracing of the FTIR analysis of IPA and d8-IPA, again showing clear areas where these spectra are distinguishable from each other.
  • FTIR Spectra A shows the HC ⁇ O stretch for acetone at 2985 cm ⁇ 1 versus the DC ⁇ O stretch for d6-acetone at 2261 cm ⁇ 1 .
  • FTIR Spectra B shows the H3C—OH stretch for IPA at 2970 cm ⁇ 1 versus the D3C—OH stretch for d3-IPA at 2231 cm ⁇ 1 . Both of these spectral shifts are easily distinguishable.
  • FIG. 67 FTIR Spectra of Acetone and Isopropyl Alcohol with their perdeuterated isotopologues, with a detail of each tracing in the Fingerprint Region (1170 cm ⁇ 1 to 1300 cm ⁇ 1 , 8.5470 mm to 7.6923 mm).
  • FIG. 68 FTIR Analysis of Acetone and Isopropyl Alcohol along with their perdeuterated isotopologues; 68 A, FTIR Spectra of d6-acetone versus Blank Breath, with details of portions of these spectra being shown in FIGS. 68B and 68C .
  • FIG. 70-74 Breath kinetics of exhaled d6-acetone following the ingestion of 100 mg of d8-isopropanol per diem for 5 days.
  • FIG. 70 shows that native acetone peak heights remained reasonably constant throughout the study.
  • FIG. 71 shows that baseline levels for ion 82 (the ion used to monitor d6-acetone) were low and less than 1000 ( ⁇ 1% of typical acetone levels). An increase of exhaled d6-acetone was apparent within 2-4 minutes of ingesting each dose of d8-IPA. Maximum breath levels were achieved after 1-2 h and ranged from 450,000 to 800,000 peak height ( ⁇ 2-5 ⁇ concentrations of endogenous/native acetone).
  • FIG. 72 shows that 24-hour trough levels were relatively unchanged over the course of the study and were ⁇ 10% of peak maximum.
  • FIG. 73 shows that the decline of d6-acetone in exhaled breath followed a first order decay (2-24 h post ingestion). The rate constant (k) for this decay was consistent throughout the study.
  • FIG. 74 shows that at this rate of elimination, approximately 6-10% of maximum peak response remains after 24 h. Such kinetics should produce steady-state trough levels that are also ⁇ 10% of the maximum peak. This matches the observed trough levels during the study.
  • LOD lower limit of detection
  • 75 b demonstrate the similarity of these relationships for both exhaled markers
  • FIG. 76 Shown in Panel A of FIG. 76 is the 1 st derivative mGC response (proportional to EDIM breath concentration) in a Type 1 SMART Device for acetone and 2-butanone as a function of breath sampling times post ingestion of the capsule. Shown in Panel B is the same data as a difference from baseline (little change in the appearance of the 2-butanone curve due to little or no background, but shifting of the acetone curve downward after subtraction of background acetone).
  • FIG. 77 IPA as an AEM using a Type I SMART® Device according to this invention.
  • 77 a mGC-MOS Chromatograms for IPA Calibration Curve;
  • 77 b IPA Calibraton Curve analyzed on the mGC-MOS;
  • 77 c acetone in exhaled breath (concentration in ppb) vs. time.
  • Ingestion of 100 mg of isopropyl alcohol (IPA) rapidly increased the acetone concentrations in breath above baseline values. The rise was greater than 6 ⁇ (baseline: 450 ppb vs maximum: 2800 ppb) that of baseline acetone concentrations.
  • FIG. 78 Fundamental pharmacokinetic relationships for six successive administrations of an oral drug.
  • the light line is the pattern of drug accumulation during repeated administration of a drug at an interval equal to its elimination half life, when drug absorption is very rapid relative to elimination.
  • the heavy line depicts the pattern during administrating of equivalent dosage by continuous intravenous infusion. Curves are based upon a one compartment model.
  • the x axis represents time, as indicated by multiples of elimination half life (t 1/2a ).
  • Abbreviation Key C Trough , trough concentration of EDIM (circle symbols); C MAX , maximum concentration of EDIM in breath (horizontal dotted lines).
  • FIG. 79 First Dose PK using d8-Isopropyl Alcohol (IPA) as the AEM.
  • IPA d8-Isopropyl Alcohol
  • the experimental data was curve fit (parameter estimates ⁇ SE) to Equation 1 using a non-linear, least squares (Marquardt-Levenburg) algorithm (SigmaPlot 11, Systat Software, Inc., San Jose, Calif.).
  • the T AdhWindow for C Trough and C MAX levels of d6-acetone according to Equation 9 is 96.8 hrs (4.0 days) and 120.3 hrs (5.0 days), respectively.
  • the logarithmic scale is used on the y axis.
  • FIG. 80 d6-acetone (EDIM) concentration-time curve in a human after 5 sequential doses (D1 to D5) of d8-IPA (100 mg) with adherence “look back” windows shown at various device LoDs.
  • EDIM d6-acetone
  • FIG. 81 Simulated EDIM concentration-time relationships generated from Equation 1 following ingestion of d8-IPA (40 mg) and d10-2-butanol (40 mg) using actual (experimental) human PK parameters for IPA and 2-butanol.
  • the rate constant of 2-butanone, which is immediately and completely generated from 2-butanol, for absorption (k s ) and elimination (k e ) were 0.025/hr and 0.367/hr, respectively.
  • the rate constants of acetone, which is immediately and completely generated from IPA, for absorption (k a ) and elimination (k e ) were 2.40/hr and 0.0815/hr, respectively.
  • the trough concentrations always return to baseline values.
  • the presence or absence of d8-2-butanone in breath can be used to effectively detect and prevent deceit by subjects when using d8-IPA for AMAM and/or CMAM.
  • the d8-2-butanone generated from d10-2-butanol has a short t 1/2e , its presence should not be there if a breath is being provided later than 3 hours after ingesting the medication, or if performing a breath sample to measure C Trough for acetone. Hence, it can serve to prevent deception and eliminate potential interferents to the system.
  • d8-2-butanone should not be present in the baseline breath sample during the 8 AM morning dosing.
  • the lack of 2-butanone in breath ensures that the subject did not simply ingest the medication containing the AEMs immediately before the 8 AM dosing when they were randomly called to provide a breath sample to the SMART® device to ensure compliance.
  • the subjects were randomly called at night to provide breath samples at 8 PM (12 hours after the daily morning dose), again, no d8-2-butanone should be present.
  • the latter approach has the advantage of providing major convenience to the subjects (one breath script at night) without having to provide breath samples during the busy morning time). Note: the logarithmic scale is used on the y axis.
  • FIG. 82 Procedure to Use d6-Acetone (EDIM) Trough Concentrations (C Trough ) to Determine EDIM elimination half life (t 1/2a ) and the Adherence Look Back Window (T AdhWindow ) using C Trough at the Individual Subject Level.
  • EDIM d6-Acetone
  • C Trough Concentrations
  • T AdhWindow Adherence Look Back Window
  • Shown in the top panel is hypothetical acetone (EDIM) concentration-time data, modeled after inputting experimental values into Equation 1, for a specific subject receiving an oral medication containing 100 mg d8-IPA at a dosage interval of 1 day (administered once per day, or QD) for an introductory 7 day test period, which serves to acclimate the subject to the SMART® Adherence System and determine steady state trough levels of d6-acetone.
  • QD administered once per day
  • the only parameter measured in this subject is C Trough for acetone, as indicated by the circles in the top panel.
  • the C Trough values are measured just prior to administering the new dose of medication containing 100 mg d8-IPA.
  • the bottom panel shows the C Trough versus time over the 7 dosing days at one dose per day.
  • the experimental C Trough -time data was curve fit to the equation shown in the bottom panel using a non-linear, least squares (Marquardt-Levenburg) algorithm (SigmaPlot 11, Systat Software, Inc., San Jose, Calif.) to determine a C Trough at steady state (C Trough,SS ) and the elimination rate constant (k e ) of 646 ppb and 1.282/day, respectively.
  • this value of t 1/2a using a Type 2 SMART device (IR-based) with a LoD of either 100 or 10 ppt correspond to values of T AdhWindow of 164.6 hrs (6.9 d) and 207.8 hrs (8.7 d), respectively.
  • T AdhWindow 164.6 hrs (6.9 d) and 207.8 hrs (8.7 d)
  • the d6-acetone C Trough levels stay constant.
  • the value of C Trough should be the same (within the range of values) as what was determined from the 7 day introductory period.
  • the C Trough level measured when the subject is randomly called is lower than the C Trough,SS , the period of time since he/she did not take their medication can be calculated by using Equation 3.
  • FIG. 83 A. Breath acetone normalized to baseline as measured by the mGC following the ingestion of a placebo capsule (dashed line) and a capsule containing 100 mg of Na-2-propyl carbonate. B. Breath acetone (dashed line) and 2-butanone (solid line) as measured by the mGC following the ingestion of 100 mg of Na-2-butyl-carbonate.
  • FIG. 84A-D show the ability, using different AEM strategies, to achieve different rates of EBM production, from as quick as 10 minutes from ingestion for peak EBM to much longer peak EBM production times.
  • the following conceptual framework is provided at the outset as a guide, or map, as to how the various cooperating components of the new system interface with each other to provide the operative system exhibiting sufficient in-built flexibility to accommodate definitive medication adherence monitoring in at least the following significantly different contexts: Acute, Intermediate and Chronic Medication Adherence Monitoring (AMAM, IMAM and CMAM, respectively).
  • AMAM Acute, Intermediate and Chronic Medication Adherence Monitoring
  • IMAM IMAM
  • CMAM CMAM
  • the triad of circumstances consisting of an EDIM having the longest half life in breath being detected with the most sensitive sensor with no background interference (e.g an EBM already present or other breath markers that could mimic the EBM to the sensor) provides an optimal SMART architecture for a CMAM system.
  • a triad of circumstances consisting of an EDIM having a short half life in breath being detected with a less sensitive sensor with significant background interference provides a SMART architecture most suitable as an AMAM system.
  • a baseline breath may be all that is required.
  • a single AEM may be utilized in each such mode (AMAM, IMAM, CMAM), different AEMs may be used for each such mode, or combinations of AEMS may be utilized to achieve definitive medication adherence monitoring and exclusion of interferents.
  • medication adherence is monitored typically on a dose-to-dose basis, and usually from immediately or almost immediately (seconds to minutes) after a given dose of a medication is or should have been taken, up to about an hour after a given dose has been or should have been taken.
  • this is the typical context for medication adherence monitoring. That notwithstanding, as will be apparent from a review of the complete disclosure which follows, the present invention disclosure provides novel and inventive advances relevant to the SMART® medication adherence device, compositions of matter, methods of making and using these and an integrated system for SMART® medication adherence monitoring.
  • the time frame for monitoring medication adherence per this aspect of the invention is typically from as immediately as possible after a medication is taken by a subject up to about an hour or two after the medication is taken or administered in which a marker according to this invention is included with the medication for appearance and detection in the exhaled breath.
  • a marker according to this invention is included with the medication for appearance and detection in the exhaled breath.
  • EBM Exhaled Breath Marker
  • AMAM enabling markers AEMs
  • IMAM and CMAM this is less critical (i.e., the marker may be taken up in the duodenum, or lower in the digestive tract).
  • IPA isopropyl alcohol
  • medication adherence is monitored typically on a more than single dose-to-dose basis or, even if just on a dose-to-dose basis, the time-window for monitoring is substantially more flexible than having to confirm adherence within an hour to two hours after a medication is taken. That is, a major advance provided by the present disclosure is that it enables medication adherence monitoring to occur immediately (if significant gastric absorption of the AEM occurs) to a period of several hours (up to a day) after a given dose of a medication is or should have been taken.
  • the system has features of AMAM (pill by pill adherence) and IMAM (adherence look back window up to one day).
  • the system could be used to monitor IMAM but not AMAM.
  • the time frame for monitoring medication adherence per this aspect of the invention is typically from about one hour to up to about twelve hours following a given medication dose in which a marker is included with the medication for appearance and detection in the exhaled breath.
  • monitoring according to this aspect of the invention may be conducted five, six, seven, eight, nine, ten, eleven or even twelve hours after a given medication dose is taken. That is, there is increased flexibility such that adherence may be confirmed any time during a specified window after taking a dose, at pre-specified time points within the relevant window, or at random times within the window.
  • more than one dose of a given medication may be confirmed in such time period, and doses of different medications may likewise be monitored in this time frame.
  • CMAM Chronic Medication Adherence Monitoring
  • medication adherence is monitored typically on a more than single dose-to-dose basis, and the time window for medication adherence monitoring post dose is even further extended. Insight into whether a subject is following a medication regimen as instructed is obtained. That is, a major advance provided by the present disclosure is that it enables medication adherence monitoring to occur at any time, including many hours or even days after a given dose of a medication is or should have been taken. In the art to date, there is no known system which can provide definitive medication adherence monitoring with the flexibility of this much delay from the time of taking a medication to the time when adherence has to be confirmed.
  • the time frame for monitoring medication adherence per this aspect of the invention is typically from about eight hours, and up to about forty eight hours or more following a given medication dose in which a marker is included with the medication for appearance and detection in the exhaled breath.
  • monitoring according to this aspect of the invention may be conducted eight, nine, ten, eleven, twelve, twenty four, forty eight or even more hours after a given medication dose is taken.
  • more than one dose of a given medication may be confirmed in such time period, and doses of different medications may likewise be monitored in this time frame.
  • Section 9 specific but non-limiting exemplary support is provided to extend the enabling written description and to provide guidance on specific implementations of the invention in different contexts.
  • an “Adherence Enabling Marker” or “AEM” is included in a medication dosage which results in the production in exhaled breath of an “Exhaled Drug Ingestion Marker” or “EDIM”, also referred to herein as an Exhaled Breath Marker or “EBM”.
  • EDIM Exhaled Drug Ingestion Marker
  • EBM Exhaled Breath Marker
  • the AEM and EDIM may be the same compound, or the EDIM may be a metabolite of the AEM.
  • Table 1 below provides a convenient guide to some of the key permutations and combinations as disclosed and described in detail in the written description which follows:
  • a device is generically disclosed to determine whether a patient has taken a medication which operates by providing to a patient a medication comprising a combination of at least one active therapeutic agent and a marker which was not chemically part of the active therapeutic agent itself, but which was detectable in gaseous exhaled breath; obtaining a sample of the patient's gaseous exhaled breath; analyzing the sample of the patient's breath utilizing an electronic nose to detect the marker in gaseous exhaled breath to ascertain the presence or absence of the marker in the patient's breath.
  • SMART® device which has a detection limit as low as 5 parts per billion (ppb) for particular EDIMs (e.g., 2-butanone, using 2-butanol as the AEM). Detection at these and lower concentrations (see below) are established for this device with confidence limits of at least 90% and higher (see the examples). Where non-ordinary isotopes are utilized as part of the marker, detection limits in the parts per trillion (e.g.
  • 10 PPT-1000 PPT; or 10 PPT-1 PPB; or 100 PPT-10 PPB are enabled by particular embodiments of the SMART® device described herein. Improved combinations of biometric capture concurrent with sample collection are provided to ensure definitive medication adherence monitoring and elimination or substantially reduced possibility for “gaming the system”. Portability, reliability and other enhancements are likewise provided.
  • the device of the present invention may take any one of the following forms, each of which is described in detail herein below:
  • compositions including AEMs for use with a given device type are described and then systems integrated for use of a given device type in combination with a given composition are described.
  • a SMART® device is a device comprising integrated subsystems for reliable and accurate medication adherence monitoring when a SMART® medication is taken by or is administered to a subject.
  • the device at the heart of this invention is, where compound separation occurs, a miniature Gas Chromatograph (mGC) integrated with a sensor, such as a Metal Oxide Sensor (MOS), or an Infrared Sensor, or a Surface Acoustic Wave (SAW) sensor, together referred to herein as the mGC-MOS, mGC-IR, or mGC-SAW, respectively.
  • MOS Metal Oxide Sensor
  • SAW Surface Acoustic Wave
  • a Self Monitoring and Reporting Therapeutics (SMART®) apparatus facilitates definitive documentation of medication adherence, as described herein below.
  • the SMART® system uses FDA-approved food additives, termed adherence-enabling markers (AEMs), which are or which generate volatile compounds, which appear in the exhaled breath, including the AEM itself or metabolites thereof in vivo, referred to herein as the Exhaled Drug Ingestion Marker, or EDIM, or Exhaled Drug Emplacement Marker, or EDEM, to distinguish between ingested medications with a marker (EDIM) and medications that are delivered non-orally, e.g., vaginally, rectally, transdermally, etc. (the EDEM).
  • EDIMs and EDEMs are collectively referred to herein as Exhaled Breath Markers, EBMs.
  • the EDIM or EDEM is exhaled by a subject following ingestion, emplacement or other means of administration of a medication including the AEM. Measurement of these markers and/or metabolites thereof in a breath sample unambiguously documents adherence (ingestion, administration or application of the medication).
  • the AEMs are FDA designated Generally Recognized as Safe (GRAS) compounds, they are co-packaged or co-formulated with an active drug, also referred to herein as the Active Pharmaceutical Ingredient (API), into a capsule, tablet, cream, suppository, transdermal patch, or any other appropriate dosage form, in a manner that preferably alters neither the drug's manufacturing processes nor bioavailability.
  • the AEM may just as well be associated with a placebo, active control or other clinical material, rather than the API, and the same or different AEM's may be used to tag different API's, placebos and/or active controls.
  • the AEM(s) is/are absorbed by the stomach and small intestine, or is taken up across the skin, vaginal or rectal lining, and which then appears directly in the exhaled breath or is metabolized to a volatile marker(s) which appear(s) in exhaled breath (see FIG. 1 ) according to kinetics known for that marker.
  • a portable gas chromatographic apparatus which, in combination with a sensor (e.g., a MOS sensor, an Infrared sensor, a SAW sensor, or the like), provides low parts per billion or even parts per trillion sensitivity with precision and accuracy, for particular analytes in exhaled breath.
  • a sensor e.g., a MOS sensor, an Infrared sensor, a SAW sensor, or the like
  • the EDIM 2-butanol
  • All data are stored locally in the mGC device on an, e.g., internal USB flash drive or equivalent storage medium for later collection and/or transmitted in near real-time using integrated encrypted Health Insurance Portability and Accountability Act (HIPAA)-compliant wireless or cellular router technology to a central data repository for analysis.
  • HIPAA Health Insurance Portability and Accountability Act
  • Additional, optional, data streams are available to investigators or other clinical study personnel should the study or medication regimen requirements warrant collection when compared to subject privacy concerns: 1) a camera in the SMART® device is time-gated to concurrent breath collection; this biometric capture (e.g., facial picture; in one embodiment, if the biometric data captured does not match biometric data stored in the device or in a central data collection facility, the breath collection may be terminated, or the data may be flagged, or appropriate personnel may be alerted) allows investigators to definitively confirm that the breath analyzed by the SMART® device originated from a specific subject at a particular time (when the breath sample was collected), and, 2) the concentration of other compounds, e.g., ethanol in a subject's breath sample that may be of particular interest to investigators in a given field (e.g., for investigators studying psychotropic drugs, or drugs with CNS effects, it is relevant to know if observed behavioral effects arise as a result of the study medication or due to confounding effects produced by ingestion of other compounds,
  • biometric or subject identification means may be employed.
  • a retinal scanner may be used.
  • each subject may be accorded a radio frequency identification (RFID) transmitter or the like, so that actuation of the SMART® device includes confirmation by the device that the RFID of the subject providing a given exhaled breath sample is the appropriate individual being monitored.
  • RFID radio frequency identification
  • the device is adapted to detect an RFID on a blister pack, medication container or the medication itself to confirm appropriate medication and/or dose is being taken.
  • intentional “gaming” of the system could potentially still occur by, for example, handoff of an RFID tag by a given subject. Accordingly, biometric confirmation concurrent with exhaled breath sample provision is preferred.
  • Data acquired by the device are logged into secure, for example internet-based, HIPAA-compliant storage for review by authorized investigators anywhere on the globe with an internet or equivalent distributed data connection.
  • Investigators may choose to actively review the data on a daily basis to understand day-to-day adherence (active management), to maintain data securely in a blinded fashion until assignment unmasking (passive management), or some combination of active/passive review desired by the study team.
  • Active management day-to-day adherence
  • passive management passive management
  • Considerable flexibility may be built into this aspect of the system. For example, Data may or may not be reviewed as it is acquired. If reviewed, it may be reviewed in a blinded or unblinded context (with respect to subject identity, treatment modality), and action can be taken based on incoming data review or not.
  • biometrics are encrypted.
  • the biometric data are automatically checked against a biometric record of a given subject, without the need for any human access to the biometric.
  • photographic images of a subject are obtained via a camera adjusted for focus to a very close focal length, so that essentially only the face of the subject is captured in the image, without much or any background capture, to avoid privacy concerns. As the camera is time gated to breath sample provision, other privacy concerns are likewise eliminated.
  • the adherence measurement system is easily portable and designed to be self-administered by subjects in their own residences, workplaces, or in an appropriate clinical setting.
  • This feature offers significant subject convenience and investigator economic benefits compared to frequent appointments with study staff for directly observed therapy (DOT), the “gold standard” of adherence, (to the extent that up to now any gold standard could be said to exist).
  • DOT directly observed therapy
  • the SMART® system provides a cost-effective option for definitive adherence monitoring and data acquisition, as compared with DOT, which is generally available only during business hours and not during weekends or holidays.
  • the change in subject behavior is simply an approximately 5 or so second breath exhalation into the mGC within an optimal time period after orally consuming or otherwise emplacing a medication comprising a SMART® AEM.
  • a somewhat longer lag time may be required for transdermally delivered medications, but the principles are the same.
  • the rate of appearance in breath and duration of marker persistence in breath can be adjusted to maximize versatility of the SMART® system. All breath analyses and data logging/transmissions are preferably automatic (i.e. do not require subject action).
  • the device is adapted to receive an active indication by a subject that a dose of medication has been taken, and that data may be included in the acquired data that is logged, transmitted and available for analysis.
  • HART highly active antiretroviral therapy
  • Xhale, Inc. has focused its development efforts on commercial development of the SMART® adherence devices for use in combination with Solid Oral Dosage Forms, SODFs, particularly tablet- or capsule-based medications, which are swallowed, enter the stomach, and are absorbed in the gastrointestinal tract.
  • definitive adherence is indicated within minutes or at most hours from the time of ingestion of such a SODF by the detection in the exhaled breath of a metabolite of an AEM, also referred to herein as a taggant (preferably a GRAS flavorant and most preferably a direct food additive) which may also be the EDIM or which is the source for the production of the EDIM.
  • a taggant preferably a GRAS flavorant and most preferably a direct food additive
  • the taggant is packaged together with the API in the final SODF, although means for separation of the taggant from the API is preferably employed, according to the disclosure found in WO2013/040494.
  • the SMART® system has successfully employed 1) various formulation strategies that incorporate taggants into the final dosage form, preferably without or minimally altering the CMC per se of the CTM (Clinical Trial Material), investigational drug, or marketed drug, and 2) a mGC-MOS as the SMART® device to measure the EDIMs.
  • the EDIM(s) which can be measured to verify that A was orally ingested by the patient, four chemical candidates are available: 1) A; 2) a major metabolite of A, Al; 3) a taggant, T, which was ingested with the medication containing A; or 4) a metabolite of any taggant (T), T1, which was generated via enzyme metabolism of a taggant (T).
  • T1 the Active Pharmaceutical Ingredient, or API or CTM
  • a taggant is included in, for example, a soft gel capsule or in another physical or chemical form which is stable, (see exemplary support for e.g. a carbonate which is surface coated onto or surface printed onto an API dosage form, while preserving, where considered necessary, an impermeable physico-chemical barrier between the taggant and the API, and which is rapidly converted into the Exhaled Breath Marker, EBM, on introduction into the biological system), and which is well tolerated by subjects, which generates markers in the exhaled breath which are quickly and reliably detected, and which do not interfere with co-delivered APIs.
  • EBM Exhaled Breath Marker
  • Any appropriate AEM composition (and resultant EBMs, including EDIMs, EDEMs), including but not limited to the taggants, markers, dosage forms and the like disclosed in, for example, “Marker detection method and apparatus to monitor drug compliance”, U.S. Pat. No. 7,820,108; US 2005/0233459; “System and Method of Monitoring Health Using Exhaled Breath”, US2007016785; “Methods and Systems for Preventing Diversion of Prescription Drugs”, US20080059226; “Medication Adherence Monitoring System”, US 2010/0255598; or in WO2013/040494, published 21 Mar. 2013, entitled “SMARTTM SOLID ORAL DOSAGE FORMS”, may be used in combination with the SMART® device disclosed herein.
  • Components described as being “operatively coupled” are components that are at least in communication with each other and operation of one of the operatively coupled components has an impact on the operation of the other operatively coupled components.
  • This can include one of the operatively coupled components directly or indirectly controlling the operation of the other component, as in a CPU programmed to control peripheral elements of a device or system.
  • This can also mean that operation of the first operatively coupled component results in modification of the operation of the second component, including when the first component does not directly or indirectly control operation of the second component.
  • Contacting a device with a gas means that a sample of the gas is introduced into the device's operative mechanism for analysis of components of the gas. This may include separation of components of the gas. It may include detection of particular species in the gas. It may include quantitation of species in the gase. It may include contacting of the gas with sensors of different specificity such that by comparing what is sensed by a first sensor with what is sensed by a second sensor, the difference in what the two sensors detect provides affirmative information about the presence, absence and even concentration of a given gas species.
  • CPU Central Processing Unit
  • GUI Graphical User Interface
  • operative communication or “operative coupling” or “operative electrical coupling” mean, based on the context of where these terms are used, that the described elements communicate with each other or one element is controlled by another, either electrically or mechanically, based on system design features and/or programming scripts included in a controller device to which other devices are linked.
  • EDIM Exhaled Drug Ingestion Marker
  • EBM Exhaled Breath Marker
  • EDEM Exhaled Drug Emplacement Marker
  • EBM Exhaled Breath Marker
  • AEM Biological Enabling Marker, which itself can be the EBM (EDIM or EDEM), or which gives rise to the EDIM or EDEM via metabolism, in vivo, of the AEM; while specific secondary alcohols are provided as examples, such examples should be considered non-limiting for the AEM; preferably, the AEM according to this invention is a GRAS compound, including but not limited to food additives which give rise to volatile metabolites in the body when metabolized.
  • EBM Exhaled Breath Marker (e.g., EDIM, EDEM).
  • the SMART® mGC system 100 is an easy-to-use, handheld instrument which is essentially a miniature gas chromatograph (“mGC”) comprising a housing 110 , a display 120 which may also include, in a preferred embodiment, a photographic image capture device 121 to concurrently document the image of the subject exhaling into the device, an exhaled breath receiving mouthpiece 130 , inert to VOCs in the exhaled breath, also referred to herein as a “straw”, which is inserted into the mouthpiece receiver port 131 , and an activation or “Start” button 140 .
  • mGC miniature gas chromatograph
  • FIG. 2B there is shown an embodiment of the SMART® device, 100 , identical to that shown in FIG. 2 a , (and therefore elements labeled in FIG. 2 a are not again labeled in this figure), with an added representation of a loudspeaker 141 which provides audible alerts and user prompts.
  • the mouthpiece 130 has been removed to more clearly reveal the mouthpiece receiver port 131 .
  • an input power jack and electrical power connection 142 for powering the device or, in an embodiment which includes an internal or external rechargeable power pack, recharging the battery pack via an external wall transformer.
  • the battery pack itself may be exchanged out of the device or be rechargeable or other forms of replaceable power may be utilized, such as standard disposable batteries.
  • the SMART® mGC System is designed to analyze gaseous samples (e.g., human breath or breath of other vertebrates) for suitable organic molecules of clinical interest, and, particularly, EDIMs and/or EDEMs.
  • gaseous samples e.g., human breath or breath of other vertebrates
  • suitable organic molecules of clinical interest e.g., EDIMs and/or EDEMs.
  • Gas chromatography is an extensively used analytical technology, and the physicochemical basis of its operation is well documented and understood. While the principles of operation for the breath analysis (or gas sample analysis) performed by the SMART® mGC are similar to the principles of operation for a standard gas sample analysis using currently marketed bench-top gas chromatographs, the specifics of the mGC SMART® device according to this invention are unique. Thus, an aspect of the present invention is the provision of a robust, miniaturized, portable, accurate, HIPAA-compliant commercial device and systems and methods for using this device for medication adherence monitoring. Naturally, of course, the mGC according to this invention may be utilized in a wide variety of applications wherever an accurate portable gas chromatograph would be of use.
  • the mGC according to this invention would be an accurate and valuable tool.
  • features included in the present disclosure need not necessarily be included—such as, for example, the biometrics capture discussed herein above.
  • FIGS. 3 and 4 detail key subsystems and their interconnections within the SMART® mGC apparatus according to this aspect of the invention.
  • FIG. 3 there is shown an embodiment of the mouthpiece that accepts the breath sample, also referred to as a disposable straw, 130 , which is configured to supply breath components to a breath detection and sampling subsystem, 132 , which is operatively coupled to a gas chromatograph analyzer subsystem 150 .
  • the mouthpiece 130 On insertion into the device, the mouthpiece 130 is detected by a straw/mouthpiece sensor 133 to confirm proper engagement and readiness to receive an exhaled breath sample.
  • An ambient air stream is routed via a disposable air scrubber (see description below, FIG. 4C , elements 300 - 310 ), to provide a carrier air system for the gas chromatograph analyzer subsystem 150 .
  • a microcontroller subsystem 160 integrates with the gas chromatograph analyzer subsystem 150 , and concurrently controls the operation of a camera and display subsystem 170 , and a WiFi, cellular or other communication means including data transceiver or mobile cellular data hotspot subsystem 180 .
  • a wall power transformer 190 provides power to the device including, optionally, a rechargeable battery pack subsystem 191 .
  • FIG. 4A Further detail of each subsystem and the order of operative flow of the SMART® device 100 is shown in FIG. 4A , with detailed description provided for each subsystem being provided in FIGS. 4B-4E .
  • the disposable mouthpiece subsystem 130 is shown.
  • a vent, 136 such that exhaled air passing through the mouthpiece is vented to the exterior of the device.
  • a breath flow sensor 132 to indicate to the system that a breath sample is being received by the device 100
  • a straw sensor 133 which is activated when a breath collection straw is inserted into the device 100 for breath sample collection.
  • a conduit 134 provides for a metered quantity of breath to be routed from the disposable mouthpiece 130 into the SMART® device 100 for gas chromatographic analysis.
  • the breath volume collected is controlled by the time that the sample pump is energized.
  • the sample rate is controlled by the vacuum pressure developed by the vacuum pump and the flow resistance presented by the concentrator.
  • FIG. 5 detailed photographs are shown of the disposable, single patient use mouthpiece (straw) 130 provided to facilitate collection of the breath sample.
  • FIG. 5A shows the mouthpiece/straw from a top view
  • FIG. 5B shows the straw bottom view.
  • each straw 130 includes a breath inlet end 135 , a flow restrictor/vent port 136 , (in this embodiment, the second end of the straw is sealed), a breath sample port 137 which couples with the conduit 134 which provides for a metered quantity of breath to be routed from the disposable mouthpiece 130 into the SMARM device 100 for gas chromatographic analysis.
  • a flow sensor port 138 which couples with the breath flow sensor 132 .
  • the SMARM device may also receive samples via gas-sampling bags or gas-tight syringes by coupling these devices to the breath inlet end 135 of a straw, or directly to the breath sample conduit 134 .
  • FIG. 6 provides a schematic showing a first embodiment of how the mouthpiece/straw 130 aligns with the device. Failure to align the mouthpiece correctly prevents it from locking into place in the SMART® device straw holder 131 , particularly with respect to alignment of the breath sample port 137 and the flow sensor port 138 .
  • FIG. 7A provides a photographic representation of an embodiment of the mouthpiece receiver 131 of the SMARM device, including the vapor inlet port 134 , the breath flow sensor 132 , the straw optosensor 133 , all of which align with and engage the mouthpiece shown in FIGS. 5 and 6 . Also shown is the start button, 176 .
  • the mouthpiece/straw 130 is simplified to use of a simple tube, as shown in FIG. 2A , open at both ends, 135 and 136 for delivering exhaled breath from the subject to the device.
  • the ports, sensors and other elements shown in FIGS. 4B, 5, 6, and 7A are all removed from the mouthpiece straw 130 into the docking port, 131 , visible from the exterior of the device only as a port, as can be seen in FIG. 2B . This substantially reduces the complexity and cost of the straw and simplifies the use thereof for the user of the SMART® device.
  • the internal structure of the straw/mouthpiece port 131 is shown via a cross section through the top of the device 100 through the port 131 , represented in FIGS. 2A and 2B .
  • An isolated view of this cross-section through the port 131 is provided in FIG. 7C .
  • a simple straw with an inlet and an outlet and no other features other than it being inert and of dimensions to tightly fit the port is inserted into the straw/mouthpiece receiver port 131 .
  • the port comprises a first cylindrical chamber area 139 with a diameter sufficient to easily accommodate insertion of the straw 130 therethrough.
  • a second area 143 follows area 139 with a diameter which tapers from that of antechamber 139 , which is greater than that of the mouthpiece tube/straw, down to a final diameter of a narrower cylindrical area 149 , the diameter of which is less than that of the mouthpiece tube/straw.
  • the ends of the mouthpiece straw and the surface at the start of the cylindrical area 143 are preferably machined to have mating surfaces and taper such that the inserted end of the straw locks in place within area 143 on correct insertion of the end of the mouthpiece straw.
  • the inserted end of the straw 130 thus mates with but cannot enter into area 143 much beyond the very initial section of area 143 as the narrowing taper thereof prevents this.
  • an air-tight seal is formed between the external surface of straw 130 and the internal walls of the mouthpiece receiver port 131 in area 143 .
  • Alternative embodiments include providing threading on the ends of the straw and mating threads in area 143 .
  • Further alternative embodiments include press-fit, flanging or other means for the straw end to be retained in the receiver port in an air-tight fashion.
  • exhaled air is channeled from the end of the straw into area 143 , and from there passes into area 149 and excess exhaled air is vented out of vent port 144 .
  • Vent port 144 is in communication with the external aspect of the device 100 housing via external vent 145 , which permits excess exhaled breath and any breath condensate to be discharged from the device.
  • Exhaled air sample port 134 (leading to exhaled breath sample conduit 147 and from there into the separation and detection subunits, see below) and flow sensor 132 are both in fluid communication with the exhaled air stream by being open to the conduit defined by areas 143 and 149 .
  • Correct placement of the straw in docking port 131 is confirmed by the straw sensor (e.g., an optosensor) 148 shown in FIG. 7C .
  • a retaining screw 146 is provided to retain the docking port 131 in correct placement within device 100 .
  • the inlet port is composed of a material which prevents condensation. Silico-steel, for example, is a preferred embodiment for this element.
  • the inlet tube is heated to prevent condensation—particularly important for embodiments of the device intended for use in cold climates.
  • an exhaled breath sample receiver port 151 coupled to the conduit 134 , via conduit 147 (preferably which provides the breath sample from the disposable mouthpiece 130 when a subject exhales into the SMART® device 100 , as described in detail above.
  • the exhaled breath sample is directed from the exhaled breath sample receiver port 151 into a thermally desorbable concentrator subsystem 200 , comprising a hydrophobic concentrator column 201 around which is wound or otherwise intimately associated a heating coil 202 or equivalent heating element such as a thermoelectric heating element, such as but not limited to a Peltier device which, when activated, heats the thermally desorbable concentrator column 201 , to thereby desorb any bound compounds from the concentrator column.
  • a fan 205 is provided to ensure even heat distribution over the column and efficient and rapid dissipation of heat within the enclosure 110 .
  • valves, 203 and 204 are provided on the proximal and distal ends, respectively.
  • the valve 203 on the end proximal to sample receiver port 151 controls the receipt of the exhaled breath sample from the exhaled breath sample receiver port 151 into the thermally desorbable concentrator column 201 when the breath flow sensor 132 indicates that an exhaled breath is being received.
  • the sample pump is de-energized to stop the collection of the breath sample onto the thermally desorbable concentrator column 201 , and any excess air is vented via the vent 330 .
  • the heating element 202 heats the concentrator 201 to release bound compounds, and the valve 203 on the proximate end of the concentrator 201 opens to permit delivery of bound molecules to the gas chromatograph column 152 , housed inside a column oven 153 which includes a heater 154 and temperature sensor 155 for precise regulation of the gas chromatograph column 152 .
  • the desorbed molecules travel from the concentrator 201 via valve 203 through connector 156 and into the gas chromatograph column 152 via GC inlet port 157 .
  • valve 204 opens to permit delivery of carrier gas from the carrier pump 304 via carrier pump coupling 305 , flow restrictor 307 , disposable dessicant cartridge 308 , port 309 to port 310 , and, via valve 302 to valve 204 to drive the desorbed molecules into and through the GC column 152 .
  • valve 302 remains open permitting scrubbed ambient air which has been drawn through a disposable charcoal filter 303 to drive the sample through the GC column 152 then through the GC detector 158 and out of vent 159 .
  • valves 203 , 204 , and 302 are required to ensure that desorbed molecules from the concentrator 201 are driven into the GC column 152 at the appropriate rate, temperature and pressure.
  • This coordination is achieved by the electronic microcontroller subsystem, 160 , which, in a preferred embodiment, also coordinates the taking of a biometric record, in a preferred embodiment, a photograph, of the subject at the time of delivery of the exhaled breath sample.
  • a carrier air pressure sensor 311 which feeds back to the carrier pump 304 via electronic microcontroller 160 to control carrier air pressure.
  • the desorbed molecules travel from the concentrator 201 into the GC column 152 they are fractionated and then detected by a GC detector 158 and then vented from the SMART® device 100 via vent 159 .
  • the detector, 158 may be a MOS detector, an infrared detector, and, as discussed in some detail below, for certain embodiments according to this invention, the detector includes a catalytic incineration feature. While a preferred embodiment according to this invention utilizes a mGC, coupled to a MOS, those skilled in the art will appreciate that other means of separation and/or detection may be utilized for a particular application. For example, a concentrator and an array of surface acoustic wave (SAW) sensors may be utilized as an “electronic nose” in place of the GC column and MOS sensor.
  • SAW surface acoustic wave
  • the chromatographic separation of the various breath components and markers occurs on the column 152 which, in one embodiment, consists of a 5 meter long piece of 0.53 mm ID metal tubing whose walls are coated with a polymeric stationary phase (e.g, Restek MXT BAC-1).
  • the stationary phase adsorbs and desorbs the various chemical vapors injected in the initial plug.
  • the adsorption and desorption rates of each vapor vary, depending on physicochemical characteristics such as boiling point and hydrogen bonding affinity.
  • the detector 158 that produces a signal proportional to the number of organic molecules exiting the tube is used to record when the different molecules emerge.
  • each compound can be identified by its retention time, and the concentration can be determined by the peak height, when comparing it to analytical standards of known concentration.
  • the GC detector used in the SMART® GC is, in one preferred embodiment, a solid-state, metal oxide semiconductor (MOS) chip sensitive to the presence of oxidizable hydrocarbons.
  • MOS metal oxide semiconductor
  • the SMART® column 152 is operated at a constant temperature, e.g., 40° C. via regulation by the column oven 153 , and the associated temperature sensor 155 and heater 154 .
  • the temperature is regulated to keep the temperature steady.
  • the biometric e.g., time-stamped photograph of the subject, and collection of the exhaled breath sample
  • the sample is analyzed as in a fully-integrated embodiment.
  • the advantage of this embodiment is that the breath sample and biometric may be trapped at any location, without the need to carry the entire device. This creates an even more portable option for users of the system.
  • the components of this embodiment would include the breath straw, a camera, a pressure sensor, and a desorbable concentrator column—as discussed above.
  • this module On combining this module with the remainder of the device, ordinary operation of the device is initiated by desorption of the collected sample and injection of the sample into the GC column.
  • Alternate configurations of this aspect of the invention may include just a mouthpiece/straw, which acts as the sample capture device (e.g., the mouthpiece itself operates as a desorbable concentrator column).
  • the portable components of this aspect and other aspects or embodiments of the invention or the rest of the apparatus components of this invention will include, e.g. a mass spectrometer on a chip, (see, for example, the high pressure mass spectrometer included in the M908 device available from 908 Devices, Inc., 27 Drydock Ave., 7th Floor, Boston, Mass. 02210, and U.S. Pat. Nos. 8,816,272; 8,525,111; and 8,921,774) an IR spectrometer on a chip, or other versions of such technologies which provide enhanced portability, reduced cost, increased precision in analysis, the ability to analyze different isotopologues included in the EBM and the like at the point of use.
  • a mass spectrometer on a chip see, for example, the high pressure mass spectrometer included in the M908 device available from 908 Devices, Inc., 27 Drydock Ave., 7th Floor, Boston, Mass. 02210, and U.S. Pat. Nos. 8,816,272
  • FIG. 4D there is provided a detailed schematic of the electronic microcontroller subsystem 160 and the camera and display subsystem 170 .
  • the microcontroller 160 is in operative communication 161 with the above-described disposable mouthpiece subsystem 130 ( FIG. 4B ), and the GC and sensor subsystem 150 ( FIG. 4C ), as well as the subsystems described herein below.
  • GC sensor subsystem interface electronics 162 such as, but not limited to a STM107F microprocessor, or the equivalent, now known or which hereafter comes to be known; voltage regulators 164 for gating power from the power subsystem (see discussion below) and transmission of appropriately regulated power to all other subsystems of the SMART® device; peripheral device interface electronics 165 .
  • microprocessor 163 such as, but not limited to a STM107F microprocessor, or the equivalent, now known or which hereafter comes to be known
  • voltage regulators 164 for gating power from the power subsystem (see discussion below) and transmission of appropriately regulated power to all other subsystems of the SMART® device
  • peripheral device interface electronics 165 are included in the microcontroller subsystem 160 .
  • the peripheral device electronics 165 controls, for example, all elements of the camera and display subsystem 170 , including, but not limited to: a WiFi, RFID, or mobile cellular data transceiver 171 , or combinations thereof, which permits communication between the SMART® device and external devices for data capture and analysis and for communication of control and updates to the SMART® device; an information display 120 associated with the SMART® device, such as but not limited to a sixteen character, two line, backlit LCD display; a video or still camera 172 ; an LED 173 , such as a multicolor light emitting diode to indicate system status and to provide a flash function as needed when taking an image with the digital camera.
  • a WiFi, RFID, or mobile cellular data transceiver 171 or combinations thereof, which permits communication between the SMART® device and external devices for data capture and analysis and for communication of control and updates to the SMART® device
  • an information display 120 associated with the SMART® device such as but not limited to a sixteen character, two line, backlit
  • Additional peripheral devices controlled by the peripheral device interface electronics 165 may include but are not limited to: memory 174 , such as but not limited to a USB memory stick or the like, EEPROM memory, or other electronic memory forms now known or hereafter developed for this purpose; a loudspeaker 175 to provide audible alerts and/or instructions to users of the SMART® device 100 ; a “Start” button 176 to activate the entire system for operation; the breath flow sensor 132 ; and the straw sensor 133 .
  • Each of these elements is in either two-way or one-way communication with the peripheral device interface electronics 165 , as indicated by either two-way or one-way arrows in FIG. 4D between these elements.
  • a wall power transformer subsystem 190 alone or in operative communication with an internal rechargeable battery subsystem 191 .
  • the wall power transformer subsystem 190 is, for example, a 90-240 volt AC, 50/60 Hz in, 9 volt DC. 1.5 amp output, preferably an IEC 60601 approved device.
  • the internal rechargeable battery subsystem 191 is, for example, composed of a pair 192 of UL approved rechargeable lithium cells (e.g., type 18650), providing 3.7 V, 2200 mAhr per battery.
  • over-current protection circuitry 193 included in the battery subsystem there is desirably provided over-current protection circuitry 193 , over-temperature protection circuitry, over/under voltage protection circuitry, and voltage regulation.
  • Power is supplied from the wall power transformer subsystem 190 to the internal rechargeable battery subsystem 191 via an appropriate jack 194 .
  • power supplied from the wall power transformer subsystem 190 is 9 volts DC power.
  • the SMART® mGC can operate on rechargeable batteries, 192 , which, when fully charged, (e.g., when lithium batteries are used) provides sufficient power for at least 10 complete breath measurement operations without the need to be recharged.
  • batteries are permanently installed into the battery holder and are not removable, while in other embodiments, the entire battery pack is exchangeable or primary batteries, e.g., lithium ion technology, may be used.
  • SMART® device will be utilized in less industrialized countries of the world, as well as all over the globe, where wall A/C power supply is not always available and locating and retrieving the device could potentially become a problem.
  • miniature recharging solar pack technology is included in the device.
  • a GPS tracking subsystem is likewise desirably included in an embodiment of the device and is integrated with the microcontroller 160 .
  • the internal wireless capability of the SMART® device allows interaction with other wirelessly enabled devices and technologies, including, but not limited to, for example, smart phones (iPhones, Android phones, and the like), tablet computers, other computers and the like.
  • Integrated patient/health monitoring systems and medication containers that manage or track access to medications based on communication with the device according to this invention are likewise optional adjuncts to or may be integrated into the system according to this invention.
  • a microcontroller Upon detecting breath flow, a microcontroller activates a small sampling pump that collects a representative breath sample for analysis (nominally 30 cc) over a pre-defined time period—preferably about a five-second time span—at a nominal flow rate of 300-400 sccm.
  • the breath sample is collected on the thermally desorbable concentrator 201 .
  • the excess breath flow is vented through the flow restrictor opening on the mouthpiece 136 ( FIG. 5 ).
  • a biometric e.g., camera image of the subject providing the breath, is obtained and time stamped so that time of biometric and breath sample acquisition can be confirmed as being concurrent.
  • the concentrator 201 consists of a small stainless steel tube or the like packed with a sorbent polymer (e.g, TenaxTM TA) that is commonly used in gas chromatography to adsorb molecules of interest while allowing molecules that are not of interest (e.g., water vapor and carbon dioxide) to pass through the system.
  • a sorbent polymer e.g, TenaxTM TA
  • the polymer desorbs the molecules of interest, effectively concentrating them.
  • valves 203 , 204 , 302 FIG. 4C ) are energized, causing pressurized clean, dry air from the carrier gas generator to backflush the plug of purged molecules from the concentrator onto the analytical column of the gas chromatograph.
  • Elements of the ambient air scrubber comprised of elements 300 , 303 - 309 and 311 , (see FIG. 4C ), are replaced by the manufacturer or user during routine maintenance or service.
  • the carrier gas utilized in the system is preferably generated from ambient air that is passed and cleaned through two different scrubbers.
  • a portable carrier gas could be utilized, or the device may be linked to a conventional carrier gas, but this involves additional complexity and reduced portability which the present device circumvents by inclusion of the ambient air scrubber described herein.
  • the first 303 contains activated charcoal to remove organic compounds that might be present in the ambient air and which might otherwise interfere with analysis of volatile organic compounds present in samples to be analyzed.
  • the second 308 contains molecular sieve 13 X and indicating DrieriteTM to remove humidity from the air.
  • Soda lime is useful to remove carbon dioxide.
  • Nafion® tubing (or equivalent perfluorosulfonic acid polymer) is useful to remove water.
  • the small pump 304 compresses the air from the charcoal scrubber 303 and injects it into the desiccant scrubber 308 through a small flow restrictor 307 .
  • the pressure generated by the small compressor pump 304 is monitored and controlled by the microcontroller 160 via the carrier pressure sensor 311 to maintain a constant carrier gas flow as necessary to keep the GC column 152 head pressure constant.
  • the system operation is fully automatic once the breath sample has been collected.
  • the analysis process takes about 180-220 seconds. When the analysis is completed, the system purges itself with clean air to eliminate the possibility of breath marker vapor carry-over and to prepare it for the next sample.
  • All data acquired by the SMART® GC are preferably encrypted and stored on a USB memory stick or equivalent on-board, non-volatile memory. This permits retrieval of data in the event of wireless communication failures.
  • the on-board memory has enough capacity to store all of the data and images associated with more than 100,000 breath measurements.
  • the microcontroller 160 initiates the breath sample collection process when the breath flow sensor 132 signal exceeds a threshold.
  • the mouthpiece/straw sensor 133 ( FIG. 4B ) is, in one preferred embodiment, an optoelectronic device that emits a low intensity IR beam and detects the proximity of reflective objects, such as the mouthpiece. This allows the microcontroller to wait until the user has properly inserted the straw 130 before advancing to the breath collection process.
  • the breath flow sensor 132 is, in one preferred embodiment, a heated thermistor that detects resistance changes when cooled by the flow of air passing over the sensor. Breath flow can also be sensed using a pressure sensor.
  • the GC detector signal 158 is digitized using a voltage-to-frequency converter and frequency counter in the microcontroller 160 , which provides excellent dynamic range and noise immunity. Accordingly, all output signal data are reported as “counts”.
  • the signal from the MOS detector 158 is logged e.g., twice each second by the microcontroller 160 .
  • a peak-detection algorithm resident in the microcontroller 160 locates the retention time and peak height of every compound that elutes during the predetermined chromatographic window. When a peak is found in specific windows specified in the script commands, the computer logs the successful detection of the analyte of interest and reports the presence of the compound that typically appears in that window.
  • the device detects the analyte, but it is preferably adapted to measure absolute amounts, changes in absolute amounts (referred to herein as the “delta” or A in the given parameter/measurement), and to provide an assessment (e.g., a yes/no readout) for particular compounds.
  • Key system status information is logged for each measurement. This information includes, but is not limited to, the elapsed run time, time since last service, pump and oven heater duty cycles, and battery voltage. This allows remote assessment of the system functionality.
  • FIG. 14 there is provided a logic flow diagram for a preferred embodiment according to this invention.
  • the processor layer 500 which has a two-way communication data flow with layer 1 , 501 , comprising the various drivers for each of the device's sub-components, including but not limited to the oven, pumps, camera, webserver, solenoids, etc.
  • a layer 2 the SmartEngine, 502 , which interprets SmartScript commands and invokes appropriate devices, in two-way communication with layer 1 below 501 and layer 3 503 above.
  • layer 3 503 in two-way communication with layer 2 below.
  • Layer 3 503 implements SmartScripts, permitting users and implementers of the device to program the SMART® device in plain language, implementing complex task sequences and flexibility in altering parameters of device operation.
  • Module A comprises the SMART® gas chromatograph device, including the gas chromatograph and detector which produce data which the device processes, 510 , the camera and data from the camera 511 , both of which data streams are preferably subject to encryption at 512 .
  • the data or encrypted data is then stored on an internal storage, e.g., a 1 gigabyte internal flash storage or equivalent data storage medium, 513 .
  • the stored data is uploaded to an embedded, preferably wireless, web server, 514 , for transmission to external data storage, analysis and, if appropriate, action.
  • data lines 515 and 516 comprise two-way web (HTTPS encrypted) connections, providing data to a data server, 517 , and end user(s) (via, e.g., a web browser or equivalent interface), 518 .
  • Secure storage and archiving of data is accomplished in an appropriate database and secure storage system 519 .
  • an RFID communication system whereby, on confirmation of the taking or administration of a medication dose by a subject, a signal is transmitted from the device to a medication dispenser which is locked until the next dose is due to be taken.
  • the SMART® mGC incorporates a digital camera 172 and a liquid crystal display 120 for visual prompts.
  • the camera is controlled such that a biometric measurement of the subject providing the exhaled breath sample for analysis is captured and time stamped for each collected breath sample.
  • the camera is selected to permit accurate image capture at a focal length appropriate to the distance from the camera lens to the end of the mouthpiece where each subject interfaces with the device to provide exhaled breath samples for analysis.
  • a camera is utilized which has a wide angle lens (e.g., 120 degree field of view) to ensure acquisition of a reliable image even when the device is held at unusual angles by the user.
  • a relationship is defined between the length “L” of the mouthpiece 130 , and the focal distance “D” of the a photographic image capture device 121 to concurrently document the image of the subject exhaling into the device.
  • L D ⁇ 5 cm.
  • L D ⁇ 5, 4, 3, 2 or even 1 cm. This permits optimal acuity in capturing the identity of the subject exhaling into the device without at the same time requiring use of long, cumbersome or unsightly straws/mouthpieces 130 .
  • a camera such as an OmniVision (Sunnyvale, Calif.), OV9655 1.3 megapixel camera-on-a-chip is utilized.
  • FIG. 8A the valving is shown for sample collection without numbering to keep the figure clear.
  • Exhaled air enters the SMART® device via the mouthpiece 130 and is directed to the concentrator column via conduit 134 , receiver port 151 and, via valve 203 being adsorbed to concentrator column 201 .
  • the sample pump 300 draws the sample into the concentrator 201 and vents air stripped of molecules of interest.
  • the adsorption is conducted at a reduced temperature, such as 25 degrees centigrade.
  • a reduced temperature such as 25 degrees centigrade.
  • the concentrator 201 is heated to an elevated temperature, such as 150 degrees centigrade, to thermally desorb the breath borne molecules that have been trapped on the concentrator 201 .
  • an elevated temperature such as 150 degrees centigrade
  • valve 203 at the proximal end of the concentrator 201 is closed to the mouthpiece, but opened to the GC column 152 .
  • Ambient air is drawn through the scrubber 303 by the carrier pump 304 , through the flow restrictor 307 and through the second scrubber 308 and valve 302 for delivery to the distal end of the concentrator column 201 via valve 204 , thereby driving the desorbed molecules from the concentrator 201 into the mGC column 152 through the detector 158 and, finally, out the vent 159 .
  • FIG. 9 and Example 2 for a typical chromatogram produced by this system.
  • FIG. 10A there is shown a photographic representation of the internal components and architecture of a first exemplary embodiment of the SMART® device according to this invention. Visible in this photograph are at least the following components: battery pack 192 ; external power connector 194 ; battery pack connector 192 b ; USB solid state memory 174 ; replaceable dessicant-sieve cartridge 308 ; sample pump for breath sample collection 304 ; scrubber air pump vent 304 b ; flow restrictor 307 ; carrier gas pump which pressurizes the scrubber 300 ; charcoal scrubber 303 ; and the scrubber air inlet port 303 b .
  • battery pack 192 external power connector 194
  • battery pack connector 192 b USB solid state memory 174
  • replaceable dessicant-sieve cartridge 308 sample pump for breath sample collection 304 ; scrubber air pump vent 304 b ; flow restrictor 307 ; carrier gas pump which pressurizes the scrubber 300 ; charcoal scrubber 303 ; and the scrubber air inlet port 303
  • a sling 320 for holding, in one preferred embodiment according to this invention, the dessicant-sieve cartridge 308 and charcoal scrubber 303 in flexible but firm position.
  • the sling 320 comprises a preferably elastomeric material comprising perforations therein 321 and 322 through which the dessicant-sieve cartridge 308 and charcoal scrubber 303
  • FIG. 11 the obverse view from that shown in FIG. 10 is provided as a photographic representation of the internal components and architecture of a first exemplary embodiment of the SMART® device according to this invention. Visible in this photograph are at least the following components: attachment; breath inlet port 134 c ; concentrator column 201 ; line to sample pump 300 b ; scrubber air lines 309 b ; GC column oven 153 ; fan 205 ; vent 159 from GC detector 158 .
  • FIG. 12 there is shown the air filter path in an exemplary embodiment according to the invention. Shown in this figure are: the scrubber air pump 304 which draws ambient air in through port 303 b into the charcoal scrubber 303 , via carrier pump coupling 305 , past the scrubber pump pressure sensor port 311 b , through flow restrictor 307 , then through the desiccant scrubber 308 and from there out port 309 into the valving leading to the GC column.
  • the scrubber air pump 304 which draws ambient air in through port 303 b into the charcoal scrubber 303 , via carrier pump coupling 305 , past the scrubber pump pressure sensor port 311 b , through flow restrictor 307 , then through the desiccant scrubber 308 and from there out port 309 into the valving leading to the GC column.
  • each of the elements shown herein may be further optimized by further miniaturization, such as, for example, through the use of micro-pneumatics.
  • a single breath collection is all that is required, because essentially no background exists.
  • an initial breath is obtained prior to medication being taken or administered followed by a second breath thereafter, for each dose of medication.
  • a baseline breath sample may not be required in certain embodiments of this device used in connection with particular combinations of AEMs in various AMAM, IMAM or CMAM applications.
  • a baseline breath may be dispensed with.
  • i-AEMs where essentially no background exists for particular i-EBMs.
  • the device is woken by pressing the start button 176 , which initiates a startup routine at 401 , a battery display to show the user whether the device has sufficient power to operate properly, 402 , and if so, the device displays a message that it is initializing 403 .
  • the device then initializes all settings to a starting condition ready for exhaled breath sample receipt 404 .
  • “ATTN” 404 a in the figure refers to an audible signal to alert the user that action is required.
  • the user is then prompted 405 to insert a new, clean mouthpiece “straw”.
  • a mouthpiece insertion subroutine is then initiated 406 which, if no mouthpiece is detected, prompts the user to insert the mouthpiece 405 , or, the system times out 406 a after a pre-set time, optionally about 1 hour, if no mouthpiece is inserted within the preset time period. Once correct mouthpiece insertion has occurred, this is confirmed to the user 407 , and the user is advised 407 a that, prior to taking a medication or study capsule, to blow/exhale into the mouthpiece, 408 .
  • a breath detection subroutine 409 initiates to confirm detection of breath being exhaled into the device (triggered by the flow sensor 132 ). If no breath is detected, the system times out after a short while, optionally about 4 minutes.
  • a biometric measurement of the user is captured, such as a fingerprint, or, preferably, a photograph is taken, 410 a , and the user is prompted 410 b to continue to blow into the mouthpiece until the device detects that a sufficient amount of breath has been detected 411 .
  • the subject is prompted with a “good job” or similar prompt 412 to indicate that a sufficient breath sample has been collected for analysis.
  • the device Once the device has confirmed that a sufficient pre-medication baseline sample has been acquired 411 , the subject is then prompted to take their medication, study capsule or whatever dosage form it is for which medication adherence monitoring is being conducted 413 a and the user is prompted 414 to press the start button 176 when the medication has been taken.
  • the device then enters a subroutine 415 to confirm that the user has pressed the button. If no button press is detected within a preset time, e.g., thirty minutes to an hour, the device times out 429 and goes to sleep 430 .
  • a prompt 415 a advising the user to please wait a pre-set amount of time, (a time optimized for the vast majority of subjects in clinical testing, depending on the medication/AEM combination in use, typically from about five minutes to about an hour, and preferably about ten to about twenty minutes).
  • a countdown timer routine 415 b initiates. During that period, the device warms up in readiness for receipt of the breath sample post medication 416 during which time the subject continues to wait for the full optimal time period for post medication breath collection 417 . “ATTN” in the FIG.
  • a breath detection subroutine initiates 420 . If no post-medication breath sample is detected, the device is set to time out 420 a within a pre-set time period, say about 1 hour. However, if a breath is detected, as before, a biometric is captured, preferably a photograph 420 b , and the user is prompted to keep blowing 421 until a sufficient breath sample 422 is detected. When a sufficient amount of breath has been detected, the subject is prompted with a “good job” or similar prompt to indicate that sufficient breath has been collected 423.
  • the sample collection procedure has been completed and the user is prompted to remove the used mouthpiece 424 .
  • a brief period e.g., five seconds, is provided 425 for the device to confirm that all operations have been successfully completed, at which point, the user is prompted to advise that the breath samples have been properly collected, by display of a message, e.g., “HAVE A GREAT DAY!” or the like, 426 .
  • the second breath sample is analyzed by the device 427 , with calculation of changes (delta, A) in key analytes (e.g., 2-butanone), and the results are uploaded 428 to a database, locally and/or at a remote site, where medication adherence is optionally checked, confirmed or otherwise evaluated, either automatically or by an appropriate responsible party.
  • the device preferably goes into a sleep state, 430 .
  • the Type I Self Monitoring and Reporting Therapeutics (SMART®) device comprises a miniature, portable, gas chromatograph subsystem for separation and analysis of components of a breath sample provided by a subject.
  • the gas chromatograph is, preferably, provided in the device in combination with a separated compound sensor appropriate to detection and/or quantitation of the particular exhaled breath component of interest (VOC, EBM), and at least one or a combination of any one or a combination of:
  • a mouthpiece either with ports for breath sampling, venting, correct emplacement confirmation, and excess breath venting, or, a simple tube with a mouthpiece receiver port bearing features as described above for accepting the mouthpiece, breath sampling, venting, and emplacement confirmation;
  • a breath detection and sampling subsystem in operative coupling with the mouthpiece
  • a microcontroller subsystem in operative electrical coupling with at least one, several, and preferably all electrical components of elements (a)-(f).
  • SMARM device may comprise, in various embodiments, any one or combination of the following:
  • the mouthpiece comprises: an exhaled air inlet; a breath flow sensor port; a breath sample conduit receiver port; and a vent; or simply an inlet and an outlet;
  • the breath detection and sampling subsystem in operative coupling with the mouthpiece comprises: a mouthpiece receiver comprising: a breath sample conduit for operative coupling with the breath sample conduit receiver port; a breath flow sensor for operative coupling with the breath flow sensor port; and a mouthpiece sensor for detection of proper insertion of the mouthpiece into the mouthpiece receiver;
  • the disposable air scrubber comprises an activated charcoal filter, a dessicant, or both;
  • the gas chromatograph is included in a subsystem in operative coupling with the breath detection and sampling subsystem and the disposable air scrubber comprises a thermally desorbable concentrator comprising: a thermally desorbable concentrator column; a proximal and a distal three-way valve on either end of the desorbable concentrator column; a heating element in intimate association with the thermally desorbable concentrator column; and a gas chromatograph column with a detector at the distal end thereof;
  • the wireless data transceiver subsystem comprises a WiFi, mobile cellular data transceiver, or both;
  • the biometric measurement means comprises a camera and display subsystem comprising a still or video digital camera which records an image of the subject at the time that the subject exhales into the mouthpiece;
  • the rechargeable battery pack subsystem comprises lithium batteries
  • the microcontroller subsystem in operative electrical coupling with at least one and preferably all electrical components of elements (a)-(f) comprises a microprocessor, a voltage regulator, peripheral device interface electronics and GC sensor interface electronics.
  • Exemplary support for use of the Type I device as described herein is provided in the Examples below, (in particular, but not exclusively, in Examples 1-4). It will further be appreciated by those skilled in the art that the SMART® device may include one, different combinations of, or every element (a)-(h) as listed above. In addition, the Type I embodiment of the SMART® device according to this invention may include and incorporate components and elements of other SMART® device embodiments as described herein below.
  • the Type I embodiment of the device is excellent for measurement in the exhaled breath of AEMs (which may appear in the exhaled breath) and/or EDIMs (or EDEMs, that is the Exhaled Breath Marker, EBM, which is typically a modified form of or a metabolite of the AEM) which appear shortly after ingestion of or application onto a subject of an AEM.
  • AEMs which may appear in the exhaled breath
  • EDIMs or EDEMs, that is the Exhaled Breath Marker, EBM, which is typically a modified form of or a metabolite of the AEM
  • This embodiment of the device is primarily adapted for AMAM, but, depending on the longevity of the EDIM in the exhaled breath, the signal to noise ratio and the total mass of AEM utilized, this device may also provide IMAM and CMAM options.
  • Type II device is directly applicable without change or minimal change to a description of a Type II device, unless differences/changes to a particular element or subsystem is specifically described herein below in this section.
  • the key modifications in a Type II device as compared to a Type I device are described in detail in this section.
  • the ways in which such modifications enable use of different AEM compositions of matter, methods of medication adherence, extension of the time for medication adherence monitoring in acute medication adherence monitoring and into intermediate and chronic adherence time frames and options for IMAM and CMAM, as well as alternate SMART® systems, are described here and in sections 7, 8 and 9.
  • the present invention is directed to the provision of new technology for assessing and improving medication adherence, which remains a critically important health care priority in multiple clinical settings, including pharmaceutical drug trials, management of major diseases (e.g., schizophrenia, diabetes, hypertension), and in the fight against diseases that threaten global health (e.g., TB, HIV/AIDS).
  • major diseases e.g., schizophrenia, diabetes, hypertension
  • diseases that threaten global health e.g., TB, HIV/AIDS.
  • methodologies including electronic ones (e.g., pill counters, electronic medication caps and the like), developed to solve this problem, have been inadequate to date, since none detect or document actual drug ingestion/administration/application.
  • MAMS Medication Adherence Monitoring System
  • the goal of Xhale, Inc's., medication adherence monitoring program is to employ unique chemistry-based technologies to document adherence to oral and other medications.
  • the adherence system in a preferred embodiment, comprises a smart-phone sized sensor device or smart-phone inter-operable accessory, using breath as the diagnostics matrix to measure metabolites of generally recognized as safe (GRAS) food component-based taggants, that is, the Exhaled Breath Marker (EBM, whether that be an EDIM or EDEM).
  • GRAS generally recognized as safe
  • GRAS food additive-based taggants are used to document when a dosage form (e.g., a pill) entered the gastrointestinal tract or entered another physiological compartment (e.g., via transdermal, intranasal, vaginal, rectal, or other mode of delivery), was absorbed into the blood, and was metabolized to taggant metabolite(s) detectable in the exhaled breath, a procedure called definitive medication adherence.
  • a dosage form e.g., a pill
  • another physiological compartment e.g., via transdermal, intranasal, vaginal, rectal, or other mode of delivery
  • taggant metabolite(s) detectable in the exhaled breath
  • MAMS methodology to which the present invention applies is of the definitive type.
  • AEMs GRAS food additives
  • One major strategy to achieve this goal is to utilize isotopically-labeled chemicals, preferably GRAS compounds, and particularly deuterated ones, which generate deuterated EDIM(s) (i.e. i-EBMs/i-EDIMs) in breath to document definitive medication adherence.
  • the Type I device described in section 6.1 above is modified to enable use of AEMs comprising non-ordinary (but preferably stable, i.e. non-radioactive) isotopes in the AEM.
  • AEMs comprising non-ordinary (but preferably stable, i.e. non-radioactive) isotopes in the AEM.
  • Such AEMs are referred to herein as i-AEMs, and are manufactured and selected for use with this embodiment of the device such that EDIMs which are produced following ingestion or application of the i-AEMs include the non-ordinary isotope, and are, therefore i-EDIMs.
  • this section of this patent disclosure describes and enables methods of making and using medications, medicinal compositions, devices, and systems and for production and detection of, in exhaled breath of a subject, volatile organic compounds (VOCs) which include non-ordinary, but preferably stable (non-radioactive), atomic isotopes, referred to as i-EBMs, (Exhaled Breath Markers containing at least one non-ordinary, but stable (non-radioactive) isotope), for definitive medication adherence monitoring.
  • VOCs volatile organic compounds
  • i-EBMs Exhaled Breath Markers containing at least one non-ordinary, but stable (non-radioactive) isotope
  • IR infrared
  • the device includes a catalytic combustion chamber to convert VOCs into water and carbon dioxide.
  • a catalytic combustion chamber to convert VOCs into water and carbon dioxide.
  • Inclusion of the catalytic incinerator simplifies detection in this embodiment of the device by allowing the IR detector to be tuned to the particular non-ordinary isotope sought to be detected, whereas, without the catalytic incineration component, a tunable IR sensor may be required to permit the device to be tuned to detect different VOCs of interest.
  • inclusion of the catalytic incinerator essentially converts a particular IR sensor into a universal IR sensor.
  • the catalytic element for IR applications is only required where an IR detector is sought to be used in the same manner as described above for use of a MOS detector in an mGC-MOS embodiment of the device. Further details and description on these aspects of the invention are found herein below.
  • a device and a method of using the device for detecting in an exhaled breath sample a VOC comprising a non-ordinary but stable (non-radioactive) atom, e.g., deuterium, wherein, in a preferred embodiment, the device comprises:
  • SMART® Self Monitoring and Reporting Therapeutics—embodiments of a device, medication, composition, system and method wherein adherence by a subject in taking/receiving a medication is facilitated by detecting a volatile molecule in the exhaled breath of a subject, wherein the volatile molecule only appears in the exhaled breath of a subject a known period of time and at a known concentration after a medication is taken by the correct person, at the correct time, at the correct dose.
  • i-SMART® as for SMART®, but including compositions, methods, systems and devices optimized for detection of compounds in the exhaled breath which include a non-ordinary, but preferably stable (non-radioactive) isotope, as further described herein below; those skilled in the art will appreciate that it is the presence of an isotope at an abundance that is completely different than the abundance of the isotope as it occurs in nature (due to that isotope having been selected for inclusion in the i-AEM) that is detected in this mode of practicing this invention, and any detector or sensor now known in the art or which later comes to be know which is sufficiently sensitive to detect the particular isotope of interest and its abundance (concentration) may be used for this purpose.
  • API Active Pharmaceutical Ingredient
  • i-API An API containing at least one non-ordinary, but stable (non-radioactive) isotope of hydrogen (i.e. deuterium), carbon (e.g., C 13 ), or the like, and which, on introduction into a living subject, results in the production of at least one i-EBM. This is typically as a result of the metabolism of the i-API to produce a cognate i-EBM specific to that particular i-API. In some cases, the i-API itself may be the i-EBM—e.g., deuterated propofol would appear in the exhaled breath, as does non-deuterated propofol. It will be appreciated that not the entire fraction of the API need contain the non-ordinary isotope, and that fraction that does is referred to herein as the i-API fraction.
  • EBMs Exhaled Breath Markers—molecules which appear in the exhaled breath following ingestion or other form of administration of a medication containing a marker which gives rise to the EBM.
  • i-EBMs Exhaled Breath Markers (including EDIMs and EDEMs) containing at least one non-ordinary, but stable (non-radioactive) isotope of hydrogen (i.e. deuterium), carbon (e.g., C 13 ), or the like.
  • hydrogen i.e. deuterium
  • carbon e.g., C 13
  • EDIM Exhaled Drug Ingestion Marker—a molecule detected in the exhaled breath of a subject who has ingested a medication (drug) which includes, as part of the Active Pharmaceutical Ingredient (API) or as part of a separate molecule packaged for co-delivery with the API.
  • API Active Pharmaceutical Ingredient
  • i-EDIM an EDIM comprising at least one non-ordinary but non-radioactive (i.e. stable) isotope.
  • EDEM Exhaled Drug Emplacement Marker—a molecule detected in the exhaled breath of a subject who receives a medication (drug) which includes, as part of the Active Pharmaceutical Ingredient (API) or as a separate molecule packaged for co-delivery with the API, when received by a route other than ingestion.
  • API Active Pharmaceutical Ingredient
  • i-EDEM an EDEM comprising at least one non-ordinary but non-radioactive (i.e. stable) isotope.
  • AEM Adherence Enabling Marker—a molecule included in a medication which according to this invention gives rise to EBMs in the exhaled breath of subjects who have taken or been administered the medication including the AEM.
  • i-AEM An AEM which includes at least one non-ordinary but non-radioactive (i.e. stable) isotope which according to this invention gives rise to i-EBMs in the exhaled breath of subjects who have taken or been administered the medication including the i-AEM.
  • ADME Absorption, Distribution, Metabolism, Excretion.
  • the isotopic labeling of molecular entities that serve as substrates that, via enzymatic degradation or other processes, liberate isotopically-labeled i-EBMs, is a critically important strategy toward designing and developing an optimal MAMS—particularly for IMAM and CMAM embodiments.
  • FTIR gas phase Fourier Transform Infrared
  • FTIR spectra for a given alcohol is highly distinctive and can be used to discriminate among them (i.e., CD 3 -OH vs CH 3 —OH or CD 3 D 2 -OH vs CH 3 CH 2 —OH) (see FIG. 66 ).
  • GC-MS can easily distinguish between all these species.
  • the miniature gas chromatograph (mGC) can easily distinguish between specific alcohols of different carbon number but not among deuterated and non-deuterated alcohols with the same number of carbons.
  • FTIR does not provide a high degree of discrimination between deuterated and ordinary aldehydes of similar structure; the FTIR absorption spectra for ordinary formaldehyde and acetaldehyde as well as deuterated formaldehyde and acetaldehyde are similar.
  • FTIR spectra for a given aldehyde is highly distinctive and can be used to discriminate among them (e.g., CD 3 CDO vs CH 3 CHO or CD 2 O vs CH 2 O).
  • Deuterium depending upon the class of molecules they are placed on, the number of deuterations on a molecule, and their proximity to various bond types (e.g., amine, sulfhydryl, aromatic, etc.) on the molecule, can provide various types of molecular entities with unique analytical “signatures” in various biological media, including but not limited to breath, blood, urine, sweat or saliva.
  • various bond types e.g., amine, sulfhydryl, aromatic, etc.
  • Various analytical techniques such as IR or mass spectroscopy can be used to not only distinguish deuterated parent compounds from their deuterated metabolites (both in the gas and/or liquid states), but can also easily discriminate deuterated molecules from those identical natural compounds containing ordinary hydrogen (e.g., ethanol versus deuterated alcohol; aldehyde versus deuterated aldehyde; methanol versus deuterated methanol). Its use will reduce the need or even eliminate the step of obtaining baseline breath samples, as well as markedly simplify the FDA regulatory process for new drugs allowing for faster time to market with inexpensive and reliable technology.
  • Deuterated compounds are generally regarded as nontoxic and as having the same (or very similar) pharmacodynamic and pharmacokinetic properties as their undeuterated parent compounds. Last, deuterated approaches can be used to potentially monitor the metabolism of many important therapeutic agents.
  • carbonyl e.g., acetone with per deuterations on methyl groups
  • aliphatic e.g., 2-butanone with deuterations on non-alpha carbons
  • aromatic e.g., benzaldehyde, with per deuterations on ring—wavenumber 2290 cm ⁇ 1 .
  • FIGS. 22 and 43-53 Metabolic considerations are shown in greater detail in FIGS. 22 and 43-53 to assist in describing, and enabling those skilled in the art, in the practice of designing appropriate i-AEMs to achieve inclusion of non-ordinary isotopes in the i-EBMs.
  • FIGS. 23-42 are provided to show the power of FTIR to distinguish signals obtained from ordinary and non-ordinary isotopes in different candidate i-EBMs, depending on the nature and degree of non-ordinary isotope substitution in select i-AEMS. Further details regarding these figures are provided in the Examples section included herein.
  • A. provision of medications comprising a SMARM medication comprising an Active Pharmaceutical Ingredient (API or i-API) alone or in combination with at least one non-toxic, preferably Generally Recognized as Safe (GRAS) volatile organic compound (VOC) or incipiently volatile organic compound, the i-EBM (including i-EDIMs and i-EDEMs), preferably a direct food additive, wherein at least one atom of said i-AEM is replaced with a non-ordinary, stable (non-radioactive) isotope, such that, on administration (ingestion, topical application, or other means of delivery) of the medication or a component thereof comprising the labeled VOC, or a metabolite thereof comprising the non-ordinary isotope, the i-EBM, is entrained and is detectable in the exhaled breath or other bodily fluid;
  • API or i-API Active Pharmaceutical Ingredient
  • VOC Generally Recognized as Safe
  • VOC volatile organic compound
  • the device comprises a means for stripping the exhaled breath sample of moisture, a catalyst for converting the VOC to carbon dioxide and water, such that the non-ordinary isotope from the VOC is included in the water or CO 2 fraction, such that, following catalysis, e.g., deuterated water or CO 2 containing isotopes of carbon or oxygen are detected and quantitated in the exhaled breath sample; and
  • a VOC preferably selected from, but not limited to, the group consisting of secondary and tertiary alcohols in which for example hydrogens are replaced with deuterium atoms, or oxygen or carbon atoms are replaced by stable non-ordinary isotopes, is included in a medication for ingestion or delivery by other means (transdermal, vaginal, rectal, etc).
  • the present invention demonstrates that, while kinetics of appearance of e.g., deuterated VOCs in the exhaled breath differs depending on the route of administration, whether delivered orally, transdermally, or via another route of delivery, and depending on the precise nature of the molecule in which deuterium is included, deuterated VOCs are readily detectable in the exhaled breath and are, therefore, excellent markers to definitively confirm medication adherence, to track medications use and to detect and preferably prevent medication diversion or counterfeiting.
  • i-EBMs produced from e.g., deuterated AEMs or AEMs containing other non-ordinary but stable isotopes, (i.e. i-AEMs) or metabolites thereof in the exhaled breath
  • a miniature portable gas chromatograph similar to but an improvement over a first generation miniature GC device described in Morey et al., “Measurement of Ethanol in Gaseous Breath Using a Miniature Gas Chromatograph”, J. Anal. Toxicol., Vol. 35, p. 134-142, (2011).
  • the improvements in the present device include, but are not limited to, inclusion of a forward facing camera which is synchronized with breath sample acquisition to ensure that the breath sample and the identity of the subject providing the breath sample (e.g., by photographic identification) are concurrently time-stamped; and adaptation for maximum efficiency in detecting non-ordinary isotopes.
  • a sample de-humidification means and CO 2 stripper through which exhaled breath samples are passed to remove all water (including any background deuterated water which might interfere with subsequent quantitation of deuterated water following catalysis of VOCs to water and carbon dioxide);
  • b. a catalyst for conversion of VOCs in the exhaled breath sample to H 2 O or D 2 O and Carbon dioxide (see, for example, Eltron Research & Development Inc., and their U.S. Pat. No. 6,458,741 Catalysts for Low-Temperature Destruction of Volatile Organic Compounds in Air; U.S. Pat. No. 6,787,118 Selective Removal of Carbon Monoxide; U.S. Pat. No.
  • a non-ordinary isotope detector preferably a D 2 O detector.
  • a breath sample, 1001 comprising 1002 CO 2 , H 2 O in the form of water vapor, volatile organic compounds (VOCs), and the included Exhaled Breath Marker (i-EBMs) comprising at least one non-ordinary isotope, is introduced into the Stage 1 of the device, 1010 .
  • This stage of the device is for sample collection and analyte isolation, from which only VOCs in the exhaled breath and the i-EBMs comprising the non-ordinary isotope, is released into Stage 2 of the device, 1020 , where analyte detection and data collection occurs.
  • Stage 1, 1010 where, after the breath sample 1001 (comprising CO 2 , H 2 O in the form of water vapor, volatile organic compounds, and the included exhaled breath marker (i-EBMs) comprising at least one non-ordinary isotope, 1002 ), is introduced into the device, the introduced breath sample receives any of several different treatments, e.g., A, B, C, or modifications, variations, permutations., equivalents and/or combinations thereof.
  • the breath sample 1001 comprising CO 2 , H 2 O in the form of water vapor, volatile organic compounds, and the included exhaled breath marker (i-EBMs) comprising at least one non-ordinary isotope, 1002
  • the introduced breath sample receives any of several different treatments, e.g., A, B, C, or modifications, variations, permutations., equivalents and/or combinations thereof.
  • the breath sample 1001 (comprising water, carbon dioxide, VOCs and the i-EBM(s)) is passed through a dryer/scrubber 1011 , which removes all or substantially all of the water and carbon dioxide endogenous to the exhaled breath sample 1001 .
  • treatment B of Stage 1 1010
  • the breath sample 1001 is directed into a concentrator 1012 (e.g., a tenax column or the like) which binds VOCs including the i-EBMs, but not water or carbon dioxide, which merely flow through the concentrator and are vented to the atmosphere, while retained i-EBMs are, for example, thermally desorbed from the column after these contaminants have been removed.
  • a concentrator 1012 e.g., a tenax column or the like
  • the breath sample 1001 is introduced into a concentrator 1012 , as in treatment B, but, in addition, the retained materials are fractionated via a fractionation means, e.g., a chromatographic column.
  • the chromatographic column is a miniature gas chromatography (GC) column, thus making it possible for the entire device to be portable.
  • the concentrator, 1012 is preferably a material which efficiently retains VOCs, including i-EBMs, while allowing all other breath components to flow through (i.e./e.g., moisture, carbon dioxide), but is easily desorbed of retained VOCs/i-EBMs, e.g., by application of heat.
  • both a dryer/scrubber 1011 and concentrator 1012 may be utilized in series to ensure removal of all water and carbon dioxide endogenous to the exhaled breath sample, prior to further treatment (GC column separation and Stage 2 treatment).
  • Stage 2 of the device, 1020 whereby the i-EBMs emergent from Stage 1 can be treated by a treatment such as treatment A or Treatment B in Stage 2 or in equivalents, modifications, permutations or combinations thereof.
  • treatment A the i-EBMs 1003 are directly passed through an infra-red (IR) detector and the signals obtained from passage of the sample through the detector is collected and analyzed.
  • treatment B the i-EBMs are subjected to catalytic combustion 1022 , to produce carbon dioxide and water from the i-EBMs and VOCs.
  • non-ordinary isotopes are included in the i-EBMS, these appear in the carbon dioxide or water (deuterium oxide) fraction and are then passed through an IR detector for data collection and analysis 1025 .
  • any VOCs aside from the i-EBMs introduced into Stage 2 will also be converted by this latter treatment into carbon dioxide and water, but, since these produces are not labeled with a non-ordinary isotope, such as deuterium, the IR detector 1021 is easily tuned to provide distinct signals based on e.g., deuterium content.
  • Stage 1 1010 there has been a separation of compounds e.g., by chromatographic means ( 1013 ) the VOCs including i-EBMs are separated prior to introduction into the IR Detector, whether catalytic combustion is utilized or not.
  • the advantage of including catalytic combustion is that, rather than needing to utilize a tunable IR sensor, which tends to be complex and expensive, a very simple and inexpensive IR sensor, tuned to detect e.g., deuterated carbon dioxide or deuterated water, may be utilized.
  • the device 1000 comprises a sample inlet 2000 , which is directed to a three-way valve 2001 .
  • the three-way valve 2001 permits ambient air 2002 to pass through an air scrubber 2003 to drive a sample of exhaled breath through a flow-through sample dryer/CO2 scrubber 2004 which removes endogenous water and carbon dioxide from the sample, while allowing VOCs and i-EBMs to pass through.
  • a heater, 2005 is associated with the flow-through dryer/CO 2 scrubber to establish controlled temperature conditions, and, in the event that a VOC/i-EBM concentrator is also used, to induce thermal desorption from the concentrator at the desired time point. Where catalytic conversion of VOCs is utilized, a heater is provided to generate elevated temperatures, although systems for conversion of VOCs to CO 2 and H 2 O at about 50° C. are also available for this purpose.
  • the sample On emerging from the flow-through dryer/CO2 scrubber 2004 , the sample is directed through another three-way valve 2006 , which directs the sample through an IR detector 2007 , and from there, via another three-way valve 2008 , via carrier pump 2009 , to a vent 2010 .
  • use of a tunable IR sensor may be required to distinguish between i-EBMs and other VOCs which do not contain non-ordinary isotopes.
  • FIG. 21 there is shown another embodiment of the device 1000 of this aspect of the invention according to which, per FIG. 19 , Stage 1, treatment B, and Stage 2, treatment B, are arranged in series.
  • the exhaled breath sample is passed through a separation means, preferably e.g., a separation column such as an appropriate GC column 2018 , and then into a catalytic combustion chamber 2022 prior to being passed into a detector 2024 .
  • a separation means preferably e.g., a separation column such as an appropriate GC column 2018
  • the separation column 2018 may be bypassed or simply not included in an embodiment according to this aspect of the invention, by directly connecting the outlet from the concentrator 2012 directly to the inlet of the catalytic combustion chamber 2022 .
  • the device of this invention is utilized by introducing a sample of exhaled air into sample inlet 2000 and from there, the sample is passed via three-way valve 2001 and is trapped/concentrated in a thermally desorbable concentrator 2012 —e.g., a hydrophobic column, (e.g., tenax) from which adsorbed molecules are desorbed by activation of heating means 2005 , e.g., a peltier device or heating coil wound around the thermally desorbable concentrator 2012 .
  • a thermally desorbable concentrator 2012 e.g., a hydrophobic column, (e.g., tenax) from which adsorbed molecules are desorbed by activation of heating means 2005 , e.g., a peltier device or heating coil wound around the thermally desorbable concentrator 2012 .
  • Sample pump 2013 provides pressure as needed to draw sample in via sample inlet 2001 and to vent 2010 as needed.
  • a fan 2014 is included to ensure efficient and even heating of the concentrator 2012 and dissipation of heat from the device 1000 .
  • a three-way valve 2015 at the distal end of the concentrator 2012 permits ambient air 2002 to pass through an air scrubber 2003 to thereby provide scrubbed ambient air via the three way valve 2015 to the distal end of the concentrator 2012 .
  • the sample On actuation of the heating element 2005 , the sample is desorbed from the thermally desorbable concentrator 2012 , and is driven from the concentrator proximal end of the concentrator 2012 via three-way valve 2001 onto separation column 2018 , (if included in the particular embodiment, or directly to the chamber 2022 , as noted above), preferably a gas chromatographic column selected to separate molecules according to their partition coefficient (boiling temperature) relative to the mobile and stationary phases in the column 2018 .
  • separation column 2018 preferably a gas chromatographic column selected to separate molecules according to their partition coefficient (boiling temperature) relative to the mobile and stationary phases in the column 2018 .
  • the column 2018 is heated to a controlled temperature by heater 2011 to achieve reproducible molecular separation and retention times on the column 2018 . Sample molecules emerge from the distal end 2019 of the column 2018 at characteristic retention times.
  • the sample stream is directed to enter a catalytic combustion chamber 2022 where any VOCs and i-EBMs are converted to ordinary carbon dioxide and water, if arising from endogenous VOCs or comprising non-ordinary isotopes, if arising from i-EBMs. Any such molecules are then detected, at characteristic retention times, via IR detector, 2024 which, of course, detects the water or carbon dioxide coming off the column, albeit at the characteristic retention times of the VOCs from which they have been generated. The IR detector, of course, distinguishes any water or carbon dioxide thus generated depending on whether non-ordinary isotopes are present in the water and carbon dioxide, or not.
  • the IR detector 2024 may be tuned to detect, e.g., water or carbon dioxide containing non-ordinary isotopes (e.g., of hydrogen, carbon or oxygen), while ignoring detection of carbon dioxide or water arising from catalytic combustion of endogenous VOCs which do not contain non-ordinary isotopes.
  • the detector 2024 does not require tuning and is set to detect the characteristic signal of a particular non-ordinary isotope of interest (e.g., deuterium, carbon or oxygen).
  • i-EBMs are collected from the breath and separated from water, carbon dioxide and, optionally, other volatile organic compounds (VOCs) that may interfere with the subsequent analysis.
  • VOCs volatile organic compounds
  • Stage 1-A this may be accomplished by simply passing a portion of the breath through a low pressure scrubber (e.g., Nafion tubing) prior to entering the detector.
  • the scrubber can be replaced with a concentrator (Stage 1-B), and for samples containing multiple i-EBMs, chromatographic separation can be included (Stage 1-C).
  • Stage 2 the captured i-EBMs are detected, analyzed, and optionally quantitated by an appropriate sensor, such as an IR-based detector.
  • the parent molecule is measured directly (Stage 2-A). In cases where this is not true, it may be necessary to convert the i-EBM into a more readily detected species.
  • an organic molecule is combusted, carbon atoms from the molecule are oxidized into CO 2 and hydrogen atoms are oxidized to produce water.
  • Isotopically-labeled organic compounds give rise to corresponding isotopically-labeled combustion products. For example, an isotopologue of acetone containing 13 C in place of place of hydrogen would generate 13 CO 2 and D 2 O, respectively. 13 CO 2 and D 2 O are readily measured IR active species.
  • FIG. 19 The various elements depicted in FIG. 19 can be combined to produce several distinct devices.
  • the most basic of these devices is produced by joining the Stage 1-A and Stage 2-A paths in series.
  • the most complex design combines paths 1-C and 2-B, see FIG. 21 .
  • the device is a novel medication adherence device based on measurements of, for example, cold isotopologues of water in human breath.
  • Stable cold isotopologues of water include, but are not limited to: 1) H 2 18 O, 2) H 2 16 O, 3) H 16 OD, 4) D 2 16 O, and 5) H 18 OD, and/or stable cold isotopologues of carbon dioxide.
  • Appropriate routes of drug administration include but are not limited to: oral, intravenous (IV), transdermal, rectal, vaginal.
  • IV intravenous
  • transdermal a key point of novelty in this device is that the water and CO 2 being used to detect medication adherence are NOT being generated by the body, but rather by mechanisms within the sensor.
  • the system allows a common detection algorithm to be used to detect a great many different drugs, markers, VOCs and the like.
  • EDIMs Exhaled Drug Ingestion Markers
  • the device according to this invention exploits the use of a well-developed cold isotopic monitoring systems for water and/or CO2 for many types of i-EDIMs/i-AEMs/i-EBMs and can function with or without the use of a baseline breath sample.
  • a baseline breath sample can be used to subtract off any background VOCs in the breath, e.g., DHO and D 2 O, but the baseline levels for these compounds are likely so low that no baseline breath sample may be needed.
  • the detection can be accomplished with or without a mini-gas chromatograph (mGC). Without using the mGC, there is little delay which is required in an mGC-based process, and results can be obtained in very nearly real time with time otherwise required for separation thereby eliminated. That is, in this embodiment, after the breath is sampled onto the tenax trap, the trap temperature is rapidly increased to about 180° C. to desorb the VOCs from the trap and into the catalytic combustion stage. Depending on the particular VOCs to be analyzed, an optimal contact time with the catalyst to efficiently convert the i-EDIM to D 2 O is selected. The D 2 O then passes into the IR cell, where it may take a few seconds to be analyzed (typically 16-64 IR scans are run for reliable statistics). This whole process may take between 30 seconds to 1 minute.
  • mGC mini-gas chromatograph
  • This mode of analysis is limited to detecting only an integrated mass of DHO and D 2 O.
  • the system can separate compounds based on boiling points prior to entering an IR detector or alternate detector element. Where IR is used, this may be used in a manner similar to MOS used in an existing mGC-MOS configuration. It permits robust detection of DHO and D 2 O in breath to identify many different types of deuterated or other non-ordinary isotope containing i-EDIMs (i-AEM or metabolites of i-AEMs).
  • Picarro, Inc. provides a Micro-Combustion Module (A0214) to remove interfering organics from water samples, in-line and efficiently. That module is disclosed as able to: improve data quality for water isotope analysis, treat samples in-line to decompose interfering organics; integrate seamlessly with Picarro's A0211 High-Precision Vaporizer, and to deploy effortlessly in the lab or the field—minimal footprint and energy requirements.
  • the Micro-Combustion Module is described as providing seamless operation by passing a gaseous phase sample from the vaporizer over an enclosed element. The resulting oxidation converts organics into minute quantities of carbon dioxide and nascent water.
  • the MCM includes a self-contained micro-reactor element that can be easily replaced in the field. The MCM effectively removes spectral interference for commonly occurring alcohols and plant products including multicomponent mixtures of alcohols, terpenes and green leaf volatiles.
  • This Picarro module may be incorporated into the Type II device according to this invention.
  • IR sensor technology enables use of deuterated and other non-ordinary isotope containing markers. Depending on the size of the gas sampling cell, detection of deuterated breath markers at levels above 1000 ppbv are readily detected. In the past, gas phase IR technology has typically not been able to go much below 1000 ppbv unless a large, multi-pass gas cell or a molecule that has a huge IR absorption is used. This is rapidly changing, however, and new solutions are constantly being developed in this field.
  • a Nicolet 6700 FTIR has a detection limit of around 1 ppm for acetone/IPA/deuterated acetone/deuterated IPA using a 5-L gas sampling cell. Inclusion of a concentrator (such as that disclosed herein above in connection with the mGC), 1-L of breath is concentrated down to a volume of about 1-10 cc. This decreases detection limits to enable detection of EDIMs in breath after pill ingestion.
  • a diode laser-based IR instrument is preferred for detection as they emit a much higher intensity light versus continuous light sources (e.g., the ETC Everglo source used in the Nicolet 6700 FTIR). Using such a modification provides detection limits 10-100 times lower than in the unmodified device.
  • NIR Near InfraRed
  • mIR Mid Infrared
  • FTIR Frequency-to-Red
  • CRDS Cavity Ring Down Spectroscopy
  • Picarro, Inc. affirms its sensors to measure in the low (e.g. 10) parts per trillion range for particular analytes.
  • Organic compounds can be analyzed by infrared (IR) spectroscopy for both qualitative and quantitative purposes.
  • Either a FTIR (fourier transform infrared) spectrometer can be used to continuously monitor the entire mid-IR wavelength range (4000-400 cm ⁇ 1 or 2.5-25 ⁇ m) or a tunable laser diode with an IR detector can be used to monitor selected wavelengths within this range (for example 4.3, 6.8, 8.3, 9.1 and 10.8 ⁇ m laser diodes available from Daylight Solutions.
  • a laser diode-based IR spectrometer can also be used in a cavity ringdown mode (CRDS) to monitor the IR absorption of a gas as a time-based measurement instead of an intensity-based absorption measurement used in FTIR spectrometry.
  • CRDS cavity ringdown mode
  • the SMART® device comprises a miniature gas chromatograph, or mGC.
  • volatile organic compounds (VOCs) in the exhaled breath of subjects is introduced into a portable mGC device which separates the VOCs according to partition coefficients for the VOCs as between a mobile phase and a stationary phase inside the mGC column.
  • VOCs volatile organic compounds
  • a portable mGC device which separates the VOCs according to partition coefficients for the VOCs as between a mobile phase and a stationary phase inside the mGC column.
  • methods known in the art can be brought to bear for this purpose.
  • Andrews, A. R. J., Z. Wu, and A. Zlatkis The separation of hydrogen and deuterium homologues by inclusion gas chromatography,” Chromatographia 34.9-10 (1992): 457-460.
  • Such systems may include, but are not limited to, for example, Sigma Aldrich b-Dex 110 Product No. 24302, 60 m ⁇ 0.25 mm i.d. 0.25 mm film thickness; b-Dex 110 Product No. 24301, 30 m ⁇ 0.25 mm i.d. 0.25 mm film thickness; CD Type: b (beta) Derivative: Dimethyl Phase: Non-bonded; 10% 2,3-di-O-methyl-6-0-TBDMS-b-cyclodextrin embedded in SPB-35 poly(35% phenyl/65% dimethylsiloxane) (intermediate polarity phase); Sigma Aldrich b-Dex 325, Product No.
  • the Type III device is a much simplified device for medication adherence monitoring.
  • components of the Type I device as described above in section 6.1 are included, while others are dispensed with.
  • the Type III device may, but does not necessarily, include exhaled breath capture and concentration. Where this is not included, exhaled breath is directly exposed to sensors.
  • compound separation is not required as discrimination is achieved at the level of compound detection.
  • at least two sensors are utilized: —One specific to the EBM or i-EBM and one sensitive to other VOCs. By difference, the concentration of the EBM of interest is calculated by on-board logic.
  • Type I and Type II embodiments of the SMART® device according to this invention as described herein provides just such a device, and, in addition to MAM applications, those devices may be well applied for the metabolic monitoring purposes of concern to Toyooka at al. Nonetheless, Toyooka et al., describe a prototype portable breath acetone analyzer that has two types of semiconductor-based gas sensors with different sensitivity characteristics, enabling the acetone concentration to be calculated while taking into account the presence of ethanol, hydrogen, and humidity. To investigate the accuracy of their prototype and its use in diet support, they conducted experiments on healthy adult volunteers in which they found that breath acetone concentrations obtained from their prototype and from gas chromatography showed a strong correlation.
  • the device described by Toyooka et al. included a pressure sensor to detect exhaled breath and used a first gas sensor with “particularly high sensitivity to acetone”, (platinum-doped tungsten oxide, Itami, Japan), and a second sensor which has “almost equal sensitivity to both acetone and interference gases such as hydrogen and ethanol” (tin oxide, SB-30, FIS, Inc.).
  • the sensors were operated at 400 deg. C., and differential calculations of output from the two sensors was used to determine the acetone increases and decreases in exhaled breath on different activities by subjects.
  • a commercial embodiment of a platinum-doped, tungsten oxide sensor is produced and utilized for acetone-specific detection where an AEM or i-AEM which generates breath acetone elevations (e.g., using isopropanol as the AEM) is used.
  • the first sensor may be selected for alternate EBM specificity than for acetone.
  • a second sensor such as the tin-oxide SB-sensor, is utilized in combination to measure other compounds in the exhaled breath, to enable acetone (or other EBM) specific calculations to be achieved.
  • Such an embodiment of a Type III device using dual-MOS sensors affords only 2-dimensions of selectivity (i.e.
  • a concentrator as described above in the Type I and Type II SMART® device is included ahead of the dual MOS array, thereby providing 4-dimensions of selectivity and sensitivity, (concentrator sorbent, desorption temperature, array coating and signal processing), a significant enhancement over the device described by Toyooka et al.
  • the included concentrator protects the “naked” MOS detectors from environmental contaminants and would therefore also greatly improve longevity.
  • the concentrator would separate humidity, hydrogen, carbon dioxide, carbon monoxide, methane and other contaminants from the e.g., acetone signal.
  • the Type III SMART® device according to this aspect of the invention would preferably be approximately “cigarette-pack” sized.
  • Type III SMART® device In an preferred embodiment of the Type III SMART® device according to the invention, all components of the Type I device as described above are included and are incorporated here by reference, except that the separation means, e.g., the mGC, is excluded, and the sensor according to this embodiment of the device are dual sensors with differential sensitivities to analytes to enable detection and measurement of specific analyte(s) of interest.
  • the separation means e.g., the mGC
  • exhaled breath sampling module exhaled breath analysis module and exhaled breath kinetics module are preferably, but not necessarily all included in a unitary, portable device.
  • WinNonlin can be used to model and predict intra-individual and inter-individual variability of key PK parameters (Pharsight Corporation, Mountain View, Calif.).
  • analysis of measured exhaled breath components is optionally conducted on a central data repository after EDIM concentration-time data is uploaded/transmitted from the portable device, or it is conducted locally on the SMART® device itself.
  • the invention includes a device or system wherein the exhaled breath kinetics module calculates, for a given marker identified by analysis of the constituent components of an exhaled breath sample of a subject obtained at a time t 1 , whether the concentration of the marker is consistent with the expected concentration of the marker at the given time t 1 . This is done with reference to stored pharmacokinetic parameters from the subject for the given marker and the dosage interval (T), if the subject had been adherent to a set regimen for introduction of the marker or a precursor of the marker into the subject over a defined time period prior to obtention of the exhaled breath sample.
  • T dosage interval
  • the exhaled breath kinetics module calculates, for a given marker identified by analysis of the constituent components of an exhaled breath sample of a subject obtained at a time t 1 , whether the concentration of the marker is consistent with the expected concentration of the marker at a time t 1 , with reference to stored pharmacokinetic parameters obtained from a large population of subjects for the marker and the dosage interval (T), if the subject had been adherent to a set regimen for introduction of the marker or a precursor of the marker into the subject over a defined time period prior to obtention of the exhaled breath sample.
  • An optimized device or system according to this invention is optimized by including in the device:
  • the characterizing data for storage preferably includes measurement data, to within defined confidence limits, of:
  • Such a device is preferably configured to integrate the pharmacokinetic parameters defined above to provide an adherence lookback window, T AdhWindow , defined as the period of time required for the marker (EDIM) concentration in breath of the subject to decay from an initial value (C EDIMo ) to a lower concentration (C EDIM,Limit )
  • T AdhWindow t 1 / 2 ⁇ e 0.693 * ln ⁇ ( C EDIMo C EDIMLimit )
  • C EDIMo original or starting concentration of marker (EDIM) in breath at times equal to or greater than T MAX (i.e., C EDIMo ⁇ C MAX ) of said patient;
  • Such a device preferably exhibits a T AdhWindow between about 1 hour and about 400 hours, and includes a sensor with a LoD for the marker of between 1 part per trillion and 5 parts per billion.
  • the sensor is adapted to distinguish between ordinary and non-ordinary isotopes present in EDIMs and volatile compounds which otherwise would interfere with selective measurement of EDIMs in the exhaled breath.
  • SMART® medication adherence monitoring e.g., AMAM, IMAMA, CMAM
  • an embodiment of SMART® device in use Type I, II, or III
  • an appropriately matched SMART® composition is employed.
  • AEMs and compositions of matter comprising AEMs which are adapted for use in a SMART® system which includes the Type I embodiment of the SMART® device according to this invention.
  • i-AEMs and compositions of matter comprising i-AEMs which are adapted for use in an i-SMART system which includes the Type II embodiment of the SMART® device according to this invention.
  • compositions of matter disclosed herein provide advancements in the art by resolving such matters as flashpoint of volatile AEMs during formulation and soft gel encapsulation of the marker, acceptability of the AEM to subjects receiving administered medication, and by disclosing a combination of marker and excipients which optimize handling and/or processing of the marker composition, encapsulation properties, and improving tolerability and acceptability of the marker(s) when included in API dosage forms.
  • a “soft” gelatin capsule In a first AEM composition according to this invention, at least or exclusively the following key components are contained within a “soft” gelatin capsule:
  • a gelatin capsule which is then combined with or administered concurrently with an API for medication adherence monitoring.
  • the AEM is combined with one or more additional components, including but not limited to flavorants, bulking agents, other excipients, or the like, as described above.
  • AEMs other than 2-butanol or IPA may be appropriate for a particular application and can, based on the disclosure and guidance provided herein, make appropriate modifications to the formulation to accommodate alternate AEMs, volumes, concentrations and chemical interactions.
  • Flashpoint considerations with respect to the AEM if it is a volatile compound such as 2-butanol, define parameters for consideration in the safe handling of medication fill formulations in commercial contexts. Working temperatures above 25 degrees centigrade using compounds with a 22 degree centigrade flashpoint, for example, are less than optimal. The flashpoint of neat 2-butanol is about 22 degrees centigrade.
  • the bulking agent is utilized to bring the total volume of the formulation to a desired total volume. For a consistent volume to be filled in each soft-gel capsule, it is important for the total volume to not be too small for the relevant commercial fill operation, otherwise undue errors are introduced into the total concentration of AEM between different capsules. Those skilled in the art know how to calculate volumes for particular fills which will eliminate or reduce this aspect of variance such that essentially no statistically significant variance in EDIM measurement on the breath can be attributed to differences in AEM fill volumes used in the soft-gel capsules. Second, the bulking agent is preferably one which does not retard release of the AEM upon dissolution of the capsule containing the AEM.
  • soft-gel capsules include at least one or a combination of the following components: a shell forming composition, such as but not limited to gelatin; a plasticizer, such as but not limited to glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
  • a shell forming composition such as but not limited to gelatin
  • a plasticizer such as but not limited to glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
  • the AEM composition is contained within a soft-gel composition as follows:
  • Formulation A 20 mg 2-butanol+0.7 mg DL-menthol+5 mg vanillin+9.3 mg PEG-400
  • Formulation B 40 mg 2-butanol+1.4 mg DL-menthol+10 mg vanillin+18.6 mg PEG-400
  • PEG-400 is selected as a preferred component of the AEM formulation according to this invention due to its combination of solubility, viscosity, and other characteristics. It is soluble in water, it acts as a solvent and carrier for the 2-butanol, and flavorants and has a positive effect in increasing the flashpoint of the formulation.
  • Other grades of PEG including, but not limited to PEG-200, PEG-600, and the like. These grades of PEG are functional in the present invention, but we have found that he PEG-400 grade is optimal when the selected AEM is 2-butanol.
  • PEG-400 and PEG-600 are both listed in the US FDA's listing of Inactive Ingredients for approved drugs.
  • the ratios of the AEM e.g., 2-butanol
  • PEG-400 e.g., PEG-400
  • flavorants e.g., 2-butanol
  • the ratios of these components is retained when twice the amount of AEM is included in the formulation.
  • the ratio disclosed herein has been found to be preferred, providing miscibility of the marker in the formulation, stability in temperature cycling and chilling studies, room temperature stability, and dispersion in 0.01 1N HCl and neutral buffered solution.
  • the formulation in addition, can be scaled to produce GMP batches for clinical trials and commercial use, it releases rapidly and reliably in the stomach, and is anticipated to exhibit long-term stability 1-2 year shelf life at room temperature), while, at the same time, permitting encapsulation in the smallest possible size (i.e. less than 6 mm or less than 5 mm or smaller, if possible) of soft gel capsule (thereby taking up the minimum amount of volume to permit API filling of capsules and other SODF's containing the AEM-soft gel formulation). It is also preferred that the gel capsule thickness containing the AEM be as thin as possible where AMAM is desired to be achieved. A softgel containing the AEM (whether 2-butanol alone or in combination with other excipients) is provided.
  • each formulation is placed directly (i.e. without encapsulation of the AEM in a soft gelatin capsule) in a white size 4 LiCaps® hard gelatin capsule and sealed.
  • the sealed white size 4 LiCaps® capsule will then be placed in a white size 0 LiCaps® capsule which is NOT sealed.
  • the AEM formulation is preferably included in a soft-gel capsule which is then included in a solid dosage form including the API, in a format such as was disclosed in WO2013/040494 but improved as disclosed herein.
  • the soft-gel capsule comprising the AEM formulation according to this invention is introduced into the apical half of a hard gelatin capsule. The lower portion of the capsule is filled with API composition, and the capsule is closed, thereby containing both the AEM soft-gel capsule and the API in a single dosage form.
  • the capsule containing the AEM is optimized for rapid, intermediate or slow dissolution in the biological system.
  • extremely thin wall thickness is preferred (see below) so that appearance of the EBM in the exhaled breath is not unduly delayed.
  • Typical hard gel capsules, such as LiCaps® capsule and Conisnaps® capsules are approximately 0.11 mm thick (Capsugel, Morristown, N.J.), whereas softgel capsules typically have a wall thickness of 0.64-0.76 mm (Catalent, Somerset, N.J.).
  • IMAM and CMAM these considerations may be less critical, and, in fact, appropriate retardants to dissolution may be utilized to extend the time from which a medication is taken to the time that adherence has to be confirmed using an appropriate embodiment of the SMART® device according to this invention.
  • soft gelatin capsule technology is based on hermetically sealing a liquid in a gelatin shell. It is typically practiced using the rotary die method, although other manufacturing technologies exist.
  • 2 gelatin films are fed between a set of dies containing pockets for forming the capsules.
  • a wedge is used between the dies to inject the fill material between the ribbons such that it forms the capsules in the die cavities as they rotate together.
  • the 2 gelatin ribbons are sealed using a combination of heat and pressure to hermetically encapsulate the fill material.
  • the gelatin formulation is selected based on the desired properties of the capsule and to be compatible with the fill.
  • Typical gelatin encapsulation formulations include glycerin and/or sorbitol as plasticizers in ratios to gelatin between about 0.5:1 to 0.8:1.
  • plasticizer and thickness of the ribbon are adjusted to form capsules that are strong enough to withstand normal handling.
  • the relationship between plasticizer level, shell thickness, and capsule geometry, to capsule strength and VOC permeability is intuitive, but also highly interactive, i.e., changing one will often be additive or subtractive with another.
  • VOC loss and capsule breakage When choosing a system for encapsulation of a VOC into a soft gelatin capsule, the following considerations come into play regarding VOC loss and capsule breakage.
  • Thick capsule shell Reduced VOC permeation and increased capsule strength (less likely to break), but may impact the rate of release of the VOC.
  • Typical shell thickness levels range from 0.025′′ to 0.040′′, with no real constraint provided the tooling is optimized for the thickness. Values outside of these levels are not typical and are optimized for production of the soft gelatin capsules containing the AEM disclosed and claimed herein.
  • the soft gelatin capsules according to this invention are made by mixing any excipients (including, but not limited to, bulking agents and/or flavorants), preferably under vacuum until all materials are dissolved and then the AEM is added under positive pressure, preferably under a blanket of inert gas, such as, but not limited to, nitrogen.
  • the formulation is stored under an inert atmosphere and is utilized in the encapsulation procedure as described above, followed by drying and packaging.
  • a coating to the capsule to reduce the permeation of the AEM from the capsule.
  • Surface coating methods may include, but are not limited to, spray coating, ink jet printing, thermal transfer, laser printing, dip coating and the like.
  • soft gelatin capsules containing the AEM in a preferred embodiment are over-coated.
  • Coatings for this purpose are known in the art, for example, by the trade names SmartSeal, ProtectSeal, Opadry II, Opadry 200, SmartCoat, BASF Protect, and the like.
  • Kollicoat Smartseal® 30 D is described by its manufacturer, BASF, as a “unique solution in pellet and particle coating, where other products are too tacky to be applied without individual items sticking together.
  • Kollicoat® Smartseal D features outstanding taste-masking, ensures quick release of the active ingredients in the stomach and offers superior protection with a reduced amount of coating, resulting in lower costs and more efficient production processes”.
  • OPADRY® 200 manufactured by Colorcon, Inc., is coated in a 24′′ fully perforated O'Hara Labcoat II coating pan. Per the manufacturer, 15 kg of biconvex placebo tablets (10 mm diameter) are coated to a 4% weight gain (WG) with the same lot of a blue Opadry 200 formulation.
  • % weight increase is an indication of the average amount of coating applied;
  • Rupture Time (RT) is the average time before AEM odor could be detected;
  • Disintegration Time (DT) is as noted above.
  • Non coated gelatin capsules resulted in disintegration in about 4.7 minutes;
  • Opadry II coating % weight increase 20, 14.5, 10.4, RT: 7.5-8 minutes; DT: 13.6, 11.5 and 8.1 minutes respectively;
  • Opadry 200 % weight increase 20, 14.6, 9.4, RT between and 8 minutes; DT: 16.2, 13.6, and 9.7 minutes respectively;
  • SmartCoat 30D % weight increase 20, 14.3, 9.6, RT: 7.0-8.0, 5.5, and 4.5 minutes; DT: 8.2, 7.3, and 5.9 minutes respectively;
  • SmartSeal 30D (20%) coated with ProtectSeal (3%), RT: 7.0-8.0 minutes, DT: 9.3 minutes;
  • BASF Protect % weight increase 15.5, 9.3, 5.2, RT 9, 6.5, 4.5; DT: 11.9
  • AEM encapsulated in a thin gelatin softgel capsule overcoated with an appropriate coating e.g., Opadry 200
  • the API itself is preferably, and typically is, contained in its own protective coating, including when delivered in a unitary dosage form with the AEM contained as described herein. Utilizing the gelatin capsule contained AEM as disclosed herein, in combination with a wide array of APIs may be conducted according to procedures and structures disclosed in WO2013/040494.
  • an additional utility for this invention is a method and compositions for measuring residence times and digestive activity.
  • Compositions comprising an AEM and a coating or coatings known to be resistant or susceptible to dissolution in different compartments of the digestive tract are thus considered to come within the scope of this invention.
  • composition comprising an AEM encapsulated, for example, in a soft gelatin capsule and coated with a coating resistant to gastric dissolution provides a system for measurement of the rate at which a particular individual or population releases a medication beyond the gastric chamber.
  • An enteric coating for example, is a polymer barrier applied on oral medication to protect drugs from the pH (i.e. acidity) of the stomach.
  • Most enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, but breaks down rapidly at a less acidic (relatively more basic) pH. For example, they will not dissolve in the acidic juices of the stomach (pH ⁇ 3), but they will in the alkaline (pH 7-9) environment present in the small intestine.
  • Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibers.
  • the AEM according to this invention is an “ordinary AEM” as compared with an i-AEM, it is desirable to ensure the AEM is not lost in the formulation process, and is stable when co-packaged/formulated with an API of interest.
  • HPC hydroxypropylcellulose, a well-known excipient in the pharmaceutical arts
  • HPC “ties up” hydrogen bonding of 2-butanol, which in turn reduces its ability to attract water from the hard gel matrix that would dehydrate the hard gel capsule and reduce its performance.
  • HPC was suggested for inclusion in fill formulations as a polymer such that a fill component (2-butanol, isopropanol, other VOCs) which, in the absence of the at least one polymer will migrate into or through a capsule shell.
  • a fill component (2-butanol, isopropanol, other VOCs) which, in the absence of the at least one polymer will migrate into or through a capsule shell.
  • Such methodologies may likewise be included for the AEM used in the system according to the present invention.
  • the AEM-dextrin powder is included in a hard gelatin capsule with an AEM.
  • the AEM-dextrin powder is encapsulated in a soft gelatin capsule, as described above in sections 7.1.2.
  • the AEM-powder is coated, as in and section 7.1.3 above.
  • the AEM-powder is included in a gelatin capsule which is then coated, as in section 7.1.3.
  • a polymeric starch based sugar bead is impregnated with liquid 2-butanol or like AEM, and optionally but preferably, coated with a PVA or similar material to trap the 2-butanol or like AEM in the sugar bead.
  • This finished “powder” is utilized in a capsule with the active drug, converted to a slurry for surface coating of a medication, or otherwise associated with an active pharmaceutical ingredient to produce a SMART® formulation for use according to the present disclosure.
  • a stable metal carbonate of a preferred alcohol marker e.g.
  • FIG. 84 shows different strategies for associating the AEM with an AEM and the resultant rate of EBM release.
  • FIG. 84A shows a capsule formed with 72 mg 2-Butanol in Maltodextrin (4:1 w:w) in size 0 LiCap top, with size 1
  • FIG. 84B shows a capsule formed with 64 mg 2-Butanol in Maltodextrin (4:1 w:w), in size 4 LiCap (interior coated with OPAGLOS) inside size 1 LiCap. As can be seen, this strategy results in a peak 2-butanol in the breath within about 30 minutes of ingestion.
  • FIG. 84C succinctly shows how the sensitivity and rate of EBM release is dependent on the configuration/strategy used to deliver the AEM, e.g. 2-butanol, to the stomach.
  • microgram quantities of 2-butanol may be required to achieve readily measurable quantities of 2-butanone in the exhaled breath shortly after delivery of the medication
  • microgram quantities of e.g., deuterated 2-butanol or isopropanol are all that is required to achieve detectable quantities of deuterated 2-butanone, or deuterated acetone.
  • SODFs Solid Oral Dosage Forms
  • capsules which are already imprinted with adequate quantities of an i-AEM, either on an external or an internal surface thereof, and adequately contained in a barrier, or included in a capsule shell compartment, are filled with an API.
  • inks comprising an appropriate i-AEM may be used to print on an existing SODF, with an over-coat spray of a rapidly dissolvable barrier being sufficient to contain loss of the i-AEM.
  • an AEM which comprises either or both (a) a non-ordinary isotope; (b) butanol, isopropanol, or both, either or both of which may include a non-ordinary isotope, or other selected secondary alcohols, or other AEMs.
  • the medication includes a surface coating comprising an i-AEM. Given the sensitivity of a D 2 O detector described herein, a low quantity (1-10 mg) of a deuterated AEM placed on the surface of SODFs (solid tablets, capsules) is adequate to permit medication adherence monitoring. Surface coating and containment, for example, in a blister pack or equivalent preserves the i-AEM on the surface of the SODF.
  • the period of time following dosage that the i-EBM is unequivocally detectable in the exhaled breath can be extended well beyond the dose-by-dose monitoring shortly after each dose is taken/administered (AMAM), which has been the standard paradigm for medication adherence monitoring to date.
  • AEM dose-by-dose monitoring shortly after each dose is taken/administered
  • Use of i-AEMs enables IMAM and CMAM, often many hours or even days following administration/taking of a given dose or multiple doses.
  • CDER Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) October 2010 Clinical/Medical, Section V (lines 292-323) for guidance on the use of “cold” (e.g., deuterium) isotopes in clinical trials, which indicates the low level of scrutiny for this type of isotopic marker from a US Regulatory Agency perspective.
  • CDER Center for Biologics Evaluation and Research
  • Non-radioactive isotopes include a number of elements (e.g., H, C, O, N, S), but for a variety of reasons deuterium is one of the most promising for our adherence application, particularly when mid-IR (mIR) techniques are contemplated to detect the i-EBM (see below Table). Accordingly, reference to deuterium herein, or any other specific isotope, is not intended to be limiting or to exclude the use of other stable (non-radioactive) isotopes.
  • the table shows examples of stable and non-stable isotopes that may have applications in biology (medicine), including application to human breath. For purposes of the present invention, it is the stable, non-radioactive isotopes shown in this table that are of principal interest.
  • Using isotopic labels in breath analysis has many advantages including but not limited to 1) creating a distinctive “fingerprint” in the breath, which can be used to distinguish labeled compounds from endogenous compounds already present in the body from natural metabolism or diet (e.g., ingestion of food, flavoring additives, drugs or excipients of drugs) and 2) can produce changes in the detection characteristics (e.g., shifts in the absorption spectra using FTIR) that make these molecules easily distinguishable from major analytical interferants in biological media.
  • the % data indicate the percent of all atoms of that particular element in this isotopic form.
  • the deuterated taggant is rapidly released from hard gel capsules, soft gel capsules, tablets, or other dosage form in which the taggant is provided, and, in turn, rapidly generates the deuterated i-EDIM (i-EBM);
  • the deuterated taggant must be interfaced to the commercial capsule, tablet or other dosage form in a manner that does not alter its performance characteristics
  • the deuterated taggants must be linked to the commercial pill or other dosage form (or clinical trial material) containing the API in a way that does not cause issues with API CMC or pharmacokinetics (PK: ADME) including bioavailability, and/or pharmacodynamics (PD); and
  • the taggant must create a deuterium-labeled i-EDIM (i-EBM) that is easily detected by a portable sensor (i.e., mIR device) in a sensitive and specific manner.
  • a portable sensor i.e., mIR device
  • GRAS taggants are preferably selected from those provided in the authoritative, proprietary Leffingwell & Associates (Canton, Ga.) “Flavor-Base 2007”. This listing is the world's most extensive database on GRAS flavoring materials and food additives (4,085 listings). All compounds in the Flavor-2007 database contain information from the relevant FDA and international regulatory databases. In all 1,603 esters, 926 alcohols, 222 aldehydes and 557 ketones were initially identified as potential taggant candidates. Of these the esters and carbonate esters can be used to easily generate a wide variety of corresponding alcohols and carboxylic acids.
  • the i-EBM could be 1) an isotopically-labeled ester, 2) an isotopically-labeled alcohol derived from the isotopically labeled ester, and/or 3) an isotopically-labeled acid derived from the isotopically-labeled ester.
  • various combinations of isotopically-labeled esters and their associated labeled acids and/or labeled alcohols could be used to provide unique i-EBM signatures in the breath.
  • the type of substituents may be varied to sterically/electronically alter the susceptibility of the ester to hydrolysis, and will thus regulate the rate of appearance of ester-based labeled i-EBM(s).
  • the physicochemical properties (e.g., physical state, volatility) of the ester will be a function of its substituents (R groups).
  • various isotopic labels preferably deuterium
  • various i-EBMs arising from the ester, acid and/or alcohol
  • isotopic labels is/are generated that fulfill the requirements of an effective MAMS.
  • i-AEMs The following criteria are relevant to selection of appropriate i-AEMs (and, indeed, to AEMs, unless specifically referenced to i-AEM selection criteria): 1) state of matter: solid versus liquid; 2) taste: absent or present (pleasant vs unpleasant); 3) physicochemical properties: boiling point, melting point, Henry's Law constant (K H ); 4) PK properties: ADME, including metabolism rates and routes (non-CYP-450 to avoid adverse drug reactions [ADRs]); 5) extensive safety data: stability, toxicological data such as permissible daily exposure (PDE) in humans and LD 50 values in various species (typically in the gms/kg range for oral administration); 6) minimal-to-no implications from a regulatory perspective (no impact on CMC of API [study drug or FDA approved drug] or PK/PD of API); and 7) metabolism of taggant generates i-EBMs that are easily detected by the mGC-MOS or mGC-mIR (
  • the list contains three 2° alcohols and eleven esters (nine 1° alcohol-based esters, plus two 2° alcohol-based esters). Secondary esters and their corresponding 2° alcohols offer many advantages in definitive adherence. For example, 133 esters were identified in the food database having boiling points ranging from 30 to 320° C., indicating the wide diversity available for a technology like mGC-MOS, mGC-midIR, which are essentially “boiling point” detectors. Aliphatic esters are rapidly hydrolyzed to their corresponding alcohol and aliphatic carboxylic acids by esterases, which could serve as i-EBMs. Tables 3 and 4 below show common alcohols and carboxylic acids, respectively, formed from esters.
  • CAS chemistry abstract number
  • MF molecular formula
  • MW molecular weight
  • BP boiling point
  • MP melting point
  • VP vapor pressure at specified temperature
  • Table 3B Shown in Table 3B are alcohols that are commonly generated via enzymatic degradation of GRAS food additives/flavorants and/or FDA approved drugs (e.g., esterase mediated degradation of esters to their corresponding acids and alcohols).
  • various isotopic labels shown in Table 1 e.g., and preferably, deuterium
  • substrates that create the various alcohols shown but not limited to the above table, or even into alcohols directly various i-EBMs are generated that fulfill the requirements of an effective MAMS.
  • VP at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF: MW: BP: ° C. MP: ° C. VP: at ° C. CAS: MF:
  • CAS chemistry abstract number
  • MF molecular formula
  • MW molecular weight
  • BP boiling point
  • MP melting point
  • VP vapor pressure at specified temperature
  • Table 4 Shown in Table 4 are different carboxylic acids that are commonly generated via enzymatic degradation of GRAS food additives/flavorants and/or FDA approved drugs (e.g., esterase mediated degradation of esters to their corresponding acids and alcohols).
  • various isotopic labels shown in Table 1 e.g., and preferably, deuterium
  • substrates that create the various acids shown but not limited to the above table, or even into acids directly various i-EBMs are generated that fulfill the requirements of an effective MAMS.
  • 1° alcohol-based aliphatic esters (1° esters) such as ethyl butyrate
  • esterases rapidly create a 1° alcohol (i.e., ethanol).
  • 2° alcohol-based aliphatic esters such as 2-pentyl butyrate
  • they are rapidly hydrolyzed to their corresponding 2° alcohol (i.e., 2-pentanol) by esterases, particularly by carboxylesterases (e.g., ⁇ -esterase).
  • carboxylesterases e.g., ⁇ -esterase
  • the carbon that carries the hydroxyl (—OH) group of primary (1°), secondary (2°) and tertiary) (3° alcohols is attached to 1, 2, and 3 alkyl groups, respectively.
  • the 1° and 2° alcohols are primarily converted (oxidized) via alcohol dehydrogenase (ADH) to their corresponding aldehydes and ketones, respectively.
  • ADH alcohol dehydrogenase
  • 3° alcohols due to steric hindrance with ADH, are very resistant to metabolism in humans and thus are not ideal for MAMS, unless a 3° alcohol-based ester liberated a 3° alcohol (e.g., tert-butyl butyrate ⁇ tert-butanol), which was used as the EDIM.
  • the aldehydes are further metabolized by aldehyde dehydrogenase (ALDH), which oxidizes (dehydrogenates) them to their corresponding carboxylic acid.
  • ADH aldehyde dehydrogenase
  • ketones undergo ⁇ -hydroxylation (e.g., conversion of 2-butanone [methyl ethyl ketone, MEK] to 3-hydroxy-2-butanone [acetoin] via CYP-2E1 and CYP-2B, or conversion of 2-pentanone [methyl propyl ketone, MPK] to 3-hydroxy-2-pentanone) and subsequent oxidation of the terminal methyl group to eventually yield corresponding ketocarboxylic acids.
  • the ketoacids are intermediary metabolites (e.g., ⁇ -ketoacids) that undergo oxidative decarboxylation to yield CO 2 and simple aliphatic carboxylic acids.
  • the acids may be completely metabolized in the fatty acid pathway and citric acid cycle.
  • Ketones generated from other sources would also be excreted by the lung.
  • these endogenous DKA-related ketones are easily distinguished from the ketones which would be generated from 2° esters or alcohols, including 2-butanone and 2-pentanone.
  • a number of critically important CYP-450 metabolic reactions for pharmaceutical agents via dealkylations ( FIG. 26 ), generate various aldehydes ( FIG. 27 ), include formaldehyde via desmethylation, acetaldehyde via desethylation, propionaldehyde via despropylation, and butyraldehyde via desbutylation.
  • CMC architecture approaches or addition of taste “maskers” to avoid the taste of these compounds.
  • FIG. 22 shows the metabolic fate of selected ordinary isotope and non-ordinary isotope labeled alcohols, aldehydes and carboxylic acids.
  • alcohol dehydrogenases are a group of dehydrogenase enzymes that catalyze the interconversion between alcohols and aldehydes (or ketones). Their primary function is to degrade alcohols. The enzyme is contained within the gastric lining and in the liver.
  • Aldehyde dehydrogenases are enzymes that catalyze the oxidation (dehydrogenation) of a various aldehydes.
  • Panel B shows potential isotopic labeling sites. *, indicates a deuterium (stable isotope) label but could be other types as shown in Table 1. Likewise, multiple deuterated labels could be placed on the molecule or alternately a combination of different isotopic labels (H, C and/or O-based) could be used; ⁇ , indicates a carbon isotopic label (see Table 1). Note: In this scheme, where appropriate, other potential isotopic labels (Table 1) could be used including 170 and/or 180 for ordinary oxygen.
  • Direct isotopic labeling of alcohols, aldehydes and acids is possible and adds to chemical diversity for MAMs.
  • the oxygen atom remains with the alcohol. It may be seen as a dehydrogenation of the alcohol i.e. only one hydrogen atom leaves the alpha carbon, and the molecule converts from alcohol to the carbonyl, which would be an aldehyde for a primary alcohol.
  • oxygen of a primary alcohol was labeled, it is possible to efficiently monitor the formation of the corresponding aldehyde after oxidation.
  • a SMART® medication in a first embodiment according to this aspect of the invention, there is disclosed a SMART® medication, and a method of making the SMART® medication (or a composition comprising the SMART® medication), comprising an Active Pharmaceutical Ingredient (API) in combination with an AEM, that is at least one non-toxic, preferably Generally Recognized as Safe (GRAS) volatile organic compound (VOC), or incipiently volatile organic compound (i.e.
  • API Active Pharmaceutical Ingredient
  • AEM Active Pharmaceutical Ingredient
  • AEM Active Pharmaceutical Ingredient
  • GRAS Generally Recognized as Safe
  • VOC volatile organic compound
  • incipiently volatile organic compound i.e.
  • the AEM on introduction into or onto a subject, the AEM is exhaled or gives rise to a compound which is exhaled), preferably a direct food additive, wherein at least one atom thereof is a non-ordinary isotope, e.g., a hydrogen of said VOC is replaced with a deuterium atom, such that, on administration (ingestion, topical application, or other means of delivery) of the medication comprising the deuterium-labeled AEM (e.g., the VOC or a metabolite thereof comprising) the deuterium atom is entrained and is detectable in the exhaled breath as an i-EBM.
  • the API itself includes the non-ordinary isotope and acts as the i-AEM or produces the i-EBM.
  • i-AEMs which produce i-EBMs detectable in the breath are discussed above.
  • different formulations and physical arrangement of the API and i-AEM are preferred, as discussed below:
  • a wide variety of oral dosage forms including AEMs are disclosed in WO2013/040494, published 21 Mar. 2013, entitled “SMARTTM SOLID ORAL DOSAGE FORMS”.
  • a number of physical forms for delivery of active therapeutic agents in combination with markers were disclosed.
  • non-ordinary isotopes may be included in the AEMs to produce i-AEMs, such that, upon introduction into the biological system, there is produced in the exhaled breath i-EBMs which may be monitored according to the present invention.
  • the contents of WO2013/040494 are herein incorporated by reference as if fully set forth herein, to describe and enable those skilled in the art to utilize the various dosage forms that could be used to include i-AEMs according to the present invention.
  • the i-AEM is contained within a barrier, which keeps the i-AEM separate from any API being co-delivered.
  • the barrier may be composed of gelatin or other containment mixture known in the art. Where a very small quantity of neat i-AEM is desired to be used, it may be printed onto or otherwise adhered to an existing dosage form and under and/or overcoated with a quickly dissolving i-AEM impermeable layer. Coatings known in the art for this purpose may be utilized.
  • microcrystalline cellulose, hydroxypropyl methyl cellulose, other polymeric or non-polymeric barriers, and the like such as disclosed in, for example, U.S. Pat. No. 6,352,719; US2007/0212411; US2004/0110891 and the like may be utilized for this purpose.
  • non-toxic, and preferably GRAS secondary and tertiary alcohols with between three and up to eight carbon atoms, including at least one non-ordinary isotope of hydrogen (i.e deuterium), carbon, oxygen or nitrogen, are useful for this purpose.
  • any or each of the following compounds which include at least one non-ordinary but stable (non-radioactive) isotope may be used according to this invention as an i-AEM for non-oral delivery of i-AEMs for use in combination with the i-SMART® system: isopropanol; 2-butanol; 2-methyl-2-butanol; 2-pentanol; 3-pentanol, and the like.
  • Preferred secondary and tertiary alcohols are those that are GRAS compounds.
  • An optimized i-AEM composition is disclosed herein which comprises at least or exclusively the following key components, mixed either prior to delivery or at the site of delivery at an appropriate concentration with a vaginal or rectal gel or other appropriate medium known in the art or which hereafter comes to be known in the art:
  • An i-AEM e.g., deuterated 2-butanol, deuterated IPA, (but which may be any of the i-AEMs discussed herein;
  • vaginal or rectal delivery formulations to accommodate alternate i-AEMs, volumes, concentrations and chemical interactions.
  • an anti-HIV API is being co-delivered with the i-AEM
  • i-EDEMs in exhaled breath is achieved following inclusion of as little as about 3 to 10 mg of e.g., deuterated 2-butanol.
  • deuterated 2-butanol these doses, especially when dissolved in standard volumes of microbicide gel (typically 4 ml), are very unlikely to elicit any inflammatory response at the site of delivery.
  • a dose range of about 3 to 30 mg of deuterated 2-butanol or IPA is delivered vaginally or rectally in an appropriate carrier medium, e.g., tenofovir placebo gel (i.e.
  • compositions, means and devices for rectal delivery include gels, as for vaginal delivery, and such dosage forms as suppositories, which may include the API in an appropriate suppository vehicle known in the art, with the i-AEM admixed therein or in a separate suppository compartment, coating or the like.
  • i-AEM for vaginal or rectal delivery concurrently with an API
  • i-AEM/API delivery which do not enhance transmission of disease causing agents, such as HIV.
  • Tenofovir placebo gel may be used with substitution of a small fraction of the glycerol with the preferred alcohol according to this invention. From a chemical standpoint the alcohol substitutes very well for glycerol in these systems, and ensures excellent compatibility and solubility of even higher doses of alcohols.
  • i-AEM's may be included in a single composition in order to permit differential kinetics of appearance in breath to be optimized.
  • more complex i-AEMs higher carbon atom content
  • the smaller, simpler i-AEM's are more quickly cleared from the breath. Understanding these kinetic considerations will permit those skilled in the art, based on the present disclosure, to select different i-AEMs and combinations of i-AEMs, in order to tailor detection kinetics in the breath for monitoring adherence with respect particular APIs and different modes of clinical use.
  • a mixture of different APIs in a delivery medium or substrate, wherein each API is associated with a different i-AEM may be utilized, and thereby, delivery of each API may be tracked by detection of distinct markers on the breath, even if/when a mixture is prepared for delivery of several different APIs/i-AEMs.
  • a gel composition used commercially for vaginal or rectal delivery of tenofovir is utilized.
  • This gel comprises 0 (placebo), 0.2, 1, or 5% tenofovir (Gilead Sciences, Inc., Foster City, Calif.) in a gel containing purified water, edentate disodium, citric acid, glycerin, propylparaben, methylparaben, and hydroxycellulose adjusted to pH 4 to 5. (Published Ahead of Print 10 Oct. 2011. 10.1128/AAC.00597-11. Antimicrob. Agents Chemother. 2012, 56(1):103.
  • microbicide or “microbicidally active” are generically applied to APIs for delivery by these routes, and while the intent is to include such compounds as tenofovir, emtricitabine, or combinations thereof (e.g., tenofovir disproxil fumarate, marketed by Gilead Sciences under the trade name VIREAD®), emtricitabine, and combinations of emtricitabine and tenofovir, e.g., TRUVADA®), the term is also intended to include any known or hereafter discovered reverse transcriptase inhibitors, protease inhibitors, other mode-of-action antiretroviral APIs and, indeed, any other API for which vaginal or rectal delivery is a known or desired route of medication administration (e.g., valium).
  • the microbicidal composition according to this invention includes an i-AEM and the microbicidally active compound is selected from the group consisting of marketed or investigational antiretroviral drugs used either solely or in combination to treat HIV infection, selected from the group consisting of:
  • the present invention contemplates means for admixture of the i-AEM at the site of delivery. This is achieved, for example, by maintaining the microbicidally active compound and the i-AEM in compartments in the drug delivery means such that they are not in contact with each other until delivered vaginally or rectally.
  • the API and i-AEM are maintained, prior to delivery, in separate barrels of a two-barreled syringe.
  • Alternate arrangements and embodiments to achieve a similar result include, for example, by including the i-AEM in (a) a Luer-lock tip which fits over the delivery means, e.g., a syringe, for the API in substrate; (b) in a slip-tip, either coaxially located, eccentrically located, or elongated, as in a catheter tip, which fits over the delivery means, e.g., a syringe, for the API in substrate.
  • the i-AEM is maintained in a softgel capsule which is broken on delivery, e.g., by impact with a plunger, pin or needle tip, or the like, thereby mixing the i-AEM with vehicle, microbicidally active compound or both, at the site of delivery.
  • the intact softgel containing the i-AEM could be delivered from the syringe along with the microbicidally active compound at the time of product use, and the softgel dissolves in the warm environment of the vagina.
  • the i-AEM is coated on a syringe applicator tip which admixes the i-AEM on delivery of the vehicle and the microbicidally active compound.
  • the Chemistry, Manufacturing and Controls (CMC) of a medication is modified to directly accommodate the i-AEM.
  • a tiny amount of glycerin is replaced with the i-AEM, such as deuterated 2-butanol or IPA.
  • i-AEM such as deuterated 2-butanol or IPA.
  • a polymeric drug delivery device provides controlled release of drug and i-AEM for intravaginal delivery over an extended period of time.
  • the drug/i-AEM delivery device is inserted into the vagina and can provide contraceptive protection, microbicidal protection, and delivery of the i-AEM.
  • the i-AEM By inclusion of the i-AEM, and confirming ongoing detection of i-EBM in the exhaled breath, clinicians can be assured that the drug delivery device is working correctly and has not been prematurely removed.
  • a gel or suppository device/composition is preferred.
  • the i-AEM may be admixed with the API and suppository vehicle, or the i-AEM may be in a separate compartment which is dissolved upon API/suppository delivery, thereby releasing the i-AEM for detection in the breath or for metabolism to generate the i-EBM.
  • transdermal medications and formulations exist and any of these may be used in combination with the i-AEMs as disclosed herein.
  • Ethosomes are the slight modification of well established drug carrier liposome. Ethosomes are lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentration and water. Ethosomes are soft vesicles made of phospholipids and ethanol (in higher quantity) and water.
  • ethosomes may vary from tens of nanometers (nm) to microns (p) ethosomes permeate through the skin layers more rapidly and possess significantly higher transdermal flux.” See also, for example, “ETHOSOMES: A NOVEL TOOL FOR TRANSDERMAL DRUG DELIVERY”, Rasheed et al., World Journal of Pharmaceutical Research, Volume 1, Issue 2, 59-71. Review Article ISSN 2277-7105. See also U.S. Pat. Nos. 5,716,638 and 5,540,934.
  • APIs with an i-AEM according to this invention is a preferred embodiment according to this invention for purposes of adherence using transdermally delivered medications.
  • modes and compositions for API/i-AEM delivery via the transdermal route those skilled in the art are directed to consider, e.g., Malakar et al., “Development and Evaluation of Microemulsions for Transdermal Delivery of Insulin”, ISRN Pharmaceutics, Volume 2011, Article ID 780150, 7 pages, doi:10.5402/2011/780150; Kalluri and Banga, Transdermal Delivery of Proteins, AAPS PharmSciTech, Vol. 12, No.
  • i-AEMs may be delivered by other modes, including, but not limited to, intravenously, intramuscularly, intraperitoneallly, intranasally, inhalationally, intraoccularly, while still producing i-EBMs detectable in the exhaled breath.
  • kinetics of i-EBM production, half-life, and other relevant considerations will come into play and appropriate modifications of compositions and times for breath monitoring will need to be adjusted accordingly.
  • certain products that are available commercially include compounds which could function as i-AEMs if they were to include a non-ordinary isotope according to this invention.
  • chlorobutanol is an alcohol that acts by increasing lipid solubility, and its antimicrobial activity is based on its ability to cross the bacterial lipid layer.
  • Chlorobutanol is a widely used, very effective preservative in many pharmaceuticals and cosmetic products, for example, injections, ointments, products for eyes, ears and nose, dental preparations, etc. It has antibacterial and antifungal properties. Chlorobutanol is typically used at a concentration of 0.5% where it lends long-term stability to multi-ingredient formulations. Phenylethanol is an antimicrobial, antiseptic, and disinfectant, which is used also as an aromatic essence and preservative in pharmaceutics and perfumery.
  • inclusion of at least a fraction of the total chlorobutanol or phenylethanol which is deuterated in such products which already include non-deuterated forms of these molecules provides a means for medication adherence monitoring by detecting the appropriate i-EBM produced in the breath.
  • SMART® Self Monitoring And Reporting Therapeutic
  • This medication comprises:
  • an i-EBM an Exhaled Breath Marker comprising at least one non-ordinary but stable isotope
  • the stable but non-ordinary isotope is selected from the group consisting of deuterium, or a stable but non-ordinary isotope of carbon, oxygen, nitrogen, or sulfur.
  • the i-AEM is selected from the group consisting of secondary and tertiary alcohols, and more preferably, the secondary or tertiary alcohol is a compound which is a Generally Recognized as Safe (GRAS) compound, or a direct food additive, or both.
  • GRAS Generally Recognized as Safe
  • the SMART® medication is preferably delivered in a dosage form selected from the group consisting of: a solid oral dosage form, (SODF), intravenously, transdermally, vaginally, rectally, intranasally, intraocularly, intramuscularly, inhalationally.
  • SODF solid oral dosage form
  • a SMART® device for detecting in a gas sample a molecule which is labeled with a non-ordinary isotope
  • the device comprises a means for stripping the gas sample of moisture and carbon dioxide, optionally a catalytic incinerator for converting the molecule to carbon dioxide and water, such that: (a) the isotope from the i-AEM is included in the water fraction, such that, following catalysis, isotopically labeled water is quantitated in the gas sample; (b) the isotope from the i-AEM is included in the carbon dioxide fraction, such that, following catalysis, isotopically labeled carbon dioxide is quantitated in the gas sample; or (c) both (a) and (b).
  • the device includes a means for separating i-EBMs in exhaled breath prior to catalysis and detection.
  • the system and method according to this aspect of the invention includes a method for medication adherence monitoring which comprises providing a SMART® medication to a subject and measuring in the exhaled breath of the subject at least one i-EBM utilizing a Type II SMART® device.
  • the method preferably includes monitoring kinetics of appearance of i-EBMs in the exhaled breath and, depending on the particular i-AEMs used and the route of administration, determining adherence characteristics for the given subject and medication.
  • monitoring is conducted from immediately to one hour, from one hour to several hours, or from several hours to several days after the SMART® medication is taken by the subject.
  • the system for medication adherence monitoring comprises:
  • an i-EBM an Exhaled Breath Marker comprising at least one non-ordinary but stable isotope
  • B Measuring in the exhaled breath of the subject an i-EBM utilizing a device which comprises a means for stripping the exhaled breath sample of moisture and carbon dioxide, optionally, a catalyst for converting the i-EBM to carbon dioxide and water, such that: (a) the isotope from the i-EBM is included in the water fraction, such that, following catalysis, isotopically labeled water is quantitated in the exhaled breath sample; (b) the isotope from the i-EBM is included in the carbon dioxide fraction, such that, following catalysis, isotopically labeled carbon dioxide is quantitated in the exhaled breath sample; or (c) both (a) and (b).
  • This patent disclosure enables novel and inventive methods, means and systems for reliably measuring acute, cumulative, chronic, and even randomly timed medication adherence monitoring within particular time windows relative to the time a SMART® medication is taken or should have been taken.
  • acute medication adherence monitoring known in the art can be analogized to a single measurement of blood glucose concentration testing in a diabetic, as compared to the HbA1C test for glycosylated hemoglobin, which provides an indication of glycemic control over a preceding time period. It furthermore significantly alleviates the burden on clinicians and subjects whose adherence is being monitored, by substantially expanding the period in which monitoring can reliably be conducted.
  • the medication adherence monitoring tools disclosed and enabled herein provide progressively greater technological capabilities that facilitate definitive measurement and monitoring of adherence on an acute (dose by dose), semi-chronic (1-2 days) and/or a chronic (preceding 3 to 14 days) basis with maximum patient convenience and system accuracy.
  • the SMART® system can be used to monitor adherence to drugs delivered via virtually any route, including but not limited to oral, i.v., transcutaneous, transdermal, intra-rectal, vaginal, i.p., inhalational, etc.
  • Oral medications represent the biggest market segment and understanding adherence to oral drugs will have the greatest impact on improving clinical trial and disease outcomes in the near future.
  • the table below is focused on adherence technologies that can be used to effectively monitor ingestion of any medication delivered within a solid oral dosage form (SODF), including capsules, hard tablets, sublingual (SL), and orally disintegrating tablets (ODTs).
  • SODF solid oral dosage form
  • ODTs orally disintegrating tablets
  • SMART ® Adherence System Type 1B Surface Type II: mid- Type 1A: Metal Oxide Sensor (MOS)- Acoustic Wave (SAW)- Infrared (mIR)- Feature of SMART ® based sensor engine based sensor engine based sensor engine Sensory Configuration mGC-MOS mGC-MOS Dual MOS SAW mGC-mIR Type of adherence Acute (pill Acute and Semi- Acute and Semi- Acute (pill Acute (pill by pill), by pill) chronic (preceding chronic (preceding by pill) Semi-chronic (preceding 1-2 days) 1-2 days) 1-2 days), and Chronic (preceding 3-14 days) Preferred Adherence- One simple (low Two simple (low One simple (low One simple (low One higher One cold isotopologues Enabling Marker boiling point) boiling point) boiling point) boiling point of simple (low boiling (AEM) direct food direct food direct food food flavorant point) direct food additive (e.g., additive
  • This aspect of the present invention provides an improved method, system, compositions of matter and apparatus for medication adherence monitoring which extends the window of time from medication ingestion to time for confirmation of medication adherence. This is achieved by (a) characterizing the kinetics of appearance and disappearance of Exhaled Drug Ingestion Markers (EDIMs) in the exhaled breath of subjects receiving medications which include selected Adherence Enabling Markers (AEMs).
  • EDIMs Exhaled Drug Ingestion Markers
  • AEMs Adherence Enabling Markers
  • the AEMs may themselves be the EDIMs or may be converted to the EBM (including EDIMs or EDEMs) in vivo via metabolism of the AEM.
  • a first AEM, AEM 1 which provides the ability to confirm adherence on an acute, dose by dose basis, by virtue of rapid appearance in and disappearance from the exhaled breath of subjects, in combination with a second AEM, AEM 2 , selected for its ability to confirm adherence over a longer time frame.
  • simple alcohols such as 2-butanol
  • AEM 1 Such markers are rapidly metabolized in vivo into simple ketones. The half-life for detection of the ketones is typically on the order of minutes to several hours, but generally less than, say, 5 hours.
  • AEM 2 in such embodiments, an AEM with a longer half-life in exhaled breath is selected.
  • Isopropyl alcohol, (IPA) is converted in vivo into acetone.
  • the half-life of acetone derived from IPA is on the order of about 6.5 hours.
  • only AEM 2 is included in the medication.
  • an AEM is selected which includes an non-radioactive, non-ordinary isotope, such that the lookback period may be significantly extended, due at least in part due to lower or almost non-existent background, and enhanced detection capabilities of the sensor and separation device utilized to confirm adherence.
  • the system for Acute Medication Adherence Monitoring (AMAM), the system according to this invention comprises a SMART® device for use in combination with at least one ordinary AEM or an i-AEM formulated in such a way that on a dose-by-dose basis, it can be definitively determined that the correct person has taken the correct dosage of the correct medication at the correct time.
  • AEM Acute Medication Adherence Monitoring
  • This is achieved by combining a Type I, Type II or Type III device with an AEM delivered for example in a softgel capsule or, for example, printed on an existing dosage form (in the case of an i-AEM) concurrent with delivery of the particular medication dosage being monitored.
  • the Type I-III device as described herein in sections 6.1-6.3, delivers definitive AMAM data (identify of the person by biometric capture, identity and concentration of EBM included in the exhaled breath) all within minutes of taking a particular medication dosage.
  • the AEM may, of course, be an AEM as described herein in section 7.1, or it may be an i-AEM, as described herein in section 7.2.
  • the device is preferably a Type II SMART® device, as described herein in section 6.2, and may be used to advantage including where only dose-by-dose AMAM is required.
  • a Type I or III device in combination with an AEM which has a long half-life for appearance of the EBM in the exhaled breath, or persistence of the EBM in the exhaled breath, is all that is required for IMAM and CMAM using ordinary AEMs.
  • Achieving a steady-state of medication delivery with a medication comprising one or more AEMs has predictable effects for purposes of EBM measurement in the exhaled breath. Deviations from the steady state EBM concentration are detected, and the subject may be queried or challenged with respect to adherence.
  • the ability to measure a marker in breath accurately for progressively longer periods of time is key. This can be accomplished in preliminary studies with a given individual or a population of individuals, and with a given AEM, to determine the half life in breath. Once if population PK has been established for a given AEM, that data may be stored on board, or used in a remote location, to analyze adherence for a given subject, and a preliminary phase for the given subject is not required.
  • 2-butanol is converted to 2-butanone within minutes of release of 2-butanol into the digestive system (i.e. following release of encapsulants or any other barriers implemented for containment of the AEM).
  • 2-Butanone has a relatively short half-life for appearance in the exhaled breath, and definitive medication adherence using 2-butanol alone is thus limited to a relatively short look-back period of a few minutes to, at most, several hours. Medication adherence thus would need to be confirmed in that relatively short time-window, and failure to test adherence in that time window means that such data may be lost altogether, even if the subject was perfectly adherent in taking the medication.
  • Using an AEM such as isopropanol provides a longer window for medication adherence monitoring.
  • Elevations in basal acetone exhalation due to ingestion of IPA as the AEM can be measured over at least one 6.5 hour half-life, or even two such half lives, but this requires measurement of the delta, that is change in acetone in exhaled breath and interference by endogenous acetone exhalation quickly becomes a confounding factor thereafter.
  • Use of more complex AEMs provide options for more extended medication adherence monitoring (IMAM and even CMAM).
  • a medication adherence monitoring system and method which comprises providing an i-SMART® medication or composition of matter, as described above (section 7.2), to a subject and using the device, as described above (section 6.2), to detect and quantitate a non-ordinary isotope in the exhaled breath of the subject.
  • the method is applied to medication adherence monitoring.
  • any device or method or system which utilizes a novel device as disclosed herein is included within the scope of this invention, including when in a field or utility unrelated to medication adherence monitoring.
  • the present invention permits minute amounts of i-AEMs to be used to generate i-EBMs which are readily detectable at the parts per billion and even at the parts per trillion level in exhaled breath.
  • i-AEMs and the i-SMART device facilitates monitoring adherence either immediately, (Acute Medication Adherence Monitoring, AMAM) several hours (Intermediate Medication Adherence Monitoring, IMAM) or even several days (Chronic Medication Adherence Monitoring, CMAM) after a particular medication dose including an i-AEM or i-API is taken or is applied or administered to a subject.
  • AMAM Acute Medication Adherence Monitoring
  • IMAM Intermediate Medication Adherence Monitoring
  • CMAM Chronic Medication Adherence Monitoring
  • Steady-state concentrations of AEMs are readily determined (for example using the SMART device according to this invention and providing careful oversight of medication delivery of medication on a regimen designed to reach steady state levels of AEMs) and related to steady-state EBM concentrations, and, therefore, based on whether a given subject at a given time exhibits appropriate concentrations of i-EBMs, it can be determined whether the subject has taken a particular dose at a particular time, and/or whether over time the subject has been adherent. Intervention can therefore be undertaken if any departure from the known, calculated and/or expected pharmacokinetics and pharmacodynamics is detected.
  • FIGS. 70-74 are instructive with respect to the power of the SMART® system which incorporates the use of a Type II SMART® device according to this invention in combination with an i-AEM.
  • a Type II SMART® device according to this invention in combination with an i-AEM.
  • the breath kinetics of exhaled d6-acetone following the ingestion of 100 mg of d8-isopropanol per diem for 5 days is readily followed, as each dose of d8-IPA is reflected in clearly distinguishable rises in d6-acetone.
  • Deviations from steady state levels of d6-acetone in the exhaled breath are detectable up to 65 hours after any given dose of d8-IPA, providing a significant window for confirming medication adherence, i.e. IMAM and CMAM.
  • the system includes computational features which are described in detail below.
  • the analytical and computational aspects of the invention are achieved by the device (Type I, II, III) of this invention providing quantitative measurements of EBMs, and, preferably in real time, comparing pharmacokinetic/pharmacodynamics parameters stored in memory with such EBM measurements.
  • Such computations represent a machine implemented software component of the system which, when integrated with the given SMART® device and AEM utilized, provides a unitary system for providing definitive medication adherence monitoring over at least dose-to-dose (AMAM) but also over multiple dosages and over multiple days (IMAM and CMAM).
  • this aspect of the invention provides a method and system for using an Adherence Enabling Marker, AEM x , (which may be an ordinary AEM or an i-AEM), or an Exhaled Drug Ingestion Marker X, EDIM x produced on ingestion or other form of administration or application (e.g. topical) of said AEM x .
  • AEM x Adherence Enabling Marker
  • EDIM x Exhaled Drug Ingestion Marker X
  • the method involves characterizing the pharmacokinetics of the particular EDIM x in the exhaled breath of a subject, Y, or in a population of subjects, Z.
  • the characterizing comprises measurement, to within defined confidence limits utilizing a SMART® detection device (or another device adequate to the task of appropriately defining such parameters for use in connection with the SMART® device or system as described herein) with sufficient accuracy to provide the parameters described herein below in Example 28.
  • a SMART® detection device or another device adequate to the task of appropriately defining such parameters for use in connection with the SMART® device or system as described herein
  • an apparatus for chronic medication adherence monitoring is provided as a SMART® device comprising:
  • the characterizing data for storage preferably includes measurement data, to within defined confidence limits, of:
  • Such a device is preferably configured to integrate the pharmacokinetic parameters defined above to provide an adherence lookback window, T AdhWindow , defined as the period of time required for the marker (EDIM) concentration in breath of the subject to decay from an initial value (C EDIMo ) to a lower concentration (C EDIM,Limit )
  • T AdhWindow t 1 / 2 ⁇ e 0.693 * ln ⁇ ( C EDIMo C EDIMLimit )
  • C EDIMo original or starting concentration of marker (EDIM) in breath at times equal to or greater than T MAX (i.e., C EDIMo ⁇ C MAX ) of said patient;
  • Such a device preferably exhibits a T AdhWindow between about 1 hour and about 400 hours, and includes a sensor with a LoD for the marker of between 1 part per trillion and 5 parts per billion.
  • the sensor is adapted to distinguish between ordinary and non-ordinary isotopes present in EDIMs and volatile compounds which otherwise would interfere with selective measurement of EDIMs in the exhaled breath.
  • an exhaled breath sample of a subject is obtained and the adherence of the subject to the required regimen is definitively determined, based on measurement of the concentration of the EDIM at the time said breath sample or samples are obtained.
  • the SMART® mGC is capable of detecting aldehydes, ketones, esters, ethers, and miscellaneous volatile organic compounds with, e.g., boiling points between 20° C. (68° F.) and 98° C. (208° F.)
  • FIG. 9 shows a typical output chromatogram detecting key constituents in the breath, including acetone and isoprene, with clear separation of 2-butanone, derived from ingestion of 2-butanol.
  • the SMART® device has the following specifications. These specifications are provided to ensure a complete and enabling written description of this invention, but those skilled in the art will appreciate that these specifications should not be interpreted as limiting on the invention.
  • the SMART® electronic controller resides on a single, multi-layer printed circuit board and contains, in a preferred embodiment, the following:
  • the controller firmware is written in C or the equivalent and supports a scripting language that allows high-level operating instructions to control the core peripheral and communications drivers, as well as signal processing.
  • the specific sequencing of the SMART GC pumps, valves, heaters, fan, and other peripherals is determined by encrypted, high-level script commands stored on the USB memory stick.
  • Patients include those for whom a clinician would like to analyze gaseous samples (e.g., human breath) for suitable organic molecules of clinical interest (e.g., ingestion of 2-butanol as an AEM).
  • gaseous samples e.g., human breath
  • suitable organic molecules of clinical interest e.g., ingestion of 2-butanol as an AEM
  • the SMART® mGC is intended to be used in a hospital, clinical laboratory, sub-acute care facility, physician's office, or in the home setting with or without supervision of a qualified individual.
  • the SMART® mGC is not in contact, direct or indirect, with the patient, except for the disposable mouthpiece.
  • the patient only exhales into the mouthpiece of the device, (straw) 130 .
  • the straw/mouthpiece 130 in one embodiment is made of ProFax SR 549M, a polypropylene copolymer, or Marlex®, a high-density polyethylene (HDPE).
  • the mouthpiece 130 is commercially available.
  • Type I of the SMART® device detects a wide variety of volatile organic compounds (VOCs), including but not limited to alcohols, aldehydes, ketones, esters, and ethers in a qualitative, semi-quantitative, and/or quantitative manner.
  • VOCs volatile organic compounds
  • the ketone, 2-butanone was selected as a prototypical VOC for detailed device testing according to Clinical and Laboratory Standards Institute (CLSI) protocols.
  • CLSI Clinical and Laboratory Standards Institute
  • a desktop gas chromatograph (GC), the Hewlett Packard Gas Chromatograph Model 5890A was used as the predicate device.
  • the mGC is operated by a trained individual, and can be used in the health care, clinical laboratory, or home settings.
  • the SMART® mGC device is intended to be used by lay people (or, of course, clinications), most frequently in their homes, and will definitively document and report, in real-time, adherence to medications in the clinical trial or disease management settings.
  • the mGC used in the SMART® Adherence System was designed to reliably measure e.g. 2-butanone in human breath after ingestion of SMART® drugs which have 2-butanol, a 2° alcohol that is designated by the FDA as a food additive (generally recognized as safe [GRAS]), incorporated into the dosage form containing the active pharmaceutical ingredient (API).
  • the ketone, 2-butanone termed the exhaled drug ingestion marker (EDIM), rapidly appears in breath after ingestion of the SMART® drug containing 2-butanol, due to its efficient enzymatic oxidation by alcohol dehydrogenase (ADH), primarily via the ⁇ ADH isoform.
  • EDIM exhaled drug ingestion marker
  • ADH alcohol dehydrogenase
  • the 2-butanol is incorporated into a SMART medication in a manner that has minimal-to-no impact on the chemistry, manufacturing and controls (CMC) of the API, has no impact on the bioavailability of the API, and does not introduce any extra steps in the clinical trial material (CTM) handling process.
  • CMC chemistry, manufacturing and controls
  • the formulation approaches used to incorporate the AEM, 2-butanol, into the API medication form e.g., hard gel capsule, powder, or soft gel containing 2-butanol
  • Licaps® capsules are two-piece (cap and body) gelatin capsules that can be specially sealed using a 50% v :50% v ethanol and water mixture to fuse the gelatin edges for secure containment of liquids. Study capsules were used within 24 hours of preparation.
  • the soft gelatin 2-butanol formulation was placed in an opaque, (e.g., white) size 0 Licaps® capsule.
  • the ethanol formulation was sealed inside an opaque size 4 Licaps® capsule and overencapsulated in a sealed, opaque size 0 Licaps® capsule (capsule in capsule configuration).
  • the study capsules were used within 5 days of packaging by a certified pharmacy (e.g., Westlab Pharmacy, Gainesville, Fla.) according to the randomization schedule.
  • Each SMART® device had a complete 2-butanone calibration check (0, 10, 30, 100, 300, and 1000 ppb 2-butanone standards in breath) at the beginning and end of the study, whereas a two point 2-butanone calibration check (0, 10, and 300 ppb 2-butanone standards in breath) was done prior to first use on any given study day unless noted otherwise in a protocol. Calibration data was tracked and recorded throughout the study. 2-Butanone is detected by the SMART® Device at a retention time of 100 seconds in human breath and causes a concentration-dependent increase in device response. Data transmission occurred using a wireless router.
  • HIPAA-compliant servers including but not limited to: raw signal data, breath chromatogram, yes/no ingestion event assessment generated from the peak-detection algorithm, photograph of study participant's face for biometric authentication, and SMART® Device operating conditions.
  • the study design consisted of 50 study subjects, each of whom received all four formulations (designated as formulations 1, 2, 3, and 4) over four study visits, each visit consisting of breath sampling intervals at baseline (0 min: prior to swallowing the capsule) and 10, 20, 30, 45 and 60 minutes post-ingestion.
  • Each study subject was randomized to a specific device for the duration of the study (10 devices; 5 study subjects per device) and randomized to receive all 4 formulations which were self-administered under the supervision of a nurse (directly observed ingestion of the study capsule) over 4 study visits with at least 1 day between visits.
  • This design is consistent with a traditional pharmacokinetic (PK)-type four period crossover study that assumes no carryover (i.e., sequence) effect due to adequate separation of the dosing periods (in this case, one day separation).
  • PK pharmacokinetic
  • Clinical Study 1 was to define the optimal operating configuration of the SMART® System using hard gelatin study capsules containing 2-butanol.
  • the primary outcome of Study 1 was to determine the optimal study capsule formulation (dose of 2-butanol and addition of other ingredients such as flavorants) and the breath kinetics of 2-butanone.
  • the outcome measure was 2-butanone concentration (in ppb) recorded repeatedly at each time point during the sampling interval.
  • the dependent variable for analysis was the change in 2-butanone concentration from baseline (Time 0).
  • the change in 2-butanone concentration from baseline (“delta over baseline”) provided a statistical adjustment for the potential that some subjects may have a recorded non-zero 2-butanone concentration at Time 0.
  • Additional analyses e.g., exploratory covariate analyses in main effects model) that considered the concomitant effects of demographic characteristics (e.g., age, body mass index [BMI], ethnicity, race, gender) and other factors such as the time since last meal were conducted. Collectively, all of these analyses were considered for the determination of the best candidate for study capsule formulation for Clinical Study 2.
  • demographic characteristics e.g., age, body mass index [BMI], ethnicity, race, gender
  • Study participant factors including but not limited to the following were analyzed for impact on results (references to Figure nos): 16 a Age; 16 b Gender; 16 c Ethnicity; 16 d Body Mass Index (BMI); 16 e Time From Last Meal; 16 f Alcohol Use; 16 g Tobacco Use; none of these factors appeared to be confounding factors (see below).
  • FIG. 18 g shows the 2-butanone breath concentration-mGC response relationships by device across the four AEM formulations; relationship between 2-butanone concentration and mGC response is curvilinear (i.e., square root function), but is highly linear in regions, including lower concentrations (0-100 ppb; see next slide) and higher (300-3000 ppb) concentrations relevant to the doses of 2-butanol ingested.
  • excellent stability over time ( ⁇ 5% variation) with calibration checks was noted.
  • SMART ® Devices Retention Time Shifts Retention Time (sec) Out of Range Within Range Values Values Number % 95- % Device Breath ⁇ 95 >105 Total ⁇ 105 Total ⁇ # Samples sec sec Total Device sec Device 212-01 114 0 0 0 0.0 114 100.0 212-03 6 2 0 2 33.3 4 66.7 301-01 120 0 0 0 0.0 120 100.0 301-03 120 60 0 60 50.0 60 50.0 301-06 120 4 0 4 3.3 116 96.7 301-07 120 0 0 0 0.0 120 100.0 301-09 120 23 0 23 19.2 97 80.8 301-10 126 0 0 0 0.0 126 100.0 301-14 96 0 0 0 0.0 96 100.0 301-16 119 0 0 0 0.0 119 100.0 302-06 138 0 0 0.0 0.0 138 100.0 TOTAL 1199 89 0 89 7.4 1110 92.6
  • the study was designed to determine the sensitivity, specificity, and accuracy of the SMART® System using hard gelatin study capsules containing 2-butanol.
  • the primary study objective was to determine the diagnostic accuracy of the SMART® Breath Monitoring System in distinguishing between the ingestion of study capsules containing 2-butanol versus placebo capsules containing the same amount of ethanol instead of 2-butanol.
  • the associated ingredients i.e., vanillin, DL-menthol, and PEG-400), were the same for both study capsule formulations.
  • a single formulation of the study capsule namely Formulation 4 (i.e., 2-butanol [40 mg], vanillin [10 mg], DL-menthol [1.4 mg], and PEG-400 [18.6 mg]) was studied; each study subject was randomly assigned to ingest two types of capsules, namely a capsule containing 2-butanol [SMART capsule], and a capsule containing the same mass of ethanol and associated excipients as that used for the SMART capsule (placebo capsule).
  • Formulation 4 i.e., 2-butanol [40 mg], vanillin [10 mg], DL-menthol [1.4 mg], and PEG-400 [18.6 mg]
  • Clinical Study 2 contained a total of 180 study visits.
  • Each study subject was randomized to one 1 of 30 SMART® Devices for the duration of the study. Breath samples were obtained at baseline (pre-ingestion) and at 10, 20, and 30 minutes after ingesting the study capsule.
  • the sample size, the optimal formulation, and timing of breath sampling used in Clinical Study 2 were determined based on the analysis of Clinical Study 1 results. Since the post-baseline 2-butanone breath concentration levels in study subjects who ingested the placebo capsule were observed to be close to zero (below the limit of detection) and the breath concentrations in study subjects who ingested the hard gelatin study capsule containing 2-butanol were well above 5 ppb, the difference in proportions of study subjects above this and even higher thresholds between the 2-butanol study capsule and placebo study capsule was quite large. This study enrolled 30 completed subjects to provide a sound framework for the estimation of normal distribution-based statistics.
  • ROC curves plots of Se versus 1-Sp were used to summarize the diagnostic performance of the SMART® System at 10, 20, and 30 minutes after study capsule ingestion using an automated detection algorithm (software) and an expert manual reader.
  • sensitivity/specificity analysis used 2 ⁇ 2 tables where the relative sensitivity/specificity of the SMART® System was assessed at various concentration thresholds.
  • the optimal breath sampling time after ingesting the capsule containing the AEM formulation (2-butanol) was 20 to 30 min where accuracies were approximately 95% and higher.
  • the SMART® Adherence System is highly accurate.
  • Clinical Study 3 designed on the basis of the results from Clinical Studies 1 and 2, is entitled, Clinical Study to Determine the Optimal Configuration of the SMART® Breath Monitoring System Using Soft Gelatin SMART® Capsules (see also Clinical Study 4 below), was conducted to determine the optimal configuration of the SMART® Breath Monitoring System using soft gelatin study capsules containing 2-butanol.
  • the goals of this study were: 1) to establish the optimal cutoff 2-butanone breath concentration (e.g., increase of 5 ppb above baseline values) using Receiver Operating Characteristics (ROC) curves analysis, 2) to determine the SMART® Breath Monitoring System sensitivity, specificity, and accuracy at the optimal 2-butanone cutoff breath concentration, 3) to determine the range of optimal breath sampling time(s) (i.e., 20, 30, 40, 60, and 90 minutes) following 2-butanol study capsule ingestion, and 4) to establish the duration of 2-butanone persistence in breath.
  • ROC Receiver Operating Characteristics
  • a single formulation of the soft gelatin study capsule (i.e., 2-butanol [40 mg], vanillin [10 mg], DL-menthol [1.4 mg], and PEG-400 [18.6 mg]) was studied.
  • Each subject was randomly assigned to ingest two types of capsule formulations over 2 subject visits: 1) a capsule containing 2-butanol (SMART® Capsule); and 2) a placebo capsule containing ethanol.
  • the placebo capsule contained the same mass of ethanol and associated excipients as used in the 2-butanol capsule.
  • Ingestion of a capsule at each subject visit was verified through direct observation (i.e., directly observed therapy [DOT]) by the Clinical Research Coordinator(s).
  • DOT directly observed therapy
  • sample size The sample size, the optimal formulation, and the timing of breath sampling were determined based on the analysis of Clinical Study 1 results of hard gelatin SMART® Capsules.
  • the outcome measure was 2-butanone concentration (in ppb) recorded repeatedly at each time point during the sampling interval.
  • the dependent variable was the change in 2-butanone breath concentration from baseline (Time 0) values.
  • the change in 2-butanone concentration from baseline (“delta over baseline”) provided a statistical adjustment for the potential that some subjects may have a recorded non-zero 2-butanone concentration at Time 0.
  • Performance metrics of the SMART® Breath Monitoring System were based on Receiver Operating Characteristic (ROC) curves analysis, including 2-butanone cutoff determination (e.g., 5 ppb rise above baseline values), sensitivity/specificity analysis, and accuracy determination endpoints. Analysis followed the guidance from the Clinical and Laboratory Standards Institute (CLSI) EP24-A2, entitled “Assessment of the Diagnostic Accuracy of Laboratory Tests Using Receiver Operating Characteristic Curves”.
  • CCSI Clinical and Laboratory Standards Institute
  • ROC curves plots of Se versus 1-Sp; and plots of cutoff concentrations versus Se and Sp were used to summarize the diagnostic performance of the SMART® System at 20, 30, 40, 60, and 90 minutes after capsule ingestion at a single cutoff 2-butanone breath concentration (e.g., 5 ppb rise above baseline values), using an automated detection algorithm (software) and the manual mGC reader.
  • the SMART Adherence System using softgels to deliver the AEM (2-butanol) is highly accurate, but requires longer breath sampling times to do so.
  • the purpose of this study was to validate the usability of the SMART® Device and its accompanying user documentation.
  • the study objectives were to: 1) demonstrate that the SMART® Device can be set up and used by representative users under simulated use conditions without producing patterns of failures that could result in a negative impact or injury to themselves, 2) verify that the device documentation and training provided as part of this study are effective, 3). ensure that the potential use-related safety issues associated with using the device were adequately mitigated, and 4) verify whether the validation success criteria were met.
  • test moderator recorded completion rates and noted positive and negative comments, usability issues, errors, and number of times subjects required assistance to use the device appropriately. Following the completion of all tasks, the moderator conducted a separate, in-depth interview to gather more detailed understanding of any observed use errors, usability problems, and near misses.
  • Xhale Smart analyzed any failures uncovered in this testing and updated the risk analysis.
  • the follow-up risk analysis used the same approach that Xhale Smart took in the course of its prior risk management assessments, leading to the final disposition of use errors and usability issues as acceptable or not.
  • the failures were described, as well as whether or not failures that occurred were associated with the design of the device, its labeling or documentation system and the extent of the association.
  • the analysis of residual risk determined if design modifications were indicated or if not, the analysis demonstrated the impossibility or impracticality of reducing these risks further and that the residual risk was outweighed by the benefits offered by the device. If design modifications were indicated, and were significant, they were implemented and validated.
  • Type 1-based SMART system was found to be not only patient friendly in terms of usability across a wide range of disease states, but its performance was also favorable across a wide range of subject factors, including age, gender, race, body mass index (BMI), disease conditions, and time of food ingestion, and even in populations enriched with subjects who chronically consumed alcohol and/or used tobacco products.
  • BMI body mass index
  • VOCs typically associated with the use of construction materials
  • the SMART® mGC system uses a baseline breath sample to measure background concentrations of 2-butanone concentrations in breath, 2) the equilibration between ambient concentrations of 2-butanone levels in the air and those in the blood of humans occur relatively slowly (e.g., hours), 4,5 and 3) much higher levels of 2-butanone are typically generated in breath, relative to those found in homes with new construction, following ingestion of AEM, 2-butanol.
  • the SMART® miniature gas chromatograph measures the concentration of 2-butanone in exhaled breath following the ingestion of the AEM, 2-butanol. Therefore, specific volatile organic compounds (VOCs), previously identified in a previous study (internal Xhale Document DR-0026), which have retention times on the SMART mGC similar to 2-butanone (i.e., 100 ⁇ 5 seconds) have the potential to interfere with the performance of the SMART® mGC Adherence System.
  • VOCs volatile organic compounds
  • VOCs Materials used in home construction including paints, sealants, synthetic or laminated flooring, carpeting and other furnishings, may release VOCs in the home environment.
  • the highest levels (i.e., worst case scenario) of VOCs in indoor home environments are found during the months immediately following the home construction. 1,2,3
  • 2-butanone or other VOCs with retention times similar to 2-butanone on the SMART® mGC i.e., 100 ⁇ 5 seconds from that of 2-butanone
  • SMART® mGCs Four SMART® mGCs were used for this study to detect of 2-butanone indoor air of new homes.
  • the SMART® mGCs with serial numbers 100113060024, 100113060028, 100113060033, and 100113060047 were used in the study. These units are identified as 600-24, 600-28, 600-33, and 600-47, respectively, in this report.
  • Tedlar gas sampling bags used for standard preparation were purchased from SKC Inc. (Eighty Four, Pa.). A single 10.0 mL Hamilton (Reno, Nev.) gas-tight syringe (Model Number 1010) was used for the dilution of the 2-butanone gas standard.
  • GC/MS samples were collected on stainless steel Tenax TA sample tubes (Model # C1-AXXX-5003) manufactured by Markes International Incorporated (Cincinnati, Ohio) using a 100 mL Hamilton (Reno, Nev.) gas-tight syringe (Model #1100).
  • the homes used for this study were new-constructions (never occupied), and contained similar materials and fixtures (e.g., painted, flooring, cabinets) that had been installed within 30 days of sample collection.
  • Homes 1 and 2 were located in the same housing development and were manufactured by the same builder.
  • Homes 3 and 4 were located in same neighborhood, and Home 5 was located in a separate development. No information was collected to identify the specific materials used in construction.
  • SMART® mGC data was automatically collected on the device and subsequently transmitted to and stored on the Xhale Inc. secured servers.
  • First derivative plots for the standards and breath samples collected by the SMART® mGCs were imported into Microsoft Excel® to determine 2-butanone peak height and retention times.
  • GC/MS data was collected on the instrument's control computer and are stored on compact disk.
  • GC/MS chromatograms were analyzed using Thermo Scientific Xcaliber® software. VOCs were identified by matching collected mass spectra to corresponding library spectra in the NIST database.
  • potential interferents were defined as those VOCs that generate a measured 2-butanone response of ⁇ 5 ppb on the SMART® mGC. Data are expressed as mean ⁇ standard deviation.
  • the effect of new home environments on the 2-butanone concentrations measured in air by the SMART® mGC were evaluated using a two-way analysis of variance (ANOVA) (factors: home and device) (SigmaPlot 11.2, Systat Software, Inc., San Jose, Calif.). P values ⁇ 0.05 were considered statistically significant.
  • VOCs identified by the GC/MS in the homes sampled in this study are consistent with the low levels of VOCs commonly found in construction materials: 1,3-dimethylcyclohexane, 1-butanol, 1-methoxy-2-propanol, 1-pentanol, 1-pentene, 2,2-dimethylhexane, 2-butanone, 2-methyl-1-propanol, 2-methylheptane, 2-methylhexane, 2-methylpentane, 2-propoxyethanol, 3-methyheptane, 3-methylhexane, acetone, acrylonitrile, benzene, butanal, butyric acid, chloroform, cyclohexane, cyclopentane, ethanol, ethyl acetate, hexanal, hexane, isobutyl alcohol, isobutyl ether, isoprene, isopropanol, methyl vinyl ketone, methylcyclohexane,
  • the 2-butanone levels measured by the SMART® mGCs in the indoor air of five new construction homes ranged between 5.9 and 16.5 ppb.
  • the indoor air 2-butanone level determined in this study may contribute to the measured breath 2-butanone concentrations of home residents.
  • the risk of the new home environment causing inaccurate (i.e., false positive or false negative) results readying by the SMART® Adherence System is minimal for at least 3 reasons.
  • the SMART® mGC system is capable of using a baseline breath sample to measure background concentrations of 2-butanone concentrations in breath, Second, the equilibration between ambient concentrations of 2-butanone levels in the air and those in the blood of humans occur relatively slowly (e.g., hours), 4,5
  • Cigarette smoke is known to contain a large number of volatile organic compounds (VOCs), many present at high concentrations.
  • VOCs volatile organic compounds
  • Compounds introduced in human breath as a result of smoking events e.g., 2-butanone, ethyl acetate
  • mGC mini-gas chromatographs
  • Cigarette smoke contains over 4400 compounds including 2-butanone.
  • 2,3 Volatile organic compounds (VOCs) present in cigarette smoke i.e., 2-butanone, ethyl acetate
  • VOCs Volatile organic compounds
  • the purpose of this study was to screen VOCs associated with smoking two widely used cigarette brands (i.e., Newport and Marlboro) that could potentially interfere with SMART® mGC function.
  • the kinetics (time-dependent behavior) of these potential interferents in human breath were evaluated in support of a plan to understand and mitigate potential risks of smoking causing detrimental effects on SMART® mGC System performance.
  • mGCs Five Xhale mGCs were used for this study. One mGC device was used per person, and the instruments were randomly assigned to each individual. The mGCs used had serial numbers 100112120003, 100113030039, 100113030041, 100113030043, and 100113030044. These units will be identified as 212-03, 303-39, 303-41, 303-43, and 303-44 in this report, respectively.
  • Tedlar gas sampling bags were purchased from SKC Inc. (Eighty Four, Pa.). Each bag was used only once. A single 10.0 mL Hamilton gas-tight syringe (Model Number 1010, Fisher Scientific part number 14-815-183) was used for the dilution of the 2-butanone gas standard.
  • 2-Butanone standards were created by diluting appropriate aliquots of a primary NIST certified dry nitrogen 10 ppm 2-butanone gas standard (Matheson Tri-Gas MICRO MAT 58 Item Number GMT2677977TH, Lot Number 109-26-07599, Expiration Date 5/11/14) into 1-L Tedlar bags containing blank breath.
  • the two cigarette brands used for this study (Marlboro and Newport) were purchased from a Clarx Supermarket in Gainesville Fla. on May 3, 2013. These brands were chosen based on cigarette brand preferences reported for the general smoking population and represent the two most popular brands of cigarettes in the United States.4
  • Exclusion criterion Subjects with severe lung disease (e.g., advanced chronic obstructive pulmonary disease, COPD) or those physically unable to provide breath samples into the SMART® mGC.
  • severe lung disease e.g., advanced chronic obstructive pulmonary disease, COPD
  • COPD chronic obstructive pulmonary disease
  • Each subject participated in the study for two (2) days.
  • the study volunteers were randomized to smoke a single cigarette from each of the two (2) mentioned brands (i.e., Marlboro and Newport).
  • a minimum of one (1) day was allowed between smoking the different cigarette brands.
  • No replicate of a given cigarette brand was carried out for a given subject.
  • Participants were allowed food products and beverages ad libitum but were instructed not to take anything by mouth for 15 minutes prior to collection of the first breath sample and to refrain from smoking for a minimum of one (1) hour prior to providing the first breath sample.
  • the study subjects had a minimum of one (1) day wait period between smoking the different cigarette brands, after which the study protocol was repeated for each individual with the remaining cigarette brand used in this interference screen (i.e., either Marlboro or Newport). During the wait period between the two study dates, the subjects were not given any restrictions with regard to their regular smoking habits.
  • the SMART® Adherence System is used to confirm ingestion of medication that is associated with the AEM, 2-butanol. This is accomplished by evaluating the change in breath 2-butanone concentrations from baseline after ingestion of 2-butanol. Cigarette smoking introduces a large number of VOCs in the breath of smokers.
  • the indoor air concentrations of 2-butanone were measured using the SMART mGCs in each home, on two separate occasions (one air sample per home visit). The mean 2-butanone levels were measured to be below the LoD ( ⁇ 5 ppb) in four of the five homes tested (Homes 1, 2, 3 and 5). Indoor air from Home 4 had the highest mean concentration of 2-butanone measured by the SMART® mGC and was 6.9 ppb, which is slightly higher than the LoD.
  • the baseline 2-butanone breath concentrations for participants SA-2 and SA-4 were below the LoD for both study visits.
  • the remaining study subjects showed large interpersonal variability in their baseline breath (i.e. prior to smoking the study cigarette) 2-butanone concentrations measured during the two home visits.
  • the baseline breath 2-butanone concentrations measured for SA-1 were 5 ppb during the first home visit and 254.7 ppb during the second.
  • SA-3 had a relatively high baseline breath 2-butanone concentration of 179.3 ppb during the first home visit, and 5 ppb during the second visit.
  • both SA-2 and SA-3 had elevated 2-butanone levels in their baseline breath on the day that they were given the Marlboro study cigarette, these concentrations were measured prior to smoking, and therefor are independent of the cigarette brand used in this study.
  • SMART® mGC 1 st derivative chromatograms show that cigarette smoke introduced breath VOCs with retention times on the SMART® mGC outside the interference window for 2-butanone (i.e., 100 ⁇ 5 seconds).
  • the SMART® mGC can discriminate between 2-butanone and VOCs with retention times greater than ⁇ 5 seconds from 2-butanone. These VOCs are outside the interference window, and do not interfere with the measurement of 2-butanone by the SMART® mGC.
  • VOCs present in the home environments had minimal effects on the 2-butanone concentration measured by the SMART® mGC. Only one of the five (1/5) homes resulted in mean indoor air 2-butanone concentrations above 5 ppb (mean concentration 6.9 ppb).
  • the presence of smoking-derived VOCs, and the kinetics of potential interferents in human breath associated with smoking events was evaluated in study subjects following use of Newport and Marlboro cigarettes. Smoking did not result in a clinically significant change (i.e., 5 ppb) from the baseline breath 2-butanone concentration on the SMART® mGC.
  • the current study screened specific consumer products, based on knowledge of their flavorant content, that could potentially interfere with the performance of the 2-butanone-based SMART® mini-gas chromatographs (mGC) System. This could occur by the consumer products providing an additional breath source of 2-butanone and/or of a non-2-butanone VOC with a SMART® mGC retention time similar to that of 2-butanone (100 ⁇ 5 sec).
  • the breath marker, 2-butanone is generated and detected (as change from baseline concentration) in human breath by the mGC after ingesting the AEM, 2-butanol.
  • Natural and synthetic flavorants present in consumer products may contain volatile organic compounds (VOCs) that can interfere with the performance of the 2-butanone-based SMART® mGC System. This could occur by the consumer products providing an additional breath source of 2-butanone and/or of a non-2-butanone VOC with a SMART® mGC retention time similar to that of 2-butanone (100 ⁇ 5 sec).
  • VOCs volatile organic compounds
  • the breath marker, 2-butanone is generated and detected (as change from baseline concentration) in human breath by the mGC after ingesting the AEM, 2-butanol.
  • SMART® mGCs from Xhale Inc. were used for this study.
  • One mGC device was used per person, and the instruments were randomly assigned to each individual.
  • the mGCs used had serial numbers 100112120001, 100112120003, 100113010007, and 100113010010. These units are identified as 212-01, 212-03, 301-07, and 301-10 in this report.
  • Tedlar gas sampling bags were purchased from SKC Inc. (Eighty Four, Pa.). Each bag was used only once. A single 10.0 mL Hamilton gas-tight syringe (Model Number 1010, Fisher Scientific part number 14-815-183) was used for the dilution of the 2-butanone gas standard.
  • 2-Butanone standards were created by diluting a primary NIST certified 10 ppm 2-butanone gas standard in dry nitrogen (Matheson Tri-Gas MICRO MAT 58 Item Number GMT2677977TH, Lot Number 109-26-07599, Expiration Date 5/11/14) into 1-L Tedlar bags containing blank breath.
  • the 15 consumer products selected for this study were all purchased from Clarx Supermarket in Gainesville Fla. the day before the study began (except for the Arcor Strawberry Buds candy, which was supplied by the study sponsor).
  • Breath samples were analyzed using the individual mGCs from four (4) adult study participants. The participants were instructed not to consume alcoholic beverages the day before the study, and not to eat, drink or smoke for 15 minutes prior to the beginning of the study.
  • the first phase screened 15 consumer products, to evaluate interference of mouth VOCs with the SMART® mGC immediately after, and 10 minutes following each product.
  • a baseline 2-butanone level was established for each subject by analyzing a “blank” breath sample 10 minutes before placing each consumer product in their mouth.
  • the subjects kept each consumer product in their mouth and mixed it around for 30 seconds, and then expectorated.
  • T 0 min
  • Delta baseline was calculated as the mean change from baseline 2-butanone (mGC SMART® 2-butanone concentration after consumer product—mGC SMART® 2-butanone at baseline) in parts per billion (ppb). 2-butanone concentrations below the LoD (i.e., 5 ppb) were considered zero for the delta baseline calculations. Descriptive statistics of the data were calculated using SigmaPlot 11.2, Systat Software, Inc. (San Jose, Calif.).
  • the SMART® Adherence System is used to confirm ingestion of a medication that is associated with the AEM, 2-butanol. This is accomplished by evaluating the change in breath 2-butanone concentrations from baseline levels, after ingestion of the AEM, 2-butanol. Eating/drinking foods, and/or using healthcare products that contain either 2-butanone, or a non-2-butanone VOC with a retention time similar to 2-butanone on the SMART® mGC (100 ⁇ 5 seconds) may result in inaccurate results (i.e., false positive or false negative results).
  • VOCs methyl acrylate, ethyl acetate, 3-butene-1-ol and cyclohexane
  • 2-butanone One of these VOCs, ethyl acetate, elutes within 1 second of 2-butanone, and is a flavoring agent found in food or health products. This acetate is naturally occurring in fruits, 3 and it is a direct food additive (40 CFR 180.910) used as fruit essence in food items.
  • the interference screen of consumer goods was done using products known to contain natural or synthetic flavoring agents that would be likely to interfere with the SMART® mGC System.
  • breath VOCs e.g., ethanol
  • the second phase of the study was done to determine if a 15 minute wait after consumer products are expelled from the mouth, is adequate for the measured 2-butanone levels to return to baseline.
  • the concentrations of 2-butanone in the baseline breath, and 15 minutes post-consumer product were determined.
  • the consumer products do not produce a clinically significant interference on the SMART® mGC 15 minutes after they are eliminated from the mouth.
  • the persistence of the interfering breath VOCs i.e., apparent 2-butanone concentrations >5 ppb above baseline
  • the second phase of the study indicates that 2-butanone response on the SMART® mGC returns to baseline within 15 minutes after expectorating the consumer products from the mouth.
  • Food, drink, or other consumer products may contain VOCs that have the potential to adversely impact the performance of the 2-butanone-based SMART® Type 1 (mGC) System. This could occur by introducing additional 2-butanone and/or non-2-butanone VOCs to human breath that have a similar SMART® mGC retention time to 2-butanone (100 ⁇ 5 sec). However, within 15 minutes from the time the products are eliminated from the mouth, the breath 2-butanone concentration response on the SMART® mGC returns to baseline (pre-consumer product).
  • mGC 2-butanone-based SMART® Type 1
  • Ethanol is a volatile organic compound (VOC) that is typically found in the exhaled breath in trace amounts (low parts per billion or ppb), as a result of endogenous processes (e.g., sugar metabolism in the colon).
  • VOC volatile organic compound
  • endogenous processes e.g., sugar metabolism in the colon.
  • endogenous ethanol present in the breath matrix did not interfere with the ability of the SMART® mGC to measure 2-butanone, the breath marker used in the SMART® System.
  • Ingesting drink products containing ethanol may increase the concentrations of breath ethanol to levels that are several orders of magnitudes greater than endogenous levels.
  • BAC blood alcohol content
  • BrAC breath alcohol concentration
  • the objective of this study was to evaluate the potential of elevated ethanol concentrations to interfere with the ability of the SMART® mGC to measure 2-butanone in human breath.
  • the mGC response i.e., 2-butanone peak height
  • 2-butanone retention time were measured in breath samples “spiked” with 50 ppb 2-butanone in the presence of progressively increasing concentrations of ethanol (0, 30,000, 100,000, and 300,000 ppb).
  • the 50 ppb concentration of 2-butanone was selected for the interference test because 1) it reflects a typical lower end concentration of 2-butanone that appears in breath after ingestion of a typical dose of 2-butanol (i.e., 20 and 40 mg) (Example 3: Clinical Study 1-3), 2) it is close to the anticipated yes/no cutoff which will be used to determine medication adherence, and 3) based on prior device validation testing, it can be reliably used to measure a potential decrease in the mGC response.
  • Interference testing was conducted using four (4) SMART® mGCs from Xhale Inc.
  • the mGCs used had serial numbers 100113010009, 100113010010, 100113010011, and 100113010015, and are identified as 10009, 10010, 10011, and 10015, respectively, in this report.
  • Tedlar gas sampling bags were purchased from SKC Inc. (Eighty Four, Pa.). Each bag was used only once. A single 10.0 mL Hamilton gas-tight syringe (Model Number 1010, Fisher Scientific part number 14-815-183) was used for the dilution of the 2-butanone gas standard.
  • the 200 proof anhydrous (>99.5%) ethanol used in this study was purchased from Sigma-Aldrich (part number 459835-100ML, Batch 54096BM). This neat standard was diluted in deionized water (DI) to make working solutions for injection into the Tedlar bags containing blank breath spiked with 2-butanone.
  • DI deionized water
  • 2-Butanone standards were created by diluting a primary NIST certified 10 ppm 2-butanone gas standard in dry nitrogen (Matheson Tri-Gas MICRO MAT 58 Item Number GMT2677977TH, Lot Number 109-26-07599, Expiration Date 5/11/14) into 1-L Tedlar bags containing blank breath.
  • the four SMART® mGCs used in this study were calibrated at the Nanoscale Research Facility of the University of Florida. Dilution of a NIST-certified 2-butanone gas standard into Tedlar gas sampling bags containing a blank breath sample was performed to create a calibration curve at four concentrations (0, 10, 25, and 50 ppb). Standard curves for 2-butanone were created on each of the four SMART® mGC.
  • Ethanol interference with 2-butanone measurement was evaluated using paired-difference testing, by measuring the SMART® mGC response of 2-butanone (50 ppb) in the presence of increasing ethanol concentrations (30,000, 100,000, and 300,000 ppb), in spiked human breath samples.
  • Breath samples were collected from five (5) adult study participants. In order to provide baseline breath samples relatively free of VOCs including ethanol, participants were instructed not to consume alcoholic beverages for one day (24 h) and not to eat, drink or smoke for 15 minutes prior to their study visits. Each study volunteer provided six separate breath samples into individual 1-L Tedlar gas sampling bags over a period of 30 minutes (up to five minute break periods were allowed between breath samples).
  • Exclusion Criteria Subjects found to have a high level of ethanol in their breath, or those physically unable to exhale 1-L breath samples into the Tedlar gas sampling bags.
  • the 50 ppb 2-butanone concentration was obtained by diluting 5 cc of the 10 ppm of a NIST-certified 2-butanone gas standard, into Tedlar gas sampling bags containing 1-L blank breath sample.
  • neat ethanol was first diluted into DI water, then 1 ⁇ L aliquots were injected into 1-L of blank breath to make the ethanol standards used in this study as follows:
  • ⁇ L of ethanol (186 ⁇ g) was diluted to 1.00 mL with water to produce a 186 ⁇ g/mL bag spiking solution.
  • One ⁇ l of spiking solution was injected into an equilibrated 1-L Tedlar bag containing blank human breath to produce a 100,000 ppb (100 ppm) breath ethanol standard.
  • 186 ⁇ g of ethanol/1 L of breath 4611 ⁇ g/24.789 L of breath
  • the interferent is Ethanol
  • the interfering effects from elevated concentrations of ethanol were determined on the ability of the SMART® mGC to detect 2-butanone at two levels using guidance from CLSI EP7: 1) response to 2-butanone as measured by the 1 st derivative, and 2) 2-butanone retention times. Summary of the 2-butanone retention times and mGC response (i.e., 1 st Derivative peak height) for control (i.e., 50 ppb 2-butanone without ethanol) and test samples (i.e., 50 ppb 2-butanol with ethanol at the specified concentrations) were created. Ethanol did not affect the retention time of 2-butanone on the SMART® mGC. In contrast, all concentrations of ethanol tested in this study caused a statistically significant decrease (P ⁇ 0.05) in the SMART® mGC response to 50 ppb 2-butanone relative to control.
  • the percent interference observed for each of the four SMART® mGCs, that resulted from ethanol (30,000, 100,000, and 300,000 ppb) added to breath samples containing 50 ppb of 2-butanone was determined.
  • the mean 2-butanone response on the mGCs ranged between ⁇ 15.3% (mGC#10010) and -48.6% (mGC #10009) relative to control (i.e., 50 ppb 2-butanone without ethanol).
  • the mean mGC 2-butanone response showed a decrease of up to ⁇ 70.3% (mGC#10010).
  • Increasing ethanol concentrations resulted in a negative bias in the SMART® mGC response to 50 ppb 2-butanone on all the SMART® mGCs.
  • Interference from ethanol with the 2-butanone response on the SMART® mGCs was calculated to be ⁇ 50% (30,000 ppb), ⁇ 64% (100,000 ppb), and ⁇ 74% (300,000 ppb).

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US20200103394A1 (en) 2020-04-02

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