WO2014159169A1 - Gel vaginal à libération contrôlée avec particules antivirales - Google Patents

Gel vaginal à libération contrôlée avec particules antivirales Download PDF

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Publication number
WO2014159169A1
WO2014159169A1 PCT/US2014/022338 US2014022338W WO2014159169A1 WO 2014159169 A1 WO2014159169 A1 WO 2014159169A1 US 2014022338 W US2014022338 W US 2014022338W WO 2014159169 A1 WO2014159169 A1 WO 2014159169A1
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WIPO (PCT)
Prior art keywords
particles
group
formulation
drug
reverse transcriptase
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English (en)
Inventor
Reid M. Rubsamen
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Flow Pharma Inc
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Flow Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the invention relates to a vaginal gel packaged with a formulation of controlled release tenofovir particles. More particularly the invention relates to vaginal gel formulations which improve patient compliance of tenofovir in order to inhibit HIV infection.
  • HIV/ AIDS HIV/AIDS
  • HAV/ AIDS HIV/AIDS
  • HIV human immunodeficiency virus
  • a person may experience a brief period of influenza- like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses it interferes more and more with the immune system, making the person much more likely to get infections,
  • HIV is transmitted primarily via unprotected sexual intercourse
  • AIDS was first recognized by the Centers for Disease Control and Prevention (CDC) in 1981 and its cause— HIV infection— was identified in the early part of the decade. Since its discovery, AIDS has caused nearly 30 million deaths (as of 2009). As of 2010, approximately 34 million people have contracted HIV globally. AIDS is considered a pandemic— a disease outbreak which is present over a large area and is actively spreading.
  • HIV/AIDS has had a great impact on society, both as an illness and as a source of discrimination.
  • the disease also has significant economic impacts.
  • There are many misconceptions about HIV/AIDS such as the belief that it can be transmitted by casual non-sexual contact.
  • the disease has also become subject to manycontroversies involving religion.
  • Treatment consists of high active antiretroviral therapy (HAART) which slows progression of the disease and as of 2010 more than 6.6 million people were taking them in low and middle income countries. Treatment also includes preventative and active treatment of opportunistic infections.
  • HAART high active antiretroviral therapy
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • NRTIs nucleoside analogue reverse transcriptase inhibitors
  • Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC).
  • ZT zidovudine
  • TDF tenofovir
  • FTC emtricitabine
  • PI aprotease inhibitors
  • Benefits of treatment include a decreased risk of progression to AIDS and a decreased risk of death.
  • Treatment also improves physical and mental health. With treatment there is a 70% reduced risk of acquiring
  • tuberculosis Additional benefits include a decreased risk of transmission of the disease to sexual partners and a decrease in mother-to-child transmission.
  • the effectiveness of treatment depends to a large part on compliance.
  • Reasons for non-adherence include: poor access to medical care, inadequate social supports, mental illness and drug abuse.
  • the complexity of treatment regimens due to pill numbers and dosing frequency) and adverse effects may create intentional non-adherence.
  • Adherence is however just as good in low income as high income countries.
  • Formulations are disclosed which are comprised of drug containing particles, and a biocompatible gel having the particles dispersed therein.
  • the drug is a reverse transcriptase inhibitor.
  • the gel may be comprised of a flavoring agent and one or more compounds which generate heat.
  • the particles may be provided in a plurality of groups (2, 3 or more) of different size spheres.
  • the spheres may be comprised of a reverse transcriptase inhibitor such as tenofovir alone or in combination with other inhibitors such as emtricitabine or lamivudine and a controlled release polymer such as poly lactic glycolic acid (PLGA) or other suitable, biocompatible material.
  • PLGA poly lactic glycolic acid
  • Formulations of the invention are designed to improve patient compliance and thereby inhibit HIV infection in at least three ways.
  • the vaginal gel formulation is flavored.
  • the formulation includes one or more compounds which generate heat via an exothermic reaction.
  • the controlled release characteristics keep the active compound in place over a longer period of time.
  • the formulation may be comprised of groups of different sizes particles
  • Each group of spherical particles may consist of multiple particles which are all substantially the same size which together with other groups are designed to provide a combination of different drug release rates when the formulation is deployed or implanted and provide a relatively constant level of drug to the surrounding area.
  • An aspect of the invention is a formulation comprised of several groups of particles wherein each group of particles is different from the particles of other groups but identical to particles within the same group.
  • the groups of particles (which may be only two groups or three or more groups) are designed to release drug at different points in time and/or rates over time and thereby provide for therapeutic levels of drug over a period of time of 24 hours to 7 days, 1 to 2 days, 1 to 3 days, 1 to 4 days, etc.
  • groups of particles is an important aspect of the invention there must be a convenient way for the particles to be placed in the vaginal cavity where the drug is released and provides the desired therapeutic level which is a level which is sufficient to prevent HIV infection.
  • Those skilled in the art will understand that there are different types of devices which could be used for vaginal delivery.
  • the formulation of groups of particles would be stored separately from a gel in a plunger syringe type device. Upon use the plunger mixes the particles into the gel and the mixture of particles and gel are injected into the vaginal cavity.
  • the formulation of particles is placed in a capsule comprised of a
  • biocompatible, dissolvable material which can be polymeric, gelatin or any combination thereof
  • the capsule could include a second capsule contained therein as well as additional capsules and the capsules designed to dissolve at different points in time thereby providing for controlled release of the drugs from the capsules.
  • a capsule as described as above can be included within a tubular
  • applicator of the type used in connection with the insertion of tampons. Such an applicator could also be used in connection with a gel and particle formulation stored separately within the application.
  • the formulation of particles can be mixed into a gel and applied to a condom or onto a cervical cap or dome comprised of latex or silicone (e.g. a diaphragm) which is then inserted into the vaginal cavity to provide birth control along with HIV infection control.
  • a condom or onto a cervical cap or dome comprised of latex or silicone (e.g. a diaphragm) which is then inserted into the vaginal cavity to provide birth control along with HIV infection control.
  • silicone e.g. a diaphragm
  • the release rate of one group of particles is decreasing (or the drug released from the group is being metabolized out of the system) while the Atty. Docket: PHRM-005WO release rate of another group of particles is increasing (or drug from one group is being added to the system) so that the combined groups of particles making up the formulation provide a substantially constant level of drug over a therapeutically effective period of time (1-7 days).
  • concentrations of drug and the release rate of these drugs may be varied.
  • Formulations of particles may be divided into separate disposable packets
  • each syringe of formulation includes a plurality of groups of spheres wherein the spheres of each group of spheres are all of substantially the same size.
  • the packet may include 2, 3,4 or more groups of spheres with a typical formulation being comprised of three groups of spheres in a small, medium, and large size.
  • the packet of formulations is specifically designed so as to obtain a desired therapeutic effect.
  • the desired therapeutic effect of the particles is to provide a therapeutic level of drug to an area to prevent HIV infection. If the level of the drug drops too low then the antiviral effect is lost. However, if the level is raised too high the drug becomes toxic to surrounding tissue.
  • the therapeutic level of the drug is not maintained for a sufficiently long period of time infection can occur. If the therapeutic level of the drug is maintained for too long of a period of time there may also be undesirable results. Thus, it is important to adjust the formulation so that the concentration of the drug delivered to the target area is not too low or too high and so that the drug is delivered for a sufficiently long period of time but not a period which is too long.
  • the formulation can be produced using one or more reverse transcriptase
  • the spheres within the formulation can be produced using a wide range of different polymers, the formulation is typically produced using a biocompatible widely used and accepted polymer such a polylacticglycolic acid (PLGA).
  • PLGA polylacticglycolic acid
  • the methodology described here substantially reduces the trial and error of producing a controlled release formulation. This is done by using particles of a known size (volume and surface areas + 10%) shape (spherical) and dissolution rate within an environment to which the particles are delivered. Because all the particles of any given Atty. Docket: PHRM-005WO group have substantially the same surface area from one particle to another the dissolution rate of a given particle and the group of particles can be calculated mathematically based on a known dissolution rate of a particle of known surface area.
  • Particles in the formulation preferably have a spherical shape and a diameter in a range of from about 2 microns to about 40 microns about 10 microns +1 micron.
  • the particle types may include particles comprised of drug alone, drug and polymer mixed and/or drug coated with polymer.
  • a typical formulation can be comprised of two groups of particles wherein the first group is comprised of particles having a diameter of about 6 microns and the second group comprised of particles having a diameter of about 20 microns. These particles have spherical conformations and each particle within each group has approximately the same size and shape with a differential +10%.
  • the particles may be configured in different ways such as having a reverse transcriptase drug on the inside and coated polymer on the outside, a typical formulation also includes spheres where the drug and polymer are intermixed. Such spheres are easily produced by mixing the drug in the polymer and thereafter forming the spheres.
  • Spheres can be produced using a technology such as that described within U.S. Patent 6,241,159 issued June 5, 2005 and U.S. Patent 6,174,469 issued January 16, 2001 as well as related issued U.S. and non-U. S. patents to Alfonso Ganan-Calvo all of which are incorporated herein by reference in their entirety to disclose and describe methods of making uniform sized small particles.
  • An aspect of this invention is to show that in addition to relying on the chemical properties of injected microparticles for their controlled release characteristics, the physical size of these particles can be used to provide another layer of control over the release profile because that the physical size of particles in different groups of particles can be controlled precisely as can the total surface area of all the particles in the group combined.
  • the particles are very small in size (e.g. 1-40 micrometers) the surface area differential from one group to the next can be made quite large by small changes in diameter.
  • Poly (lactide-co-glycolide) polymers can be used as an excipient in the creation of precisely sized microparticles for attachment to a device such as a surgical screw to produce a sustained release profile by using short chain PLGA polymer allowing the PLGA to be manipulated during the formulation process without the use of organic solvents.
  • PDLLA poly-dl-lactic acid which has a higher glass transition point (about 45° - 55°C) than PLGA having a glass transition point of about 30° - 40°C.
  • the present invention relies additionally on precise sizing of the microparticles and the use of at least two different sizes of microparticles in the formulation.
  • precise sizing of the microparticles By exploiting the precise differences in surface area to volume ratio in the different populations of microparticles in the formulation, there is intrinsically less reliance on the chemistry of the particles to produce a sustained levels of the drug in the surrounding area.
  • a simpler chemistry By relaxing the requirement that the chemistry will have the predominant effect on the controlled release behavior a simpler chemistry can be employed which is easier and less costly to manufacture, and which avoids the use of organic solvents during its production period.
  • short chain PLGA polymer can be employed which can be processed without the use of organic solvents.
  • Poly (lactide-co-glycolides) (PLGA) compositions are commercially available from Boehringer Ingelheim (Germany) under the Resomer mark e.g. PLGA 50:50 (Resomer RG-502), PLGA 75:25 (Resomer RG-752) and d, i-PLA (Resomer RG-206) and from Birmingham Polymers (Birmingham, Alabama). These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid.
  • An aspect of the invention is a biocompatible gel incorporating spherical
  • particles which provide a desired drug release profile by combining a plurality of different groups of particles wherein each group consists of particles all of which have Atty. Docket: PHRM-005WO a known size, number and shape so that the combined groups provide a rate of dissolution in a known environment where the gel is placed.
  • Another aspect of the invention is that it be comprised of a plurality (2 or more) of different groups of particles wherein the particles within each group are substantially the same in size and shape (+10%) and are different from one group to another group as regards the drug release profile of the particles in a particular group.
  • the particles preferably have a size in a range of from about 1 to about 100 micrometers in diameter and more preferably about 2 to 70 or 2 to 40 or 4 to 30 micrometers in diameter.
  • formulation of particles In addition to producing formulations comprised of different groups of particles the formulation of particles is being sealed in sterile disposable containers with a gel which may include a flavoring agent and/or a heat generating compound, all of which are generally added at the point of administration.
  • a gel which may include a flavoring agent and/or a heat generating compound, all of which are generally added at the point of administration.
  • the formulation of particles may be themselves considered devices because they are comprised of polymer and drug.
  • An aspect of the invention is a packet of formulation comprised of a first group and a second group of particles.
  • the particles are preferably spherical and are comprised of a biocompatible polymer and a pharmaceutically active drug which is a reverse transcriptase.
  • the particles are generally present in an amount of about 100 or more particles wherein all of the particles within the group have substantially the same size with a margin of error +10%.
  • There may be a plurality of groups of particles wherein the particles within the one group are the same with respect to each other but are different with respect to particles within another group. Further, the particle within one group have a rate of dissolution which is different from the particles within other groups thereby making it possible to provide a controlled release of the drug into the surrounding environment.
  • Another aspect of the invention is a formulation comprised of a plurality of particles which particles are comprised of two or more reverse transcriptase drugs and a biocompatible polymer.
  • the particles are dispersed in a pharmaceutically acceptable carrier which may be a biocompatible gel or absorbable collagen sponge.
  • the particles may have uniform size and shape or may be designed so as to have irregular sizes and shapes.
  • the formulation is designed such that when it is placed on tissue such as in a Atty. Docket: PHRM-005WO vagina, the formulation provides a therapeutically effective dose of the drug over a period of time of greater than 1 day and less than 7 days.
  • groups of particles are contained within a capsule which capsule is vaginally inserted. After insertion the capsule is dissolved and thereafter the particles within the capsule dissolve at different rates.
  • the capsule is sufficiently large so as to incorporate additional capsules each of which include groups of particles wherein the different capsules dissolve at different rates so as to provide controlled sustained release of the pharmaceutically active drug locally in the vaginal cavity.
  • the capsule is comprised of a biocompatible polymeric material which dissolves at body temperature in the presence of vaginal fluids.
  • the capsule may include from about 100 mg to about 600 mg of
  • Another aspect of the invention is a formulation comprised of a biocompatible polymer and a plurality of groups of particles.
  • the particles are comprised of a biocompatible polymer and a reverse transcriptase.
  • Still yet another aspect of the invention is groups of particles of biocompatible polymer with reverse transcriptase therein dispersed in a biocompatible gel such as FlosealTM which gel may be further comprised of a forming agent and/or a heat generating compound.
  • a biocompatible gel such as FlosealTM which gel may be further comprised of a forming agent and/or a heat generating compound.
  • Another aspect of the invention is a method comprising providing particles which may be in first and second groups of particles as defined here on a sponge having therein drug on and throughout the sponge and inserting the sponge into a vagina.
  • An aspect of the formulation comprising:
  • a plurality of particles comprised of a reverse transcriptase inhibitor and a
  • a pharmaceutically acceptable gel carrier having the particles dispersed therein.
  • transcriptase inhibitor is present in an amount in the range of 100 mg to 600 mg and wherein the reverse transcriptase inhibitor is selected from the group consisting of Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Tenofovir, Adefovir, Efavirenz, Nevirapine, Delavirdine, Etravirine.
  • the reverse transcriptase inhibitor is selected from the group consisting of Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Tenofovir, Adefovir, Efavirenz, Nevirapine, Delavirdine, Etravirine.
  • a first group of spherical particles comprising 100 or more particles wherein each particle of the first group has the same diameter as other particles in the first group with a margin of error of +10% or less;
  • a second group of spherical particles comprising 100 or more particles wherein each particle of the second group has the same diameter as other particles in the second group with a margin of error of +10% or less;
  • particles of the first group dissolve at a rate which is faster than a rate at which the particles of the second group dissolve and the formulation provides therapeutic levels of tenofovir to a target area.
  • a third group of spherical particles comprising 100 or more particles wherein each particle of the third group has the same diameter as other particles in the third group with a margin of error of +10% or less;
  • particles of the third group dissolve at a rate different from a rate at which the particles of the first and second groups dissolve.
  • a flavoring agent selected from the group consisting of lemon, mint, cherry, strawberry, bubble gum, pina colada and chocolate;
  • a compound which generates heat which is selected from the group consisting of propylene glycol, polyethylene glycol, hydroxypropyl cellulose, and lactic acid.
  • a plurality of additional groups of spherical particles comprising 100 or more particles wherein the particles of each additional group has the same diameter as other particles in that group with a margin of error of +20% or less;
  • the second group of particles have 1,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the first group of particles;
  • the third group of particles have 2,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the second group of particles.
  • the second group of particles have 5,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the first group of particles; and Atty. Docket: PHRM-005WO
  • the third group of particles have 10,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the second group of particles.
  • particles in each group have a diameter in a range of from about 40 micrometers to about 2 micrometers.
  • particles in each group have a diameter in a range of from about 30 micrometers to about 4 micrometers.
  • the second group of particles have 1,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the first group of particles;
  • the third group of particles have 2,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the second group of particles.
  • the second group of particles have 5,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the first group of particles;
  • the third group of particles have 10,000 square centimeters or more of surface area per 0.1cm of total particle volume per group of particles more than the second group of particles.
  • Another aspect of the invention is in a use or method of improving patient compliance, comprising: Atty. Docket: PHRM-005WO
  • polymer with a pharmaceutically acceptable gel to provide a dispersion of particles in the gel
  • a flavoring agent selected from the group consisting of lemon, mint, cherry, strawberry, bubble gum, pina colada and chocolate;
  • a compound which generates heat which is selected from the group consisting of propylene glycol, polyethylene glycol, hydroxypropyl cellulose, and lactic acid.
  • Another aspect of the invention is a drug formulation capsule
  • a group of particles comprised of a reverse transcriptase inhibitor and a
  • a second group of particles comprised of a reverse transcriptase inhibitor and a pharmaceutically acceptable carrier
  • the first group of particles provides for immediate release of the reverse transcriptase inhibitor and the second group of particles provides for controlled release of the reverse transcriptase inhibitor over a period of time from 24 hours to 7 days.
  • transcriptase inhibitor is present in an amount in the range of 100 mg to 600 mg and wherein the reverse transcriptase inhibitor is selected from the group consisting of Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Tenofovir, Adefovir, Efavirenz, Nevirapine, Delavirdine, Etravirine. Atty. Docket: PHRM-005WO
  • Figure 1 is a schematic view of a spray drying device which produces particles of random sizes and shapes.
  • Figure 2 is a schematic view of an embodiment of an extrusion device used to create spherical particles of substantial uniform size and spherical shape.
  • Figure 3 is a schematic view of an embodiment of an extrusion device used to create spherical coated particles of substantial uniform size and spherical shape.
  • Figure 4 is a schematic graph of time versus (amount of a compound dissolved minus the amount eliminated) for a single particle or group to substantially identical particles.
  • Figure 5 is a schematic graph of time versus (amount of a compound dissolved minus the amount eliminated) for two different particles or two different groups of particles (solid and dashed lines) where the particles within a given group are Atty. Docket: PHRM-005WO substantially identical and also showing the combined effect of the two groups (dotted lines).
  • Figure 6 is a schematic graph of time versus (amount of a compound dissolved minus the amount eliminated) for three different particles or three different groups of particles where the particles within a given group are substantially identical and also showing the combined effect of the three groups.
  • Figure 7 is a schematic diagram showing a proposed drug release rate of the invention as compared with immediate release tenofovir powder.
  • Reverse transcriptase inhibitors are compounds which block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double- stranded viral DNA, thus preventing HIV from multiplying.
  • RTIs Reverse transcriptase inhibitors
  • the viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus.
  • the RTIs block the enzyme function.
  • the hepatitis B virus for example, carries its genetic material in the form of DNA, and employs a RNA-dependent DNA polymerase to replicate.
  • Some of the same compounds used as RTIs can also block HBV replication; when used in this way they are referred to as polymerase inhibitors.
  • Reverse transcriptase inhibitors come in three forms: Nucleoside analog
  • NRTIs Non-nucleoside reverse- transcriptase inhibitors
  • NRTIs and NtRTIs are essentially the same; they are
  • NRTIs and NtRTIs lack a 3'-hydroxyl group on the deoxyribose moiety.
  • the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain.
  • chain termination a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors.
  • NNRTIs have a completely different mode of action. NNRTIs block reverse transcriptase by binding at a different site on the enzyme, compared to NRTIs and NtRTIs. NNRTIs are not incorporated into the viral DNA but instead inhibit the movement of protein domains of reverse transcriptase that are needed to carry out the process of DNA synthesis. NNRTIs are therefore classified as non-competitive inhibitors of reverse transcriptase.
  • NRTIs compose the first class of antiretroviral drugs developed.
  • NRTIs In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of
  • NRTI triphosphates three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates.
  • This phosphorylation step is carried out by cellular kinase enzymes.
  • Zidovudine also called AZT, ZDV, and azido thymidine, has the trade name
  • Zidovudine was the first antiretroviral drug approved by the FDA for the treatment of HIV.
  • Didanosine also called ddl, with the trade names Videx and Videx EC, was the second FDA-approved antiretroviral drug. It is an analog of adenosine.
  • Zalcitabine also called ddC and dideoxycytidine, has the trade name Hivid.
  • Stavudine also called d4T, has trade names Zerit and Zerit XR.
  • Lamivudine also called 3TC, has the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is the trade name Zeffix and Epivir. It is
  • Abacavir also called ABC, has the trade name Ziagen, is an analog of
  • Emtricitabine also called FTC, has the trade name Emtriva (formerly
  • Coviracil Structurally similar to lamivudine, it is approved for the treatment of HIV and undergoing clinical trials for hepatitis B.
  • Entecavir also called ETV, is a guanine analog that has the trade name
  • Apricitabine also called ATC. As of 2009, this drug is undergoing Phase-Ill evaluation, and if successful may achieve FDA approval in 2011.
  • nucleoside analogs are converted into nucleotide analogs by the body. Taking nucleotide analog reverse-transcriptase inhibitors (NtARTIs or NtRTIs) directly allows conversion steps to be skipped.
  • NtARTIs or NtRTIs nucleotide analog reverse-transcriptase inhibitors
  • Tenofovir also known as TDF is a so called 'prodrug' with the active compound deactivated by a molecular side chain that dissolves in the human body allowing a low dose of tenofovir to reach the site of desired activity.
  • TDF a so called 'prodrug' with the active compound deactivated by a molecular side chain that dissolves in the human body allowing a low dose of tenofovir to reach the site of desired activity.
  • the prodrug form is tenofovir disoproxil fumarate with the trade name Viread (Gilead Sciences Inc USA). It is a roved in the USA for the treatment of both HIV and hepatitis B.
  • Tenofovir disoproxil fumarate is a prodrug form of tenofovir.
  • Tenofovir is also available in a fixed-dose combination withemtricitabine in a product with the brand name Truvada for once-a-day dosing.
  • Atripla a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
  • Adefovir also known as bis-POM PMPA, has trade names Preveon and
  • Hepsera It was not approved by the FDA for treatment of HIV due to toxicity issues, but a lower dose is approved for the treatment of hepatitis B.
  • NRTIs Non-nucleoside reverse-transcriptase inhibitors
  • Efavirenz which has the trade names Sustiva and Stocrin.
  • Nevirapine which has the trade name Viramune.
  • Delavirdine which currently is rarely used and has the trade name
  • RT transcriptase
  • I integrase
  • HIV replication HIV can and eventually does develop mechanisms that confer the virus resistance to the drugs. HIV-1 RT does not have proof-reading activity, this combined with selective pressure from the drug leads to mutations in reverse transcriptase that make the virus less susceptible to NRTIs and NNRTIs. Aspartate residues 110, 185, and 186 in the reverse transcriptase polymerase domain are important in the binding and incorporation of nucleotides. The side chains of residues K65, R72, and Q151 interact with the next incoming nucleotide. Also important is L74, which interacts with the template strand to position it for base pairing with the nucleotide. Mutation of these key amino acids results in reduced incorporation of the analogs.
  • transcriptase that reduce the enzyme's affinity or ability to bind to the drug.
  • a prime example for this mechanism is the Ml 84V mutation that confers resistance to lamivudine (3TC) and emtricitabine (FTC).
  • Another well characterized set of mutations is the Q151M complex found in multi-drug resistant HIV which decreases reverse transcriptase's efficiency at incorporating NRTIs, but does not affect natural nucleotide incorporation.
  • the complex includes Q151M mutation along with A62V, V75I, F77L, and Fl 16Y.
  • a virus with Q151M alone is intermediately resistant to zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), and slightly resistant to abacavir (ABC).
  • a virus with Q151M complexed with the other four mutations becomes highly resistant to the above drugs, and is additionally resistant to lamivudine (3TC) and emtricitabine (FTC).
  • the second mechanism is the excision or the hydrolytic removal of the
  • Excision enhancement mutations typically M41L, D67N, K70R, L210W, T215Y/F, and K219E/Q, are selected for by thymidine analogs AZT and D4T; and are therefore called thymidine analog mutations (TAMs).
  • TAMs thymidine analog mutations
  • NNRTIs do not bind to the active site of the polymerase but in a less conserved pocket near the active site in the p66 sudomain. Their binding results in a
  • NNRTI efavirenz
  • NNP nevirapine
  • a second mechanism is the disruption of important interactions on the inside of the pocket.
  • Y181C and Y188L result in the loss of important aromatic rings involved in NNRTI binding.
  • the third type of mutations result in changes in the overall conformation or the size of the NNRTI binding pocket.
  • G190E which creates a steric bulk in the pocket, leaving little or no room for an NNRTI to tightly bind.
  • treatment used herein to generally mean obtaining a desired pharmacological or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing an infection or disease such as an infection or symptom thereof and may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease or infection.
  • Treatment covers inhibiting any viral infection such as an HIV infection in a human, and includes:
  • Treatment may be specifically directed towards treating patients who may have intercourse with an individual who is already infected with HIV in order to prevent infection of the patient.
  • a formulation of the invention might be comprised of two groups of particles.
  • the particles within each group may have the same size and shape e.g.
  • the particles in the first group will be different from the particles in the second group in a manner which results in the first group dissolving at a rate which is faster than the particles in the second group.
  • the particles are comprised of a biocompatible polymer and a drug which is a reverse transcriptase inhibitor such as a tenofovir.
  • Other groups of particles and particles of different sizes may be added to such a formulation in order to provide variations on the release profile in order to get a release rate similar to that shown in Figure 7.
  • the object is to obtain release at a low, but therapeutically effective level at the target area over a sufficiently long period of time (1-7 days) so as to prevent infection and to avoid reaching toxic levels shown in Figure 7.
  • the formulation may be designed in a form of a capsule.
  • the capsule may be designed in a form of a capsule.
  • the capsule may include groups of particles and a gel or simply include the particles without the gel where the drug is present in an amount of about 300 mg +
  • the capsule and particles may be designed such that essentially no drug is released immediately upon administration, and thereafter when the capsule dissolves drug is released in pulses (see Figure 7) beginning with immediate release particles and Atty. Docket: PHRM-005WO continuing to controlled release particles so as to provide a therapeutic level of the drug locally in the vagina over a period of time of from 24 hours to about 7 days.
  • the formulation may include any mixtures of particles in a solution, in a biocompatible gel or combination of the solution and gel with two or more reverse transcriptase inhibitors therein. More specifically, the formulation may be comprised of the particles included within a separate sealed packet. That packet may be opened just prior to use and added to an aqueous solution. In another formulation of the invention particles or the groups of particles contained within the sealed packet are opened just prior to administration and added to a biocompatible gel. The particle formulations are mixed into the gel so that the particles are evenly distributed throughout the gel. Thereafter, the formulation comprised of the gel having particles dispersed therein is administered to a patient such as by injecting the formulation from a syringe.
  • the particles or groups of particles contained within the packet or packets are removed from the packet just prior to use and added to the aqueous solution as described above. Further, just prior to administration that aqueous solution is intermixed with a biocompatible gel such as FlosealTM. The particles and solution are thoroughly mixed with a compatible gel such as FlosealTM. A combination of particles, thrombin solution and FlosealTM may be thoroughly mixed within a syringe or other appropriate container. After dispersing the solution and particles throughout the gel the formulation is administered to a vagina prior to intercourse.
  • the drug which may be a reverse transcriptase inhibitor such as tenofovir is preferably not administered systemically but rather locally. Further, it is administered in an amount so as to obtain a therapeutic level but not a toxic level 30 mcg/ml +25 Atty. Docket: PHRM-005WO mcg/ml. Still further, the therapeutic level is preferably maintained over a sufficiently long period of time so as to prevent infection (over 24 hours). Still further, low levels of drug release over long periods of time as shown in Figure 7 are preferred.
  • any of the embodiments of the invention described above can be further supplemented by adding some quick release drug which may be a powdered form of a drug such as a powdered form of a reverse transcriptase inhibitor such as tenofovir.
  • the powdered drug can be combined with the particles or groups of particles in solution, or combined with the particles, solution and gel.
  • the various components of the formulation can be intermixed in a manner so as to evenly disperse the components throughout the formulation or the different components can be added separately to a vagina prior to intercourse. With there various formulations in mind those skilled in the art should consider the mathematics of the controlled release particles as described further below.
  • the formulation packets are comprised of particles or groups of particles based on mathematics. For any given particle having a given amount of surface area the rate of dissolution will decrease as the particle dissolves and the total available surface area decreases. Thus, a spherical particle with two square units of available surface area which dissolves at a rate of X per unit of time will be dissolving at a rate of X/2 per unit of time once the particle has dissolved so that it has one square unit of available surface area. This assumes a constant environment unaffected by the dissolution.
  • Formulations of the invention are comprised of two or more groups of particles having a diameter of 2 to
  • a particle with a large available surface area has a more rapid dissolution rate that a particle with a small available surface area.
  • the group of smaller particles has a faster dissolution rate than the group of larger particles because the group of smaller particles will have a larger available surface area than the group of larger particles.
  • a predetermined amount of compound such as a drug
  • a system such as a human
  • the rate of dissolution is dictated by the available surface area.
  • One spherical particle with a given total volume will present approximately half the surface area as ten particles with the same combined volume as the one particle.
  • Formulations and/or devices coated with a formulation of the invention may include some reverse transcriptase inhibitor by itself (no polymer sphere) such as an tenofovir for immediate release to provide a fast antiviral effect in the surrounding area.
  • some reverse transcriptase inhibitor by itself such as an tenofovir for immediate release to provide a fast antiviral effect in the surrounding area.
  • greater numbers of groups of different particles can increase the duration time the drug is released and decrease changes in the concentration of the drug in the surrounding areas over time.
  • the multiple groups can be effective in keeping the concentration in the desired range - high enough to be therapeutic but low enough so as to not be toxic.
  • 2 or more, 3 or more, 4 or more or 5 or more groups can be used to maintain the desired therapeutic level over time - see Figures 4, 5 and 6.
  • centimeters the size a single sphere which will hold a 2cc volume can be readily calculated using the formula for the volume of a sphere as follows: Atty. Docket: PHRM-005WO
  • the formula for the volume of a sphere can be readily modified to determine the volume of any number of spheres "n" needed to make a total volume of 2 cubic centimeters.
  • each sphere is 0.2cm and the surface area of each sphere is
  • the total volume of the 10 spheres remains the same (i.e. 2cc) but the surface area of all 10 spheres is 16.5cm 2 as compared to 9.8217cm 2 when "n" was one.
  • the radius "r” can be solved for and found to be 0.1684cm with the volume of each of the 100 spheres being 0.02cm .
  • the surface area of each sphere is 0.3563cm 2 and the combined surface area of all 100 spheres is 35.63cm 2— Atty. Docket: PHRM-005WO the combined volume remains the same at 2cm .
  • the equations for the surface area and volume can be used to solve for the radius "r” and diameter "d” of any number of spheres "n” which equal a total volume of 2cm and the results are provided below.
  • 6.7cm 2 and from 16.5 to 35.6 is only an increase of 19.1cm 2.
  • n increases from 10 9 to 10 10 the surface area increases from 7677 to 16,539 resulting in Atty. Docket: PHRM-005WO an increase of 8,862cm 2 .
  • n increases from 10 10 to 10 11 the surface area increases from 16,539 to 35,631 resulting in an increase of 18,992cm .
  • this differential in surface area between groups will be less when the total volume is less.
  • This differential is based on a total volume of 2cm which is a large dose.
  • the dose may be 1cm 3 , 0.1cm 3 , 0.01cm 3 , 0.001cm 3 or less. With smaller volumes the total surface area differential between groups will be less.
  • formulations may have two, three or a plurality of different groups of particles therein.
  • the formulation suspension may be created where a first group has a first surface area and a second group has 1 ,000 square centimeters or more surface area than the first group or e.g. 2,000 or more; 5,000 or more; or 10,000 or more square centimeters of surface area per 0.1cm of total volume per group of particles more than the surface area of the first group.
  • Formulations of suspensions of particles may be created Atty. Docket: PHRM-005WO whereby a plurality of different groups are present and the total surface area of any one group different from the total surface area of any other group by a desired amount e.g. 1,000; 2,000; 3,000; 4,000; 5,000; and 10,000 or more square centimeters of surface area per 0.1cm of total volume per group of particles.
  • a formulation of the invention can be created which provides a desired release profile.
  • the desired release profile can be understood by reference to Figure 7 which is a schematic diagram showing areas where a given concentration of a reverse transcriptase inhibitor might be obtained over time with different groups of particles. Figure 7 shows how therapeutic levels can be maintained over a relatively long period of time.
  • the shape and size of the particles will effect the dissolution time as well as the particle configuration. More particularly, the particle may be comprised of polymer intermixed with the drug or have the drug encapsulated within a polymer. There will also be some variation depending on the patient in that patient's with poor circulation provide a different environment for the particles as compared to patient's with normal circulation.
  • the solvent or surrounding environment into which the drug is administered can be assumed to be known within the vagina.
  • the unknown that remains is the rate of dissolution of a particle of known size in a given solvent.
  • the rate of dissolution of other particle sizes with different available surface areas can be calculated. Assuming all the particles of a group of particles are spherical and also assuming that the particles in a given group of particles all have substantially the same size (available surface area), the rate of dissolution of a group of particles can be readily determined.
  • a formulation can be created with different groups or types of particles wherein each group of particles has a known drug release profile within the environment the formulation is delivered to.
  • the formulation preferably comprises a number of different groups which release drug at different rates Atty. Docket: PHRM-005WO and/or times and provide a desired drug release profile, e.g. substantially constant levels in the surrounding area over a therapeutically effective time period.
  • Particles and coated particles can be produced via any available technology.
  • cylindrical tube 1 is shown in fluid connection with a liquid source 2 which can supply liquid 3 to the tube 1.
  • the liquid 3 exits the tube 1 from an exit opening which can be any configuration but is preferably circular and has a diameter D.
  • the liquid 3 exits the opening 4 and forms a stream which breaks into segments 5 and eventually forms partial spheres 6 and then spheres 7 which are substantially equal in size and shape.
  • the spheres 7 could be used in creating a group of particles for attachment to a device such as a surgical screw. Different size spheres from different sized tubes 1 could create different groups of spheres as needed for a desired dissolution profile.
  • the coating source 8 creates a spray 9 of a coating material which is brought into contact with and sticks to particles 10, 11 and 12 often in different amounts. Further, two particles 13 may become coated together or three or more particles 14 may become coated together.
  • Coated particles of this type could be used if they provide the desired level of drug at the target site over the desired period of time.
  • the coating material can be mixed with rather than sprayed on the particles and a similar random mixture of coated particles and coated groups of particles will result.
  • the random mixture has some advantages. It can provide a Atty. Docket: PHRM-005WO greater range of release rates than a single type of particle. The greater range of release rates may provide a release profile which is desirable. However, a degree of trial and error is required in producing a desired release profile. Further, great care must be taken once the desired profile is obtained in repeating all preparation steps precisely from batch to batch. Otherwise, each new batch of formulation produced will have a different release profile.
  • the process for producing particles 7 as shown in Figure 1 has yet another disadvantage or limitation.
  • the diameter D of the tube 1 dictates that the diameter of the particles 7 formed will be approximately D x 1.89 (Rayleigh, "On the instability of jets", Proc. London Math. Soc, 4-13, 1878).
  • the inside diameter of the tube 1 must be very small.
  • the narrower tubes tend to clog easily.
  • Figure 2 shows a tube 21 supplied by a liquid source 22.
  • the liquid 23 flows out of the exit 24.
  • the liquid 23 stream is focused to a narrowed stable jet 25 by a gas 26 provided by the gas source 27 flowing into a pressure chamber 28 and out of an exit orifice 29.
  • the jet 25 disassociates into segments 30 which form spheres 31 in the same manner in which the stream of liquid 3 forms the spheres 7 shown in Figure 1.
  • the spheres 31 have a diameter which is 1.89 x the diameter D j of the jet and not 1.89 x the diameter D of the tube 21.
  • the diameter of the jet 25 (D j ) is
  • the system of Figure 2 can be used to make very small particles as compared to the system of Figure 1 without clogging the exit 24 of the tube 21 because the diameter D of the tube 21 can remain large - and without clogging the exit orifice 29 of the pressure chamber 28 because the jet 25 exits the orifice 29 surrounded by the gas 26.
  • the particles 31 can be coated using a spray on coating as shown in Figure 1.
  • the particles 31 can be used without any coating. Groups of particles can be combined to Atty. Docket: PHRM-005WO provide a desired dissolution profile.
  • the small size of the particles provides certain advantages as shown in Tables 1-5. Particles in a size range of 1-20 micrometers can not be easily produced in a system as shown in Figure 1 and particles in this size range provide the greatest differences in surface areas - see Tables 1-5 and Table 2 in particular.
  • the particles themselves are limited in terms of the dissolution profile they can produce particularly when the total volume of the particles in a formulation is limited. Thus, a coating is preferred and a preferred means of obtaining such is shown in Figure 3.
  • FIG. 3 The system schematically shown in Figure 3 includes a tube 41 in fluid
  • a tube 44 is concentrically positioned around the tube 41 and is in fluid connection with a coating source 45.
  • the exit opening 46 of the tube 41 and the exit opening 47 of the tube 44 are both positioned inside of a pressure chamber 48.
  • the chamber 48 is in fluid connection with the gas source 49 which flows out of the exit orifice 50 of the chamber 48.
  • the gas 51 focuses the streams of liquid 43 and coating 52 into a stable jet 53.
  • the jet 53 disassociates into segmented streams 54 of liquid 43 concentrically surrounded by coating 52.
  • the segmented streams 53 form spheres 55.
  • the spheres 55 are comprised of a liquid 43 center surrounded by a polymeric (e.g. PLGA) coating 52.
  • the spheres 55 are preferably very small, e.g. a diameter of less than 50 ⁇ , preferably less than 20 ⁇ and more preferably about ⁇ . The smaller the particles the more readily evaporation will take place which will cure or solidify the coating 52.
  • An energy source 56 may be used to direct energy 57 onto the particles 55 to enhance the rate of curing, hardening, evaporation, etc.
  • the energy 57 may be any type of energy including heat, forced air, I.R. or U.V. light etc. alone or in
  • Some polymer materials are designed to be cured using a particular frequency of light.
  • the light can be directed, focused and/or intensified using lenses, mirrors and the like to obtain a desired result.
  • the particles 55 could be produced and dispersed in a biocompatible gel and applied to bone and/or an orthopedic implant.
  • the coated particles 55 can include any liquid 43 coated with any coating
  • the liquid 43 be comprised of a pharmaceutically active drug which is preferably a reverse transcriptase inhibitor and more preferably a tenofovir.
  • the coating material can be comprised of any type of material which can be cured, dried or fixed in any fashion in order to form an outer spherical coating around the center.
  • the coating material be comprised of a polymer material and more preferable if the polymer material is quickly and readily curable and is a material which is commonly accepted as useful as a carried material in controlled release formulations used in pharmaceutical applications. A number of such polymer materials are disclosed within the patents and publications described below.
  • U.S. Patent 3,773,919 describes creating slow release formulations producing a steady release of drug in the bloodstream by employing polylactide-drug mixtures in the dosage form.
  • the inventors describe using a chemical based microencapsulation procedure for forming precipitates of the polylactide-drug mixtures suitable for injection. They discuss many potential applications for their invention including the administration of morphine.
  • U.S. Patent 4,942,035 describes using PLGA polymer as an excipient allowing formulations to be created to facilitate the controlled release of polypeptide active drugs into solutions.
  • U.S. Patent 5,514,380 describes modifying the cross-linking in PLGA polymer in order to obtain more controllable release profiles.
  • U.S. Patent 5,543,158 describes potential benefits of using PLGA polymer with pharmaceutically active drug to create particles in a very small size range to minimize incorporation of the injected formulation into the patient's macrophages which would result in inactivation of the drug.
  • U.S. Patent 5,654,008 describes a technique for combining PLGA and active drug into microparticles suitable for injection by using an emulsion system created using a static mixer.
  • U.S. Patent 5,759,583 describes using a quaternary ammonium surfactant as an excipient to facilitate the creation of PLGA drug combinations suitable for injection to create a controlled release formulation.
  • U.S. Patent 5,912,015 describes using metal cations as release modulators in the injectable drug formulation comprising PLGA and active drug.
  • U.S. Patent 5,916,598 describes using emulsion systems and solvent extraction techniques as tools for creating microparticles comprised of PLGA and active drug for sustained release formulations.
  • microparticles suitable for injection are suitable for injection. These techniques have focused on the use of solvent systems to produce emulsions resulting in the creation of a precipitate of crystalline microparticle in an approximate size range suitable for injection. Other systems involve removing solvents used during the fabrication process.
  • the US FDA as well as international drug regulatory authorities have drafted regulations strictly limiting the amount of residual solvent acceptable in marketed pharmaceutical preparations (ICH Harmonized Tripartite Guideline Q3C Impurities: "Guidelines for Residual Solvents").
  • Controlled release drug delivery systems may also be categorized under their basic technology areas, including, but not limited to, rate-preprogrammed drug delivery systems, activation-modulated drug delivery systems, feedback-regulated drug delivery systems, and site-targeting drug delivery systems. Atty. Docket: PHRM-005WO
  • rate-preprogrammed drug delivery systems release of drug molecules from the delivery systems is "preprogrammed" at specific rate profiles. This may be accomplished by system design, which controls the molecular diffusion of drug molecules in and/or across the barrier medium within or surrounding the delivery system. Fick's laws of diffusion are often followed.
  • release of drug molecules from the delivery systems is activated by some physical, chemical or biochemical processes and/or facilitated by the energy supplied externally.
  • the rate of drug release is then controlled by regulating the process applied, or energy input.
  • release of drug molecules from the delivery systems may be activated by a triggering event, such as a biochemical substance, in the body.
  • a triggering event such as a biochemical substance
  • the rate of drug release is then controlled by the concentration of triggering agent detected by a sensor in the feedback regulated mechanism.
  • the drug delivery system targets the active molecule to a specific site or target tissue or cell.
  • a conjugate including a site specific targeting moiety that leads the drug delivery system to the vicinity of a target tissue (or cell), a solubilizer that enables the drug delivery system to be transported to and preferentially taken up by a target tissue, and a drug moiety that is covalently bonded to the polymer backbone through a spacer and contains a cleavable group that can be cleaved only by a specific enzyme at the target tissue.
  • Another controlled release dosage form is a complex between an ion exchange resin and the lipoates.
  • Ion exchange resin-drug complexes have been used to formulate sustained-release products of acidic and basic drugs.
  • a polymeric film coating is provided to the ion exchange resin-drug complex particles, making drug release from these particles diffusion controlled. See Y. Raghunathan et al., Sustained-released drug delivery system I: Coded ion-exchange resin systems for phenylpropanolamine and other drugs, J. Pharm. Sciences 70: 379-384 (1981).
  • Injectable micro spheres are another controlled release dosage form.
  • Injectable micro spheres may be prepared by non-aqueous phase separation techniques, and Atty. Docket: PHRM-005WO spray-drying techniques.
  • Micro spheres may be prepared using polylactic acid or copoly(lactic/glycolic acid). Shigeyuki Takada, Utilization of an Amorphous Form of a Water-Soluble GPIIb/IIIa Antagonist for Controlled Release From Biodegradable Micro spheres, Pharm. Res. 14: 1146-1150 (1997), and ethyl cellulose, Yoshiyuki Koida, Studies on Dissolution Mechanism of Drugs from Ethyl Cellulose
  • the liquid 43 is forced through the channel of the tube 41.
  • the liquid is preferably a relatively high concentration of a drug such as a reverse transcriptase inhibitor in either an aqueous or alcohol based solvent or other solvent which will quickly evaporate (e.g. ether).
  • the exit opening 46 of the tube 41 and the exit opening 47 of the tube 44 are both positioned inside the pressure chamber 48.
  • the coating material 52 is initially in a liquid form and is forced through the exit opening 46 of the tube 44 which is positioned concentrically around the tube 41 in a manner which causes a stream of the liquid coating material to be expelled from the opening 47 at substantially the same velocity as the liquid 43 is forced from the opening 46 of the tube 41.
  • the stream of the coating material is concentrically positioned around the stream of the center liquid 43.
  • the streams exit the openings of the two concentrically positioned tubes as a single combined stream which then disassociates into segments streams 53 which segments form the cooled spheres 55.
  • the gas from the gas source forms the stable jet and the diameter of the jet is substantially smaller than would be the case if the gas were not focusing the streams exiting the tubes 41 and 44.
  • the diameter of the jet is defined by the following formula:
  • dj is the diameter of the stable unified jet
  • ⁇ indicates approximately equally to where an acceptable margin of error is +10%
  • pi is the average density of the liquid of the jet
  • AP g is change in gas pressure of gas surrounding the stream at a given point A at the exit
  • Q is the total flow rate of the stable unified jet.
  • the particles may be of any size but are preferably in less than 100 micrometers in diameter, more preferably less than 50 micrometers in diameter and still more preferably less than 20 micrometers in diameter.
  • the technology described above and shown in Figure 2 and 3 is capable of producing particles which are as small as approximately 1 micrometer in diameter and preferred devices of the invention will include particles which have a diameter of approximately 10 micrometers.
  • the sphere forming technology can produce particles which are substantially identical in shape (spherical) and substantially identical in size +10% variation in the particle diameter, more preferably +3% and still more preferably +1% variation in particle diameter where the particle may have a diameter as small as 1 ⁇ or more or as large as ⁇ or more.
  • PHRM-005WO system works best when the Weber Number is in a range of from about 1 to about 40 wherein the Weber Number is defined by the following equation:
  • the Weber number is in a range of about 5 to about 25.
  • ⁇ is the velocity of the liquid
  • pi is the density of the liquid
  • d is the diameter of the stable capillary microjet.
  • Figure 5 shows how the therapeutic level can be maintained over a longer
  • Controlled release within the scope of this invention can be taken to mean any one of a number of extended release dosage forms.
  • the following terms may be considered to be substantially equivalent to controlled release, for the purposes of the present invention: continuous release, controlled release, delayed release, depot, gradual release, long-term release, programmed release, prolonged release,
  • the gas source 27 could be replaced with a liquid C0 2 and the liquid C0 2 could become the focusing fluid.
  • the liquid 23 supplied into the tube 21 could be any liquid comprised of any desired material. However, the liquid 23 would preferably be a liquid which included an active compound such as a drug which is dissolved within a solvent such as water and further combined with a solvent such as ethanol.
  • the solvent liquid 23 is focused by the surrounding liquid 26 which may be C0 2 .
  • a packet of formulation can be a disposable container of spheres with a group or plurality of groups of spheres in each packet.
  • the packet may be a syringe which includes the particles in a liquid or a gel such as FlorsealTM.
  • the packet may be a sealed container such as a foil packet holding an absorbable collagen sponge Atty. Docket: PHRM-005WO having the particles dispersed evenly therein.
  • a first group of spherical particles is present wherein each particle of the first group has a same diameter as other particles in the group with a margin of error in terms of particle diameter size of approximately
  • the formulation may then include a second group of spherical particles wherein each particle of the second group has the same diameter as the other particles in the second group with a margin of error of about +10% or less.
  • the particles within the first group are different from the particles within the second group (e.g. see Table
  • the first group of particles and the second group of particles each comprise 100 or more particles, more preferably a 1,000 of more particles, and still more preferably 10,000 or more particles and may comprise 10 5 to 10 10 or more particles.
  • heterogeneous groups of particles in a formulation can be produced using particle formation technology of various types the technology as described above with respect to Figure 2 and 3 are preferred in that they produce very uniform sized and shaped particles.
  • the particles may be solid spheres which may be produced using the technology as shown in Figure 2.
  • a formulation or device of the invention may include groups of particles wherein the particles are coated using the technology as shown within Figure 3.
  • a formulation may include 3 or more groups of spherical particles wherein the particles within each group are the same relative to other particles in that group and are different between the groups.
  • a formulation may comprise at least some particles which are not coated e.g. a first group of particles with no coating and a relatively small particle size.
  • the first group of particles will provide for substantially immediate dissolution and release of all of the compound or drug which is present in the particles. This causes the drug to quickly reach a therapeutic level in the desired surrounding area.
  • the remaining groups of particles are larger and include polymers and remain undissolved.
  • diffusion will have removed from the surrounding area (e.g. the bone) a sufficient amount of the drug added by the first group such that the concentration of the Atty. Docket: PHRM-005WO drug in the surrounding area is beginning to decline.
  • the second group of particles increase their dissolution to add drug to the surrounding area thereby gradually increasing the concentration via the second group of particles at a rate substantially corresponding to the rate at which drug from the first group of particles is being decreased and diffused out of the area.
  • the process can be repeated several times with several different groups of particles and three different groups of particles are shown within the graph of Figure 6.
  • the groups may be included in a packet of formulation which may be a disposable, one use, syringe with a gel and the syringe, gel, and particles may be included in a kit.
  • the kit may include another drug which compliments the drug in the particles.
  • a reverse transcriptase inhibitor is dissolved in a solvent which may be water, ethanol or a combination of water and ethanol.
  • the solution is saturated with drug and the saturated solution is then coated with a polymer material which can be quickly cured by the addition of energy or evaporation as shown within Figure 3.
  • a group of particles is formed wherein the particles are comprised of a liquid center which liquid is comprised of a saturated solution of drug and solvent in an outer core of polymer material which is substantially inert i.e. does not provide a pharmacological effect.
  • Such particles are produced in a variety of different size ranges.
  • Each size is used to produce a group of particles which, by itself, is sufficient to provide for therapeutic levels of a drug to a given area such as an area surrounding the implant.
  • a liquid drug e.g. a drug in an aqueous solution
  • the next group of particles with a thicker coating have dissolved to the point where the drug within these particles is released raising the level of drug in the surrounding area.
  • the different groups of particles within the formulation may be particles which are all of the same size, but have different polymer materials.
  • composition of coating on one group of particles dissolves more rapidly than the coating composition on another group within the formulation.
  • Microspheres with a capsule thickness of zero are composed entirely of active drug; there is by definition no inactive ingredient forming a capsule layer. Therefore, even though a ⁇ microsphere with zero capsule thickness has the same surface area to volume ratio (1.2) as a 20 ⁇ microsphere with a 10% capsule thickness, release of active drug from the 20 ⁇ sphere will occur only after the outer layer has dissolved whereas active drug from the ⁇ sphere in this example will begin to be released as soon as microsphere dissolution begins.
  • high surface area to volume values do not necessarily mean faster release of active drug into the area surrounding the implant. This is because, for the case of non-zero capsule thickness microspheres, the outer material is an inactive ingredient.
  • a true programmable controlled release profile can be engineered by selecting (a) the capsule thickness and microsphere size and ( b) by selecting in which proportions different populations of microspheres selected in (a) are combined and bound to the implant (e.g. screw) or other device.
  • a slow release tenofovir formulation bound to indentations on a screw could consist of 1/3 zero capsule thickness 5 ⁇ microspheres for rapid release, 1/3 10% capsule thickness ⁇ spheres for intermediate release and 1/3 10% capsule thickness 20 ⁇ microspheres for long term release as part of a single formulation. Because the capsule of inactive material must be largely dissolved before active drug release, this approach has the distinct advantage of minimizing the overlap of delivery by the various formulation components. This allows the aggregate PK Atty. Docket: PHRM-005WO profile of the formulation to be formed by superposition of the release profiles of the components of the formulation.

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  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des formulations qui sont constituées de particules de ténofovir, et un gel biocompatible dans lequel les particules sont dispersées. Le gel peut être constitué d'un agent aromatisant et un ou plusieurs composés qui génèrent de la chaleur. Les particules peuvent être fournies dans une pluralité de groupes (2, 3 ou plus) de sphères de différentes tailles. Les sphères peuvent être constituées de ténofovir seul ou en combinaison avec de l'emtricitabine et un polymère à libération contrôlée tel que l'acide polylactique-glycolique (PLGA) ou un autre matériau biocompatible adapté.
PCT/US2014/022338 2013-03-14 2014-03-10 Gel vaginal à libération contrôlée avec particules antivirales Ceased WO2014159169A1 (fr)

Applications Claiming Priority (2)

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US201361783357P 2013-03-14 2013-03-14
US61/783,357 2013-03-14

Publications (1)

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WO2014159169A1 true WO2014159169A1 (fr) 2014-10-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017161136A1 (fr) * 2016-03-18 2017-09-21 Oak Crest Institute Of Science Sels acides pour l'administration vaginale d'un médicament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100291220A1 (en) * 2001-07-13 2010-11-18 Flow Focusing, Inc. Antibiotic formulation and method of treatment
US20110045076A1 (en) * 2008-01-25 2011-02-24 Kiser Patrick F Linear order release polymer
WO2013013172A1 (fr) * 2011-07-20 2013-01-24 The University Of Utah Research Foundation Dispositifs intravaginaux pour administration de médicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100291220A1 (en) * 2001-07-13 2010-11-18 Flow Focusing, Inc. Antibiotic formulation and method of treatment
US20110045076A1 (en) * 2008-01-25 2011-02-24 Kiser Patrick F Linear order release polymer
WO2013013172A1 (fr) * 2011-07-20 2013-01-24 The University Of Utah Research Foundation Dispositifs intravaginaux pour administration de médicaments

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017161136A1 (fr) * 2016-03-18 2017-09-21 Oak Crest Institute Of Science Sels acides pour l'administration vaginale d'un médicament

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