WO2004057300A2

WO2004057300A2 - Determining a minimum effective dose of an inhaled drug for an individual at a given time

Info

Publication number: WO2004057300A2
Application number: PCT/IL2003/001000
Authority: WO
Inventors: Arie Huber; Yakov Reznikov; Paltiel Weiner; Eli Toister
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-12-19
Filing date: 2003-11-26
Publication date: 2004-07-08
Anticipated expiration: 2005-06-19
Also published as: AU2003282370A8; US7185650B2; US20040118398A1; EP1581290A2; AU2003282370A1; WO2004057300A3; EP1581290A4

Abstract

A system and method for determining a minimum effective dose of an inhaled drug for an individual patient at a given time. The system includes an apparatus to measure a performance measurement of patient and a data processor capable of communication with the apparatus. The data processor provides a computed minimum effective dose for the individual patient by applying a predetermined rule. The method includes measuring a performance measurement of the patient, communicating the performance measurement to a data processor and computing a minimum effective dose for the patient by applying a predetermined rule to the performance measurement with the data processor.

Description

SYSTEMS AND METHODS FOR DETERMINING A MINIMUM EFFECTIVE DOSE OF AN INHALED DRUG FOR AN INDIVIDUAL PATIENT AT A GI VEN TIME

FIELD AND BACKGROUND OF THE INVENTION The present invention relates to systems and methods for determining a minimum effective dose of an inhaled drug for an individual patient at a given time and, more particularly, to systems and methods for computing, and optionally delivering a minimum effective dose of an inhaled medication based upon results of a single measurement of a pulmonary performance indicator immediately prior to inhalation of the medication. The invention is expected to find especial utility in care and treatment of chronic asthma patients.

Metered dose inhalers are widely employed to treat respiratory conditions. Typical ly, a metered dose inhaler delivers a predetermined dose of an aerosolized drug λvith each actuation of a deliverv mechanism. The most common configuration employs pressurized gas to move a drug through a narrow opening where it is aerosolized. The device is typically position in the mouth or nostri(s) of a patient so that the aerosolized drug is delivered to the appropriate region of the airway. Metered dose inhalers share a common inherent disadvantage. Although delivery is exact, dosage is formulated based upon research on large populations of patients. This inherent disadvanytage creates two problems. The first problem is that patients may take more medication than the actually require. The second problem is that some patients may require more medication than recommended on some occasions.

^'I he number of patients using meteded dose inhalers on a routine basis is quite large. For example, asthma affects approximately 1 0- 1 5% of children and 5- 1 0% of adults. ^'I heAmerican Thoracic Society, the American Lung Association and the European Respirator Society (Kamada ct al. Issues in the use of inhaled glueocorticoids. Am J Respir Crit Care Med 1 996; 1 53 : 1 739-48). recommend ongoing treatment for 80% of these asthma pat ients with inhaled cortico teroids or glueocorticoids (IGC). The dev ice of choice for administration of these inhaled corticosteroids is a metered dose inhaler.

It is well established that IGC are effective in the treatment of asthma. (Kamada et al . Issues in the use of inhaled glueocorticoids. Am J Respir Crit Care Med 1 996; 1 53 : 1739-48). However. IGC have the potential to cause severe adverse systemic effects. For example chronic long term use of IGC has been reported to cause adrenal suppression, osteoporosis and growth suppression in children (L)oull et al. Growth of asthmatic children on inhaled corticosteroids (abstract). Am Rev Respir Dis 1 993; _ 47 :A265, Littjewood JM, Johnson AW, Edwards PA, et al . Growth retardation in asthmatic children treated with inhaled beclomcthasone dipropionate. Lancet 1 988;/: 1 1 5-6, Wales JK H, Barnes NT), Swift PGF. Growth retardation in children on steroids in asthma. Lancet 1 99 1 ;338: 1 535-6, Wohhers OD, Pederson S. Controlled study of linear growth in asthmatic children during treatment with inhaled corticosteroids. Pediatrics 1 992;89: 839-42., Wolthers OD. Pederson S. Short-term grow th during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child 1993;68:673-6,

Prifltsk K, Milner AD, Conway E. et al. Adrenal function in asthma. Arch Dis

Child 1990;65 : 838-40). The danger of thes adverse effects increases with the amount of IGC consumed (Dahl R, Lundback B, Malo J-L. A dose ranging

- study of fluticasone propionate in adult patients with moderate asthma. Chest 1993 ; 104: 1352-8). Studies indicate that dose-dependent suppression of the hypothalamic- pituitary-adrenal axis (HPAΛ) occurs in both healthy volunteers and in asthmatics Nikolaizik et al. Nocturnal cυrtisol secretion in healthy adults before and after inhalation of budesonide. Am J Respir Crit Care Med 1 96; 1 53 97- 1 0 1 , Donnelly ct al. Effects of budesonide and fluticasone on 24- hour plasma cortisol . Am J Respir Crit Care Med 1 997 ; 1 56: 1 746-5 1 ). This suppression occurs even follow ing a single dose inhalation of IGC. Systemic bioavailability of IGC is α function of absorption of the drug across the lung vascular bed. Lung deposition and systemic bioavailability are al ered airway diamewter in patients with asthma. Further, the degree of narrowing varies w idely, both among patients within the population and as a (unction of time for ^• each individual patient (Weiner et al ._ Characteristics of asthma in the elderly. Eur Respir J 1 998; 1 2 (3)'564-8).

Thus, the inability of standard IGC therapy regimens employing fixed dose metered dose inhalers to customize the dose to the requirements of an individual patient at a speci fic time poses a signi ficant risk to many asthma patients.

Although current guidelines on asthma treatment recommend the .administration of the lowest dose of IGC compatible with asthma control, computation of this dose is most often based upon analysis of responses of a large poopulation of patients. In cases w here individual patients

e their pulmonary function quantitatively analyzed, such analyses are generally performed periodically, not daily or prior to each inhalation of IGC .

Further, it is widely believed by clinicians that improved asthma control can be achieved by increasing the dose of IGCs. Thus, there is a tendency to empirically determine how much IGC is required to provide relief from an acute asthma attack and advise patients to continue to apply this high dosage. Such practice ignores the idea that the dose of IGC should be reduced as soon as control is achieved. This is because the tendewncy for each unit of IGC delivered to the aiway to exert a systemic effect increases as the patients condition stabilizes or improves. United States Patent No. 5, 724,986 issued to Jones Jr. et al teaches a casing and spirυmcier for a metered tlose inhaler. Jones Jr. teaches measurement of a pulmonary parameter such as peak expiratory flow (PEF). However, Jones Jr. fails to teach use of this measurement to compute a 5 minimum effective dose. I nstead, Jones Jr. teaches determination of an optimum time to release medication from a metered dose inhaler. According to the teachings of Jones Jr., the optimum time is chosen to insure maximum deli\ cry of the inhaled medication to the lungs (as opposed to the upper airway) regardless of the physiologic condition of the patient. Thus the ι o teachings of Jones Jr. increase the amount of medication delivered systernicallv and increase the risks associated with systemic administration of medication.

United States Patent No. 5,826,570 issued to Goodman et al. teaches delivery of aerosol medications for inspiration. Goodman, like Jones Jr., teaches determination of an optimum time to release medication from a

15 metered dose inhaler. Goodman teaches choosing a desired location for deposition of the inhaled medication. Like Jones Jr.. Goodman teaches maximization of the rcspirable fraction of the aerosol ized medication. Thus, like Jones Jr.. Goodman teaches increasing the amount of medication delivered syste ically thereby increasing the risks associated with systemic 0 administration of medication. Further, Goodman teaches calculations based upon repeated measurements. This is an inherent disadvantage because it increases the amount of time required for a patient to measure pulmonary function prior to beginning treatment.

There is thus a w idely recognized need for, and it would be highly 5 advantageous to have, systems and methods for determining a minimum effective dose of an inhaled drug for an individual patient at a given time devoid of the above limitations. SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a 0 system for determining a minimum effective dose of an inhaled drug for an ^■ individual patient at a given time. The system includes: (a) a measuring apparatus designed and constructed to measure at least one pulmonary perfoi mance indicator measurement of the indh idual pat ient; and (b) a data processor capable of communication w ith the measuring apparatus, the data pr ocessor designed and configured to provide a computed minimum effective close for the indh idual pat ient by apply ing a predetermined rule to the pulmonary pei formance indicator meas ement.

According to another aspect of the present inv ention thci e is proMdcd a method of optimizing a (.lose of an inhaled drug to an indiv idual patient at a given time. I he method includes: (a) measuring at least one pulmonary perfoi mance indicator measurement of the individual patient: (b) communicating the pulmonary pei formance indicator measurement to a data processor; and (c) computing a minimum effective dose for the individual patient by applying a predetermined rule to the pulmonary performance indicator measurement ithin the data processor. According to yet another aspect of the present invention there is proλ ided an article of manufacture for autonomous indiv idual optimization of a treatment protocol for an individual patient suffci mg from a respiratory disorder. I he article of manufacture includes: (a) a measuring apparatus designed and constructed to measure at least one pulmonary performance indicator measurement of the indiv idual patient; (b) a data processor capable of communication w ith the measuring apparatus, the data processor designed and configured to

ide a computed minimum effective dose for the individual patient by apply ing a pi cdeter ined rule to the pulmonary performance indicator measurement, (c) an adjustable delivery mechanism designed and constructed to receive the computed minimum effective dose and to to deliver the computed minimum effective dose of the inhaled drug to the individual patient;. (d) a pharmaceutical composition identified for treatment of the respiratoiy disorder being contained within the adjustable delivery mechanism, the pharmaceutical composition including, as an active ingredient, an agent capable of relieving symptoms of the respiratory disorder; and packaging material.. According to further features in preferred embodiments of the invention described below . the sy stem includesan adjustable delivery mechanism capable of communicating w ith the data processor and receiv ing the computed minimum effective dose, the delivery mechanism designed and constructed to deliv er the computed minimum e fl eet i\ e dose of the inhaled drug to the individual patient.

According to sti l l further features in the described preferred embodiments the sy stem includes an adjustable del ivery mechanism designed and constructed to receiv e the computed minimum effective dose as a manual data input, the del iv ery mechanism designed and constructed to deliver the computed minimum effectiv e dose of the inhaled drug to the individual patient.

According to still fur ther featui cs in the described preferred embodiments the measuring apparatus is selected from a group consisting of a spirometer and a mcchanicaol peak flow meter. According to still further features in the described preferred embodiments the pulmonary pei formance indicator is selected from a group consisting of forced expiratory v olume in one second (FEV 1 ) and peak expiratory flow (PEP).

According to still further features in the described preferred embodiments the computed minimum e ffective dose is presented in a format selected from a group consisting of actual quantitative units and arbitrary units.

According to still fui ther features in the described preferred embodiments the predetermined rale includes:

y= -17.183+0.645 J measured FEV1 X 100^

I anticipated FEV1 ( w herein y is the percentage of drugs aborbed/cortisol production. According to still further features in the described preferred embodiments the predetermined rule for determining a computed minimum effective dose Z (in icrograms) includes

wherein BD indicates a basic dose at the beginning of treatment. MFRP indicates a measured FEV1 relative peiccntage and wherein BfRP indicates a basic LEV! Relative Percentage ( 100% is the normal) hen the BD is determined. MFRP may be determined an time while consuming medication.

According to still fuither features in the described preferred embodiments the adjustable deli ry mechanism includes at least one item selected from a group consisting of a mechanical dispenser, an electromechanical dispenser (e g. QX4C-N manufactured by f M λ'l. Motion and Magnetic fcchnologies. Tel-Aviv. Israel) and a piezo-electric dispenser (e.g. STM manufacturccd byNanomotion Ltd, Yokneam, ISRAEL). According to various embodiments of the invention, the delivery mechanism may deliver cither a powder or aerosolized liquid droplets. According to still further features in the described preferred embodiments the method further includes (d) transmitting the minimum effect iv e dose to an adjustable delivery mechanism from the data processor v ia a channel of communication bet een the adjustable deli ery mechanism and the data processor , and (e) permitting the adjustable delivery mechanism to automatically adjust to deliver the minimum effective dose of the inhaled drug to the individual patient and to deliver the minimum effective dose. According to still further features in the described preferred embodiments the method further includes' (d) manually inputting the minimum effective dose to an adjustable delivery mechanism; and (e) delivering the minimum effective dose of the inhaled drug to the individual patient by means of the adjustable delivery mechanism . According to still further features in the described preferred embodiments the measur ing is accomplished by a dev ice selected from a group consisting of a spirυmetcr and a mechanical peak flow meter.

According to st il l further features in the described pr eferred 5 embodiments the adjustable deli er y mechanism receives the computed minimum e ffectiv e dose f rom the data processor automatically.

According to still fur ther features in the desc ribed preferred embodiments the measuring appar atus . the data processor and the adjustable deliv ery mechanism are integrally formed together or connected one to ι o another.

According to still fur ther features in the described pref erred embυdimentsthe measur ing apparatus and the data processor are integrally formed together or connected one to another and the adjustable deliv ery mechanism is conncctable thereto. 15 The present invention successfully addresses the shortcomings of the presently known configurations by providing systems and methods for determining a minimum effective dose of an inhaled drug for κin individual patient at a given time based upon results of a single measurement of a pulmonary performance indicator immediately prior to inhalation of the 0 medication.

Implementation of the method and system of the present invention involves per forming or completing selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of preferred embodiments of the method 5 and system of the present invention, several selected steps could be implemented by hardware or by software on any operating system of any firmware or a combination thereof. For example, as hardware, selected steps of the invention could be implemented as a chip or a circuit. As software, selected steps of the invention could be implemented as a 0 plurality of software instructions being executed by a computer using any suitable operating system. In any case, selected steps of the method and system of the invention could be described as being performed by a data processor, such as a computing platform for executing a plurality of instructions.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention ma)' be embodied in practice.

In the drawings:

FIG. 1 is a schematic representation of a system for determining a minimum effective dose of an inhaled dnig for an individual patient at a given time according to the present invention.

FIG.2 is a simplified flow diagram illustrating possible sequences of events in performance of a method of determining a minimum effecti e dose of an inhaled drug for an individual patient at a given time according to the present invention. FIGs.3a and 3b are side cut away views illustrating operation of one embodiment of an adjustable delivery mechanism suited for use in the context of the present invention.

FIG.4 is a side view of an adjustable delivery mechanism suited for use in the context of the present invention. FIG.5 is graph % eortisol drugs absorbed/ cortisol production as a function of % of normal FEV1,

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of systems and rnethυds^'for determining a minimum effective dose of an inhaled drug for an individual patient at a given time which can reduce the risks associated with chronic long term use of inhaled drugs. Systems according tυ the present invention may optionally be supplied as articles of manufacture. Specifically, the present invention can be used to compute, and optionally deliver, a minimum effective dose of an inhaled medication based upon results of a single measurement of a pulmonary performance indicator immediately prior to inhalation of the medication. The invention is expected to find especial utility in care and treatment of chronic asthma patients by reducing the total amount of glueocorticoids inhaled over a period of time. This reduction in glucocorticoid consumption is capable of reducing the adverse impact of coticosteroid compounds.

The principles and operation of systems and methods for determining a minimum effective dose of an inhaled drug according tυ the present invention may be better understootl with reference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Referring now to the drawings, Figure 1 illustrates a system 20 for determining a minimum effective dose of an inhaled drug 36 for an individual pat ient 2 1 at a given time Sy stem 20 includes a measuring apparatus 22 designed and constructed to measure at least one pulmonary performance idicator measurement 24 of an individual patient 21 . Measur ing apparatus 22 may be. for example, a spirometcr or a mechanical peak flow meter. Patient 21 w uld thus exhale into air passage 25 (see figures 3a. 3b and 5) in order to measure pulmonary performance ιndicatυr24. Pulmonary pei formance indicator measurement 24 may be. for example, forced expiratory olume in one second (FEN l ) or peak expiratory flow (PEF) S stem 20 further inchulcs a data processor 26 capable of communication with measuring apparatus 22 for

10 purposes of receiving pulmonary performance indicator measurement 24 therefrom. Communication may be effected through any channel of communication including, but not limited to. a w ired connection, an inf rared frequency transmission connection, a local area network connection, a radio frequency connection, a fiber-optic connection or an electromagnetic

15 connection.

Thus, according to some preferred embodiments of the invention, measuring apparatus 22 and data processor 26 arc integrally formed together and connected, for example, by a w ired connection. More preferably, data processor 26 is incorporated into measuring apparatus 22 as, for example, a

20 microchip or printed circuit.

In some instances it may de desirable to incorporate an existing data processor, such as a personal computer or personal digital assistant, into sy tem 2Θ as data processor 26. Alternately, but also preferably, measuring apparatus 22 and data processor 26 are separate units w hich are connectable.

_:. for example by a wire, a local area netw ork connection, or a fiber-optic connection for purposes of communication. Alternately, but also preferably, measuring apparatus 22 and data processor 26 are separate units w hich communicate without benefit of a physical connection by means of, for example, an infrared frequency transmission connection, a radio frequency connection, or an electromagnetic connection. Regardless of the physical relationship between measuring apparatus 22 and data processor 26, data processor 26 is designed and configured to provide a computed minimum effective dose 30 for individual patient 21 by applying a predetermined rule 28 tυ pulmonary performance indicator measurement 24. Depending upon the exact configuration of system 20, it may be adv ntageous to present computed minimum effective dose 30 as actual quantitative units (e.g μg or IU) or arbitrary units (e.g. numerals or letters). In reducing the present invention to practice it has been discovered that a linear iclationship (Figure 5) exists between { cortisol drugs absorbedtcortisol produced X 100} and observed FEVl expressed as a percentage of normal (i.e. expected) FEVl. fhe correlation between these expressions is linear (R2=0.865: P<0.). Thus it is useful to employ a predetermined rule which includes Equation 1 or Equation 2 or a combination thereof for purposes of configuring data processor 26 of system 20. Relation of FEVl to drugs absorbed / cortisol production is summarized in EQUATION 1 : y= -17.183 + 0.615 J measured FEVl X 1 Oθ^"

I anticip ted FEVl i wherein y is the percentage of drugs aborbcd/cortisol production. Determination of a computed minimum effective dose Z (in imcrograms) is accomplished by EQUATION 2:

wherein BD indicates a basic dose at the beginning of treatment, MFRP indicates a measured FEVl relative percentage and wherein BFRP indicates a basic FEV 1 Relative Percentage ( 100% is the normal) when the BD is determined. MFRP may be determined anytime while consuming medication. System 20 may further include an adjustable delivery mechanism 34 capable of communicating with data processor 26 and receiving computed minimum effective dose 30. Delivery mechanism 34 is designed and constructed to deliver computed close 30 of inhaled drug 36 to individual patient 21. Inhaled drug 36 is often supplied in the form of a pharmaceutical composition 42 including additional ingredients. It is expected that during the life of this patent many rele nt adjustable delivery mechanisms ill be developed and the scope of the term "adjustable delivery mechanism" is intended to include all such new technologies a priori.

Alternately, but also preferably adjustable delivery mechanism 34 is designed and constructed to receive computed minimum effective dose 30 as a manual data input by means of a data input device 40 (Figure 4) on delivery mechanism 34. In this case, computed dose 30 is displayed on display device 32 and observed by patient 21. For purposes o ths specification and the accompanying claims the phrase "display device" refers to any device for presentation of data to a patient. The definition includes, but is not limited to mccanical displays, speakers, LCD screens, I-LT) displays, CRT displays and active matrix displays. Patient 21 the inputs computed dose 30 into input device 40 on delivery mechanism 34. Delivery mechanism 34 is further designed and constructed to deliver computed minimum effective dose 30 of inhaled drug 36 to individual patient 21 either as a result of the manual data input via input device 40 or as a result of subsequent actation of delivery mechanism 34. Figure 4 shows display 39 of data input in arbitrary units. In the pictured embodiment of delivery mechanism 34, input device 40 is a rotating ring (rotation depicted by curved arrow). Each increment of rotation is depicted on display 39 (e.g. as the number 4 on an arbitrary scale from 1-7. Examination of display 39 helps patient 21 to ascertain that they have correctly input computed dose 30 to deliveiymechanism 34. While numerals are pictured in figure 4, it may be - advantageous to express computed dose 30 in non-numerical units (e.g. colors, letters, asnimals, geometric forms) in order to prevent patient 21 from being aw are o f the size of dose 30.

Adjustable del ivery echan ism 34 may include, for example, a mechanical dispenser, an electronic dispenser, an electromechanical dispenser, a piezυ-electric dispenser or an aerosol dispenser or combinat i ons including at l east one of these dispenser types. Del ivery mechanism 34 may del iver aerosolized droplets or powder.

The present invent ion is addit ionally embodieed by a method 50 (figure 2) of optimizing a dose 30 of an inhaled drug 36 to an individual patient 21 at a given time. Method 50 includes measuring 52 at least one pulmonary performance ind icator measurement 24 of individual patient 2 1. Measuring 52 is pre ferably accompl ished a spirometcr or a mechanical peak flow meter, although other devices could be employed vvithot signi ficantly e ffecting method 50 or an outcome thereo f Method 50 further includes communicating 54 pulmonary performance indicator measurement 24 to data processor 26 and computing 56 minimum effective dose 30 for i ndividual patient 2 1 by applying predetermined rule 28 to pulmonary performance ind icator measurement 24 within e data processor 26.

Optional ly, but pre ferably, method 50 further includes transmitting 58 minimum e ffective dose 30 to adjustable delivery mechanism 34 from data processor 26 via a channel of communication between adjustable delivery mechanism 34 and data processor 26 and permitt ing 60 adjustable delivery mechanism 34 to automatically adj ust to del iver the minimum effective dose of inhaled drug 36 to individual patient 21 and to del iver 64 the minimum ef f ective dose 30 to patient 21 .

Alternately, but also preferably, method 50 further includes manually inputting 62 minimum effective dose 30 to adjustable delivery mechanism 34 and delivering 64 minimum effective dose 30 of inhaled drug 36 to individual patient 21 by means of adjustable delivery mechanism 34 . System 20 is optionally, but preferably supplied as an article of

^" manufacture for autonomous individual optimization of a treatment protocol for an i nd ividual patient su ffering from a respiratory disorder (e.g. asthma). "Optim izat ion" as used herein referers to opt imization at a specific point in t ime. That is. patient 2 1 computes 56 an opt imum dose 30 immedi ately pri or to each use o f inhaled dru g 36. The article o f manu facture includes measuring apparatus 22, data processor 26 and adjustable del ivery mechanism 34 as described hereinabove. According to this embodiment of the invention, adjustable del ivery mechanism 34 contains pharmaceutical composition 42 identified tor treatment of the respiratory disorder and including, as an active ingredient, an agent 36 capable of relieving symptoms of the respiratory disorder; and packaging material .

Pharmaceutical composition 42 may contain a "physiologically acceptable carrier" which; as used herein, refers to a carrier or a diluent that does not cause signi ficant irritation to an organism and docs not abrogate the biological activity and properties of administered compound 36. An adjuvant is included within this definition.

Pharmaceutical composition 42 may further contain an "cxcipicnt" w hich, as used herein, refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

For administration by nasal or oral inhalation, the active ingredients for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable prυpellant, e.g., dichlorodifluoromcthane, trichlorofluoromethane, dichloro- tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Articles of manufacture of the present invention may, if desired, be presented in a pack, such as an FDA approved kit, which may contain one or more unit dosage forms containing active ingredient 36. The pack may, for example, compr ise metal or plastic foi l, such as a blister pack. I^'he pack may he accompanied by instructions f or easui ment and administration. The pack may also include a notice associated w ith the container in a form prescr ibed by a go ernmental agencv regulatinu the manu factui e. use or sale of pharmaceuticals, which notice is reflecti e of appro al by the agency of the form of the compositions or human administration. Such notice, l r example, may be of labeling approved by the U S Food and Drug Administration for prescription drugs or of an approv ed product insert. Preferably the article of manu facture is designed and constructed so that adjustable deli ery mechanism 34 receives computed minimum effective dose 30 from data processor 26 automatically.

According to some preferr ed embodiments of the invention, measuring apparatus 22 . data processor 22 and adjustable deli ery mechanism 34 are integrally formed together or connected one to another.

According to alternate preferred embodiments of the invention measuring apparatus 22 and data processor 26 are integrally formed together or connected one to another and adjustable delivery mechanism 34 is connectable thereto. It is appreciated that certain features of the inv ention, which are, for c '-r ity, described in the context of separate embodiments, may also be prov ided in combination in a single embodiment. Conversely, various features of the inv ention, w hich are. for brev ity, described in the context of a single embodiment, may also be prov ided separately or in any suitable subcombination

As an illustrative, non-limiting, example of the potential benefit of a systems 20 and methods 50 according to the present invention, consider the case of a hypothetical asthma patient Ms. Bea Wreatheshard. Bea has been treated in the past with a standard metered doses inhaler which delivers 50 micrograms of an IGC based drug per actuation. Fler doctor has instructed her to inhale two actuations in the morning upon arising and two actuations before retiring at night. As a result, Bea inhales 200 micrograms/day of IGC or 6 mi ll igrams every thirty days.

Accor ding to the present inv ention, measuring apparatus 22 w ould measure a pulmonary perfoi mance indicator 24 be fore each treatment . Data processor 26 w ould apply a predeter mined rule 28 to determine a minimum effect iv e dose 30 (e g Z according tυ equation 2) speci fically for Bea at the speci fic t ime she is going to be tr eated. Dose 30 may sometimes be greater than 1 00 micrograms but w ill generally be less than 1 00 micrυgrams. As a r esult. Bea w ill consume w ell below 6 milligrams per month of IGC although she will feel better because dose 30 will be in excess of 1 00 micrograms hen Bea is suffering most from Asthma. On dav s w hen Bea is breathing normally, she w ill still actuate delivery mechanism 34 1 times but may recei e no medic ation at all. Further, according to preferred embodiments of the incventioπ, Bea will be unaware of the dose 30 she is receiving. I his may be accomplished, for example, by use of an automated delivery mechanism 34 with no display or by use of display dev ice 32 and data input device 34 which employ non- alphanumeric sy mbols For example, names of classical music composers or animals might be employed to indicate different dosage levels. As a r esult, stress, w hich is believed to be a contributing factor in Asthma, is reduced. Thus, as a resu lt of the present invention. Bea benefits from reduced IGC consumption, an increased feeling of w ellness and reduced stress

Although the invention has been described in conjunction w ith specific embodiments thereof, it is ev ident that many alter natives, modi ficat ions and variations w ill be apparent to those skilled in the ai t. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this speci fication are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WH AT I S CLAI MED I S:

1 . A system for determining a minimum effective dose of an inhaled drug for an individual patient at a giv en time, the system comprising'

(a) a measuring apparatus designed and constructed to measui e at least one pulmonary performance indicator measurement of the indiv idual patient: and

(b) a data processor capable of communication with said measuring apparatus, said data processor designed and configured to prov ide a computed m inimum effective dose for the individual patient by applv'ing a predetermined rule to said pulmonary performance indicator measurement.

2. The system of claim 1. further comprising:

(c) an adjustable delivery mechanism capable of communicating with said data processor and receiving said computed minimum effective dose, said delivery mechanism designed and constructed to deliver said computed minimum effective dose of the inhaled drug to the individual patient.

3. The system of claim 1 , further comprising:

(c) an adjustable delivery mechanism designed and constructed to receive said computed minimum effective dose as a manual data input, said delivery mechanism designed and constructed to deliver said computed minimum effective dose of the inhaled drug to the individual patient.

4. The system of claim 1 , wherein said measuring apparatus is selected from a group consisting of a spirometer and a mechanicaol peak flow meter.

5. The system of claim 1 , w herein said pulmonary performance indicator is selected from a group consisting of forced expiratory v olume in one second (FEV l ) and peak expiratory flow (PEL).

6. The. system of claim 1 , w herein said computed minimum effectiv e close is presented in a format selected from a group consisting of actual quantitative units and arbitrary units.

7. The system of claim 1 . w herein said predetermined rule includes:

Z = BD 0.645

wherein B D indicates a basic dose at a beginning of a treatment; w herein MFRP indicates a measured T X 1 relative percentage; wherein BFRP indicates a basic FEV l Relative Percentage when BD is determincchand wherein Z represents the computed minimum effective dose.

8. The system of claim 2, w herein said adjustable delivery mechanism includes at least one item selected from a group consisting of a mechanical dispenser, an electromechanical dispenser and a piezo-electric dispenser.

9. The s stem of claim 3. wherein said adjustable delivery mechanism includes at least one item selected from a group consisting of a mechanical dispenser, an electromechanical dispenser and a piezo-electric dispenser.

1 0. A method of optimizing a dose of an inhaled drug to an individual patient at a given time, the method comprising:

(a) measuring at least one pulmonary performance indicator measurement of the individual patient; (b) communicating said pulmonary performance indicator measur ement to a data processor: and

(c) computing a minimum effective dose for the individual patient by. pplying a predetermined rule to said pulmonary performance indicator measurement within said data processor.

1 1 . The method of claim 10, further comprising:

(d) transmitting said minimum effective dose to an adjustable deliv ery mechanism from said data processor via a channel of communication betw een said adjustable deliver}/ mechanism and said data processor ; and

(e) permitting said adjustable delivery mechanism to automatically adjust to deliver said minimum effective dose of the inhaled drug to the individual patient and to deliver said minimum effective dose.

12. The method of claim 10, further comprising:

(d) manually inputting said minimum effective dose to an adjustable deliv ery mechanism; and

(e) delivering said minimum effective dose of the inhaled drug to the indi idual patient by means of said adjustable delivery mechanism .

1 3. The method of claim 1 0, wherein said measuring is accomplished by a de ice selected from a group consisting of a spirometer and a mechanical peak flow meter.

14. The method of claim 10, wherein said pulmonary performance indicator is selected from a group consisting of forced expiratory volume in one second (FEN l ) and peak expiratory flow (PEF).

1 5. The method of claim 10, wherein said minimum effective dose is presented in a format selected from a group consisting of actual quantitative units and arbitrary units.

1 6. hc method of claim 1 . wherein said predetermined rule includes:

Z = B D - B D X ( [M FRP - BFRP]/1 ()0)> .\ 0.645

w herein BD indicates a basic dose at a beginning of a treatment; w herein MFRP indicates a measured FEN l relativ e percentage: w herein BFRP indicates a basic FEV l Relative Percentage when BD is deteπnmcdtand w herein Z represents the computed minimum effective dose.

1 7. t he method of claim 1 1 , w herein said adjustable delivery mechanism includes at least one item selected from a group consisting of a mechanical dispenser, an elccti omechanical dispenser and a piezo-electric dispenser.

1 8. The method of claim 12. wherein said adjustable delivery mechanism includes at least one item selected from a group consisting of a mechanical dispenser, an electromechanical dispenser and a piezo-electric dispenser.

19 An article of manufacture for autonomous individual optimization of a treatment protocol for an individual patient suffering from a respiratory disorder, the article of manufacture comprising:

(a) a measuring apparatus designed and constructed to measure at least one pulmonary performance indicator measurement of the individual patient; and

(b) a data processor capable of communication with said measuring apparatus, said data processor designed and configured to provide a computed minimum effective dose for the individual patient by applying a predetermined rule to said pulmonary performance indicator measurement.

(c) an adjustable deliv ery mechanism designed and constructed to receive said computed minimum e ffecti e dose and to to deliver said computed minimum ef fective dose of the inhaled drug to the individual patient.

(d) a pharmaceutical composition identi fied for treatment of the respiratory disorder being contained within said adjustable delivery mechanism, said pharmaceutical composition including, as an active ingredient, an agent capable of relieving symptoms of the respiratory disorder; and

(e) packaging material ..

20. The article of manu facture of claim 1 9, wherein said adjustable delivery mechanism receives said computed minimum effective dose from said data processor automatically.

21 . The article of manu facture of claim 19, wherein said measuring apparatus , said data processor and said adjustable delivery mechanism are integrally formed together or connected one to another.

22. The article of manu f acture of claim 1 9, wherein said measuring apparatus and said data processor are integrally formed together or connected one to another and said adjustable delivery mechanism is connectable therto.