JP6154803B2 - Fast dissolving tablet composition for vaginal administration - Google Patents

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application No. 61 / 481,582, filed May 2, 2011, which is hereby incorporated by reference in its entirety. Are incorporated by reference for all purposes.

Vaginal drug delivery is a promising route for local action or systemic absorption of active pharmaceutical ingredients and treatment by uterine targeting. Vaginal drug delivery offers the following advantages:
• Large surface area • Avoidance of the first pass effect of the liver, which can result in a significant increase in bioavailability or a reduction in dose intensity or side effect profile.
• Dense network of blood vessels • High permeability to high molecular weight drugs such as peptides and proteins • Low systemic drug exposure (ie for products used for local symptoms)
Low enzyme activity and possible preferential transfer of absorbed drugs to the uterus (referred to as “first uterine passage effect”)
・ Easy removal when necessary

  Despite these advantages, the vaginal route of administration for drug delivery has been utilized only to a limited extent. Traditional vaginal drug delivery systems such as tablets are traditionally used to deliver contraceptives and bactericides to treat vaginal infections. Vaginal tablets, rings, creams, and adhesive gels containing a wide range of drugs (eg, steroids, prostaglandins, antibiotics, proteins, and peptides) have been developed and these vaginal drug delivery systems Performance evaluation in vitro, ex vivo, and in vivo has been studied. One or more non-toxic, non-toxic, which is easy to incorporate into a vaginal dosage form and can theoretically extend the residence time of biological activity in the vagina to reduce dosage frequency and dosage Studies on vaginal drug delivery systems, such as those involving irritating bioadhesive materials, include the following: Lehr, 2000. J. et al. Control. Rel. 65, 19-29; Mandal et al. 2000. J. et al. Pharm. Biopharm. 50, 337-343; Garg et al. 2001. Pharma. Tech. 14-23; Ceschel et al. 2001. Drug Del. Ind. Pharm. 6, 541-547; Bilensoy et al. , 2006. AAPS PharmSciTech. 7, 19-29; Valenta, 2005. Advanced Drug Del. Rev. 57, 1692-1712; Bonferoni et al. , 2006. AAPS Pharm. SciTech. 7, E1-E8; Neves et al. , 2008. Eur. J. et al. Pharm. Biopharm. 69, 622-632; Ndesendo et al. , 2009. Int. J. et al. Pharm. 370, 151-159; Poelvoorde et al. , 2009. J. et al. Pharm. Biopharm. 71,280-284-343; Perioli et al. , 2009. Int. J. et al. Pharm. 377, 120-127; Yellanki et al. , 2010. Int. J. et al. PharmTech Res. 2; 1746-1750; and Wang et al. , 2002. J. et al. Contr. Rel. 82, 39-50.

  Most of the bioadhesive gels, creams, and tablets used as vaginal delivery systems disintegrate rapidly after application into the vaginal cavity, minimizing bioadhesion to the vaginal mucosa. These complications are believed to be due to miscibility with water or due to lack of physical stability at body temperature, resulting in limited therapeutic efficacy. (I) one or more globule stabilizing polymers (eg, HPMC, polyvinyl alcohol, or PEGylated lipids) and (ii) containing a therapeutically active agent; vagina, urinary tract, cervix, or other woman Emulsion-based vaginal drug delivery systems have been developed, such as drugs approved or used for the treatment, prevention, cure or alleviation of genital diseases; induction of contraception; or systemic drug therapy.

  US 20030180366 (US Pat. No. 6,899,890) is based on a microemulsion based, suitable for modified delivery of therapeutically active substances into the vaginal cavity. Discloses a novel pH-neutral vaginal drug delivery system. U.S. Patent Publication No. 20050276836 discloses a method of coating a vaginal device for delivering a therapeutic or health enhancing agent with a mucoadhesive composition. WO 20081333928 discloses a method for treating a patient suffering from epithelial lesions such as the vagina or mucin dysfunction, as well as a pharmaceutical composition containing a mucin glycoprotein in combination with a therapeutic agent such as a trilobal polypeptide. Disclosed are methods for treating pain associated with epithelial lesions and mucin dysfunction. WO 20110061284 is a sustained release intravaginal, consisting of at least one pharmaceutically active ingredient mixed with a combination of biocompatible and biodegradable polymers and adapted for insertion into a patient's vagina A pharmaceutical dosage form is disclosed. Vaginal administration of sustained-release opioids such as oxycodone has been shown to be a safe, effective and simple means of controlling cancer pain in patients who cannot tolerate adverse events caused by oral administration (X. Zhang, X-J. Ruan, C. Liu, and Z-H. Yu, Effect of residual administration of controlled oxycodone on cancer chain, Ch. 9. J. Cancer J. Cancer C. 1-4; F. Acartuerk, Mucoadhesive Drug Drug Delivery Systems.Recent Patents on Drug Delivery & Formula 2 09,3,193-205) ( "Acartuerk 2009"). Acartuerk 2009 is a recent summary of the development and improved in vitro / in vivo evaluation of formulations for transmucosal vaginal delivery.

  Disintegration or dispersion / diffusion and retention times of bioadhesive vaginal dosage forms (eg, regular tablets, multiparticulate, adhesive gel formulations) have been extensively evaluated. Even normal tablets or bioadhesive vaginal tablets are easy for users to administer with privacy; however, these dosage forms may disintegrate or diffuse too slowly and are If it is removed too quickly, no meaningful treatment improvement can be achieved. Patient compliance levels are low, and the level is affected by restrictive dosing regimens, the need to take multiple combination oral formulations, patient concerns about the effectiveness of vaginal treatment, leakage, or dosing related discomfort It is thought to receive. Furthermore, gel dosage forms require the use of a vaginal applicator, which increases packaging materials and manufacturing costs.

As the impact of human immunodeficiency virus (HIV) continues to have a profound impact on many people around the world, one area in which vaginal administration has been explored is the acquired immune deficiency syndrome (AIDS) Related to treatment. HIV is primary infected and directly and directly transmits important components of the human immune system, such as CD4 ⁺ T cells (a subset of T cells necessary for the proper functioning of the human immune system), macrophages, and dendritic cells. It is a retrovirus that is indirectly destroyed. AIDS is a group of symptoms and infections in humans due to specific damage of the immune system caused by HIV. Over 13 million men and women are affected each year in the United States by AIDS, which develops through sexually transmitted infections (STIs). Although there are treatments for AIDS and HIV to slow down viral exacerbations, there are currently no known cures. Despite the recent report from the Joint United Nations Program on HIV / AIDS (UNAIDS / WHO 2008-Report on the Global AIDS Epidemic. Geneva: UNAIDS, p.362), claiming that the HIV epidemic has stabilized. 2.7 million new infections and over 2 million deaths were observed for HIV-1 infection.

  In HIV-infected patients, the effectiveness of highly active antiretroviral (ARV) treatment by blocking various stages of the retroviral life cycle is now well understood. Since HIV is a retrovirus that replicates within cells of the immune system, intracellular drug concentrations are important in determining the efficacy and toxicity of ARV drugs. Some of the ARV drugs used for oral administration are prodrugs that require intracellular anabolic phosphorylation to be converted to the active form of the triphosphorylated metabolite. Active metabolites that have a longer plasma half-life than the parent compound have been used in the vaginal route of administration.

  Some of the studies in the area of vaginal administration and HIV treatment include: In vitro and ex vivo testing that tenofovir (TFV) as a vaginal gel formulation containing 1% TFV and 2% hydroxyethylcellulose (HEC) as a bioadhesive polymer is as effective as the HIV-1 fungicide (Mayer et al., 2006. AIDS. 20, 543-551; Rohan et al., PLoS One Feb 2010.5, 1-12). A new generation vaginal gel containing 1% TFV in combination with 5% emitricitabine (FTC) provided protection against monkey HIV exposure in macaques (Parikh et al., 2009. J. Virology). .83, 10358-10364). Studies using (i) a dual segment polyurethane intravaginal ring that sustained release of two oral antiretroviral drugs tenofovir and dapivirin, or (ii) vaginal gel containing thiocarboxanilide UC781 From the results, antiretroviral activity was examined (Friend, 2000. Pharm. Develop. Technol. 1-20; Mahalingam et al., 2010. Pharm. Res. 27, 2478-2491).

Despite promising vaginal features for drug treatment, the following development and commercialization issues remain:
・ Lack of appropriate test methods in vitro / ex vivo ・ Lack of sufficient retention time of vaginal preparation ・ Lack of sufficient diffusion characteristics of vaginal preparation ・ Other limitations include changes in the vagina associated with the menstrual cycle, Genital health issues, local side effects, intercourse disturbances, and drug permeability fluctuations. Social taboos, unrecognition, and gender specificity are also strong obstacles to the use and development of vaginal drug delivery.
• Lack of vaginal preparations that are easy to administer without causing discomfort, leading to improved patient compliance.

  The inventors are surprisingly likely to meet the unmet medical need for a vaginal dosage form that is easy to administer with privacy and is quick to insert into the vaginal cavity. We have found a method to provide a “rapidly dissolving tablet formulation” in a vaginal dosage form that disintegrates / dissolves in This dosage form forms a sticky suspension that diffuses rapidly and extensively on the vaginal mucosa and is held for a sufficiently long time to provide therapeutic efficacy by local action or systemic absorption. Unlike gel dosage forms, the use of vaginal applicators is not necessary for these tablets, so these tablets are based on the expected reduced packaging material (ie, increased portability) and reduced manufacturing costs. And an attractive dosage form. This dosage form can be used in connection with HIV therapy and other therapeutic applications.

  In some embodiments, the present invention provides a rapidly dissolving tablet composition comprising one or more active pharmaceutical ingredients intended for the treatment of disease states by local action or systemic absorption upon vaginal administration, and To the manufacture and use of such compositions.

  In some embodiments, the present invention provides pharmaceutical compositions comprising one or more active pharmaceutical ingredients suitable for vaginal routes of administration, and such compositions for treatment by local action or systemic absorption and uterine targeting. The present invention relates to manufacturing and use of products. In certain embodiments, the present invention is directed to one or more active pharmaceutical ingredients suitable for vaginal routes of administration, one or more polymeric substances having dual properties that act as binders and bioadhesive materials. A pharmaceutical composition comprising an excipient, one or more sugar alcohols or sugars, and one or more disintegrants, which disintegrates rapidly in the vaginal cavity and is treated by local action or systemic absorption To form a sticky suspension that diffuses rapidly and extensively to coat the vaginal mucosa with a drug suspension / solution.

  The pharmaceutical composition of the present invention comprises an antifungal agent, an antibacterial agent, an antimicrobial agent, an antiviral agent, an antiinfective agent, a spermicidal agent, a hormonal agent, an antibiotic, an antiviral agent, an analgesic agent, an antitrichomonas agent, and an antiprotozoal agent. Anti-mycoplasma drugs; antiretroviral drugs; nucleoside analogs; reverse transcriptase inhibitors; protease inhibitors; contraceptives; anorexic drugs and appetite suppressants; steroids; anthelmintic drugs; anesthetics; anti-arthritic drugs; Anticonvulsant; Anti-depressant; Diabetes; Antidiarrheal; Antihistamine; Anti-inflammatory; Antimigraine; Antihyperlipidemic; Antiemetic; Antitumor; Antiparkinson; Antidiarrheal; Psychotic drug; antipyretic drug; antispasmodic drug; anticholinergic drug; sympathomimetic drug; xanthine derivative; cardiovascular drug; calcium channel blocker; beta blocker; arrhythmia drug; antihypertensive drug; The end Vasodilators; brain erectile dysfunctions; central nervous stimulants; cold drugs; decongestants; diagnostics; hormones; hypnotics; immunosuppressants; muscle relaxants; parasympathomimetics; , Psychostimulants, sedatives, orally active drugs with significant first-pass effects; proteins / peptides including growth-promoting hormones and luteinizing hormone-releasing hormone (LHRH); tranquilizers; antioxidants; vitamins; minerals; And at least one drug selected from the group consisting of herbal extracts or formulations, or combinations thereof, may be included for vaginal administration.

  According to the present invention, polymeric excipients (eg, low substituted hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polycarboxylic acid, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, ethylene glycol 6000-vinyl caprolactam-vinyl acetate copolymer Bioadhesion of active ingredients (drugs) to mucosal surfaces due to the bioadhesive properties of polymers, polyvinyl alcohol, polyethylene oxide, poly (lactic acid-glycolic acid) copolymers, polyamides, alginate, carrageenan, chitosan, and cellulose gum) Sex is enhanced, thereby increasing retention time and improving treatment with local action or systemic absorption.

  In certain embodiments, the pharmaceutical composition enhances the bioadhesiveness of the surfactant and / or active ingredient to the mucosal surface or enhances / sustains systemic absorption, thereby causing local or systemic action. Lipids that will provide improved treatment and reduced side effects due to sexual absorption can be further included, particularly when the drug is poorly water soluble.

  In some other embodiments, the present invention is intended for the treatment by local action or systemic absorption, which rapidly disintegrates upon insertion into the patient's vagina and diffuses rapidly and extensively to the drug suspension / It relates to a pharmaceutical composition in the form of a fast dissolving tablet which forms a sticky suspension that coats the vaginal mucosa with a solution.

  In yet some other embodiments, the present invention relates to rapidly dissolving tablets comprising rapidly dispersible microgranules comprising at least one sugar alcohol and at least one disintegrant. The tablet can rapidly disintegrate upon insertion into the patient's vagina to form a sticky drug suspension that diffuses rapidly and extensively to coat the vaginal mucosa with the drug suspension / solution.

FIG. 1 shows a schematic diagram of a “rapid dissolution tablet” envisioned in a particular embodiment of the present invention. FIG. 2 shows a graph of mean plasma concentration-time profile of tenofovir after a single vaginal administration of tenofovir fast dissolving tablets (RDT) in female rabbits. FIG. 3 shows a graph of the mean plasma concentration-time profile of tenofovir after multiple intravaginal administrations (7 doses once daily) of tenofovir fast dissolving tablets (RDT) in female rabbits. FIG. 4 shows a graph of mean free and total tenofovir content of abdominal and vaginal tissues at 2 and 24 hours after a single vaginal administration of tenofovir rapid dissolution tablets (RDT) in female rabbits. FIG. 5 shows the mean free tenofovir content and total abdominal and vaginal tissue content and total at 2 and 24 hours after multiple intravaginal administrations (7 doses once daily) of tenofovir rapidly dissolving tablets (RDT) in female rabbits. The graph of tenofovir content is shown. FIG. 6 shows a graph of mean pre-dose and post-dose tenofovir concentrations in Weck-Cel® at 2 and 24 hours after a single vaginal administration of tenofovir fast dissolving tablets (RDT) in female rabbits. FIG. 7 shows the mean pre-dose in Weck-Cel® at 2 and 24 hours after multiple intravaginal administrations (7 doses once daily) of tenofovir rapidly dissolving tablets (RDT) in female rabbits. And a graph of tenofovir concentration after administration.

  The following specification includes information that may be useful in understanding the present invention. None of the information provided herein is admitted to be prior art, and no specific or implied publication is admitted to be prior art.

  All references cited herein are incorporated by reference in their entirety for all purposes, as if each individual reference was specifically and individually indicated to be incorporated by reference. To do. As used above and throughout the specification of the invention, unless otherwise indicated, the following terms should be understood to have the following meanings:

  As used herein, the terms “drug”, “active substance”, “bioactive substance”, “active drug”, or “active pharmaceutical ingredient” refer to a pharmaceutically acceptable and therapeutically effective compound, its pharmaceutical Pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, or prodrugs. Unless otherwise indicated, when referring to a drug in the description of various embodiments of the invention, the reference includes the base drug, its pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, Solvates (including hydrates), polymorphs, or prodrugs are included.

The term “salt” refers to the product formed by the reaction of a “free base” form of a drug with a suitable inorganic or organic acid. Suitable acids include those with low toxicity, such as those having sufficient acidity to form stable salts, such as salts approved for use in humans or animals. Non-limiting examples of acids that can be used to form salts of vaginal active agents such as metronidazole or tenofovir include inorganic acids such as HF, HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ can be mentioned; non-limiting examples of organic _acids, C 6 _{- 16} aryl sulfonic _{acids, C 6-16} heteroaryl sulfonic acid or a _{C 1-16} alkyl sulfonic acids, - for example, phenyl, alpha-naphthyl, beta-naphthyl Organic sulfuric acid such as, (S) -camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, pentyl, and hexyl sulfonic acid; Non-limiting examples of acids include C _1-16 alkyl, C _6-16 aryl carboxylic acid, and C _4-16 heteroaryl carboxylic acid, such as , Acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, glutaric acid, tartaric acid, citric acid, fumaric acid, succinic acid, malic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid Carboxylic acids such as salicylic acid and 2-phenoxybenzoic acid; non-limiting examples of organic acids include amino acids such as natural amino acids, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like. Can be mentioned. Other suitable salts are, for example, S. M.M. Birge et al. , J .; Pharm. Sci. 1977, 66, pp. 1-19. In most embodiments, “salt” refers to a salt that is biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. The drug salts useful in the present invention may be crystalline or non-crystalline, and may be a mixture of different crystalline forms or a mixture of crystalline and non-crystalline forms.

  The term “prodrug” refers to a form of a compound that is effective for its intended use, without undue toxicity, irritation, allergic reaction, etc., and suitable for administration to a patient, including ketals, esters, and amphoteric Ionic forms are included. Prodrugs are converted in vivo, for example by hydrolysis in blood. A detailed discussion can be found in T.W. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.E. C. S. Symposium Series, and Edward B. Roche, ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

  The term “rapidly dissolving tablet”, “rapid disintegrating tablet”, or “RDT” means in the patient's vaginal cavity after administration / insertion into the vaginal cavity, for example about 8 minutes, about 6 minutes, about 4 minutes, or Refers to tablets that disintegrate rapidly in about 2 minutes. When tested as described herein (eg, the United States Pharmacopeia <701> Disintegration Time Measurement Method), the disintegration rate may vary, but may be slower than the disintegration rate of the orally disintegrating tablet, Or it is faster than the disintegration rate of normal tablets or bioadhesive vaginal tablets.

  The term “substantially collapse” refers to a collapse level corresponding to at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% collapse, or about 100% collapse. . The term “disintegration” refers to the disintegration or disappearance of structural aggregation of the constituent particles, including tablets, while “dissolution” refers to the solubilization of the solid in a liquid (eg, solubilization of the drug in a solvent or gastric fluid). ) To distinguish from the term “dissolved”.

  The term “water-soluble polymer” refers to a polymer that is soluble (ie, soluble in large amounts) in an aqueous solvent, independent of pH.

  The term “bioadhesive material” improves the adherence of a pharmaceutical composition containing a bioadhesive material to the mucosa or similar biological surface compared to the adherence of a pharmaceutical composition not containing the bioadhesive material. Refers to the polymer. Non-limiting examples of bioadhesive materials include bioadhesive polymers such as hydroxypropylcellulose.

  The term “patient compliance” refers to non-adherence to the usage of a patient who is instructed to follow certain usage of a particular drug required. Non-compliance or non-adherence to usage is a major medical problem in the world that generates billions of dollars in losses and affects the lifestyles of millions of people.

  The term “about” as used herein with respect to a quantity includes the quantity of interest as well as the quantity of interest. For example, “about 60 seconds” includes values close to 60 seconds together with exactly 60 seconds (eg, 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.).

  In the claims, the use of the term “or” means “and / or” unless it is explicitly stated that it refers only to the alternative or that the options are mutually exclusive. . Specifically, any listing of items using the term “or” is to be interpreted as meaning that any of the listed items may be specifically excluded from related embodiments.

  According to long-standing patent law, in the claims or specification, when used in conjunction with the word “comprising”, the words “a” and “an” are either one or Represents multiple.

  Unless otherwise stated, the amount of various pharmaceutically acceptable actives or excipients incorporated into various pharmaceutical compositions in accordance with certain embodiments of the present invention is determined as a composition as a granule or RDT. Expressed as a percent by weight. Thus, 10% active in the RDT composition refers to the presence or content of active in the RDT is 10% by weight.

  In some embodiments, the invention provides an antibacterial agent; an antimicrobial agent; an antiviral agent; an anti-infective agent; a spermicidal agent; a hormonal agent; an antibiotic; an antiviral agent; an analgesic agent; Antimycoplasma drugs; antiretroviral drugs; nucleoside analogs; reverse transcriptase inhibitors; protease inhibitors; contraceptives; anorexic drugs and appetite suppressants; steroid drugs; anthelmintic drugs; anesthetics; anti-arthritic drugs; Anticonvulsants; Antidepressants; Diabetes drugs; Antidiarrheal drugs; Antihistamines; Anti-inflammatory drugs; Antimigraine drugs; Motion sickness drugs; Antiemetics; Antitumor drugs; Antiparkinson drugs; Antidiarrheal drugs; Drugs; Antipyretic drugs; Antispasmodic drugs; Anticholinergic drugs; Sympathomimetics; Xanthine derivatives; Cardiovascular drugs; Calcium channel blockers; Beta blockers; Arrhythmia drugs; Antihypertensive drugs; Peripheral Or cerebral vasodilators; erectile dysfunction drugs; central nervous stimulants; cold drugs; decongestants; hormonal drugs; hypnotic drugs; immunosuppressive drugs; muscle relaxants; parasympathomimetic drugs; tranquilizers; Vitamins, minerals; and herbal extracts or formulations; parasympathomimetics; psychostimulants; sedatives; orally active drugs that exhibit significant first-pass effects; or combinations thereof, proteins / peptides, reverse transcriptase inhibitors, Nucleoside / nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside / nucleotide reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), integrase inhibitors, growth promoting hormones and luteinizing hormone releasing hormone (LHRH) Or the like, or a pharmaceutically acceptable salt, solvate, or ester thereof. Containing drug, via local effects or systemic absorption, a pharmaceutical composition suitable for treatment by vaginal administration.

  The reverse transcriptase inhibitor RTI is a type of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTI inhibits the activity of reverse transcriptase, the viral DNA polymerase enzyme required for retroviruses to replicate. The mode of action of NRTI is essentially the same; they are natural deoxyribonucleotide analogs required to synthesize viral DNA. NNRTI is a compound that specifically inhibits HIV-1 replication and targets HIV-1 reverse transcriptase and, in addition to NRTI and protease inhibitors, has a decisive position in the treatment of HIV-1 infection. Have earned. PI is a type of drug used to treat or prevent infection by viruses including HIV and hepatitis C. Integrase inhibitors (eg, elvitegravir and MK-2048) are a type of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into host cell DNA.

  Accordingly, in some embodiments, the present invention provides NRTI (eg, aplicitabine, entecavir, emtricitabine, tenofovir, abacavir, adefovir, salts thereof, and mixtures thereof), NNRTI (eg, nevirapine, delavirdine, Efavirenz, rilpivirine, UC-781, MKC-442, quinoxaline HBY 097, DMP 266, salts thereof, and mixtures thereof), protease inhibitors (eg, indinavir, amprenavir, darunavir, rotinavir, nelfinavir, Ritonavir, secinavir, atazanavir, tipranavir, their salts, and mixtures thereof), and integrase inhibitors (eg, erbitegravir, MK- HIV / AIDS individuals to inhibit or eliminate the progression or severity of AIDS, comprising one or more drugs selected from the group of antiretroviral drugs consisting of 2048, their salts, and mixtures thereof) In addition to treating, it relates to a pharmaceutical composition for preventing early HIV infection. A variety of commercial vaginal creams, ointments, gels, inserts / rings, and tablets are currently available. For example, Dahl discloses in EP 1773296 the preparation of a pharmaceutical vaginal gel containing tenofovir. Because the gel / applicator may be subject to limitations such as leakage, dirt, and low residence time, as with other similar gel formulations, this dosage form is suitable for individuals with AIDS or HIV during sexual activity. May not be useful for individuals who want to avoid the risk of transmission or infection. However, it would be highly desirable to provide improved compositions and methods that reduce the risk of HIV transmission or infection during sexual activity.

  In certain embodiments, the present invention is a pharmaceutical composition in the form of a fast dissolving microgranule or tablet comprising a bisphosphonate (eg, alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, neridronate, risedronate Anti-migraine drugs such as ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, Acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol, meperidine, methadone, sumatriptan, narato Selected from the group consisting of tan, lazatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate, and divalprox sodium; E.g., metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantrador, aprepitant, cyclidine, promethazine, sildenafil, oxytocin, oxytocin, oxybutynin, bromocriptine, rifamycin, azithromycin Selected from the group consisting of: used in hormone replacement therapy or for contraception Steroids are; calcitonin; LHRH and analogs; insulin; and human growth hormone, as well as pharmaceutical compositions containing at least one drug suitable for vaginal administration selected from the group consisting of. Suppositories containing poorly soluble / biologically available drugs and foaming agents as percutaneous absorption enhancers, as well as one or more mucoadhesive polymers (eg, carbomers, chitosan, hydroxyethyl cellulose), surfactants ( For example, vaginal dosage forms such as glyceryl palmitostearate) or lipids (eg glyceryl palmitostearate, phospholipids) can be used.

  In certain embodiments, the present invention is a pharmaceutical composition in the form of rapidly dissolving microgranules, wherein the at least one drug suitable for vaginal administration, at least one sugar alcohol such as mannitol or at least one such as lactose. It relates to a pharmaceutical composition comprising a saccharide and at least one polymeric binder such as low substituted hydroxyethylcellulose. Such compositions can be used for treatment via local action or systemic absorption, for example, by insertion of the pharmaceutical composition into the vaginal cavity of a patient / subject in need thereof.

  In certain embodiments of the invention, the pharmaceutical composition in the form of fast dissolving microgranules further comprises a disintegrant such as crospovidone. This disintegrant can promote rapid disintegration of the rapidly dissolving microgranules to form a sticky drug-containing suspension in the vaginal cavity of the patient / subject in need thereof.

  In certain embodiments of the invention, the pharmaceutical composition in the form of fast dissolving microgranules further comprises at least one bioadhesive polymer such as low substituted hydroxyethylcellulose. The bioadhesive polymer can be provided at a desired concentration, and upon formation of a sticky drug-containing suspension in the patient / subject's vaginal cavity, coats the vaginal mucosa, thereby causing local or systemic effects. Its bioadhesion and therapeutic efficacy can be improved through longer residence for absorption.

  Examples of sugar alcohols / saccharides include, but are not limited to, mannitol, sorbitol, xylitol, arabitol, erythritol, glycerol, hydrogenated starch hydrolysate, isomalt, lactitol, lactose, maltitol, sucrose, maltose, and the like The combination of these is mentioned.

  Examples of suitable binders include, but are not limited to, polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropylmethylcellulose, or hypromellose (eg, Methocel E5 or E15, or Pharmacoat ™ 603), hydroxypropylcellulose ( Examples include Klucel® LF), low substituted hydroxyethyl cellulose, and polysaccharides. The binder can be present, for example, in an amount ranging from about 0.5 to 3% by weight, based on rapidly dissolving microgranules.

  Examples of disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, starch, crosslinked sodium carboxymethylcellulose, low substituted hydroxypropylcellulose, gums (eg gellan gum), and combinations thereof. Disintegrants are in pharmaceutical compositions in the form of rapidly dissolving microgranules, such as from about 1% to about 10%, from about 3% to about 7%, about 5%, and all ranges between them And subranges can be present.

  Non-limiting examples of suitable bioadhesive polymers include, but are not limited to, hydroxypropylcellulose, hypromellose, low substituted hydroxyethylcellulose, hydroxyethylethylcellulose, polycarboxylic acid, polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl acetate copolymer ( For example, Kollidon (registered trademark) VA 64 manufactured by BASF, polyvinyl alcohol, polyethylene oxide, carbomer (CARBOPOL (registered trademark) 974P, 941, 940, 934, G70), poly (lactic acid-glycolic acid) copolymer, polyamide , Carrageenan, chitosan, and various cellulose gums such as xanthan gum. The bioadhesive polymer can be incorporated into a pharmaceutical composition in the form of rapidly dissolving microgranules, for example, about 3% to about 10%, about 4% to about 8%, about 5%, all in between. Inclusive and subranged ranges can be present.

  Non-limiting examples of suitable surfactants that can be used include DL-alpha tocopherol, surfactants (eg, CAPTEX 200, Tween 20, Tween 80, Vitamin E TPGS, Capryol 90, CREMOPHOL EL, CARBITOL, PEG 400, lecithin, Brij 92, LABRASOL, triacetin, sodium lauryl sulfate, ethylene glycol monostearate, polysorbate and poloxamer (registered trademark), GELUCIRE (registered trademark), LABRAFIL (registered trademark), LABRASOL (registered trademark), IMWITOR (registered trademark) Trademark), sodium lauryl salicylate, sodium dodecyl sulfate), and mixtures thereof.

  Non-limiting examples of suitable lipids that can be used include lecithin; hydrogenated lecithin; lysolecithin, hydrogenated lysolecithin; lysophospholipid and derivatives thereof; phospholipid and derivatives thereof; alkyl sulfates; fatty acid salts; doxate sodium; Stearyl alcohol, glyceryl palmitostearate (PRECIROL® ATO 5); mono-, di-, tri-ester mixtures of glycerol (GELUCIRE®), mono- and di-esters of PEG, free PEG, And mixtures thereof.

  In certain embodiments of the invention, the pharmaceutical composition in the form of a fast dissolving tablet is prepared as co-pending US patent application Ser. No. 10 / 827,106 (U.S. Patent Application Publication No. 2005/0232988). Further comprising rapidly dispersible microgranules comprising saccharides or sugar alcohols in combination with disintegrants produced according to published). Furthermore, in certain other embodiments of the invention, the fast dissolving tablet composition is a combination of sugar alcohols such as mannitol, super disintegrants such as low substituted hydroxypropyl cellulose, starches, modified starches, and hydroxypropyl cellulose. It may further comprise rapidly dispersible microgranules comprising an additive having a multifunctional agent and disintegrant.

  Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, starch, crosslinked sodium carboxymethylcellulose, low substituted hydroxypropylcellulose, gums (eg gellan gum) and combinations thereof. Exemplary saccharides or sugar alcohols are from the group consisting of arabitol, erythritol, glycerol, hydrogenated starch hydrolysate, isomalt, lactitol, lactose, maltitol, mannitol, sorbitol, xylitol, sucrose, maltose, and combinations thereof You can choose. Sugars or sugar alcohols can also be supplemented or replaced with artificial sweeteners such as sucralose. The ratio of disintegrant to saccharide or sugar alcohol in the rapidly dispersible microgranules typically ranges from about 1:99 to about 10:90, or from about 5:95 to about 10:90 on a weight basis. A range, including all ranges and subranges between them. In some embodiments, the disintegrant and / or saccharide or sugar alcohol, or both are published as co-pending US patent application Ser. No. 10 / 827,106 (U.S. Patent Application Publication No. 2005/0232988). In the form of particles having an average particle size of about 30 μm or less, and when the composition has a multifunctional additive sugar or sugar alcohol in the form of particles having an average particle size of about 60 μm or less. Exists. The multifunctional additive can be present in the rapidly dispersible microgranular composition at, for example, 1 to 2.5% by weight. The ratio of drug-containing to rapidly disintegrating granules is about 5: 1 to about 1: 5, about 3: 1 to about 1: 3, about 2: 1 to about 1: 2, or about 1: 1. It can be a range and includes all ranges and subranges between them.

  The in vitro dissolution test of the pharmaceutical composition of the present invention uses US Pharmacopoeia I (100 rpm paddle) or II (50 rpm paddle) and an appropriate dissolution medium (900 mL) (HPLC method), depending on the drug. Implemented.

  The decay of the RDT of the present invention is tested according to the United States Pharmacopeia <701> decay test method. Alternatively, the disintegration time of a pharmaceutical composition prepared as an RDT tablet is determined using a vaginal fluid stimulant prepared according to the disclosure by Owen and Katz (Owen and Katz, 1999. Contrection. 59, 91-95). be able to. Considering the small amount of fluid available in the vaginal cavity, the dissolution test involves placing the RDT in a test tube containing a small amount of buffer consisting of ammonium acetate buffer with a pH of about 6 (eg, 3.5 mL). At an appropriate time, this can be done by centrifuging at 4000 rpm for 2 minutes and examining the sample filtered through a 0.45 μm PTFF filter by HPLC.

  In certain embodiments, the RDT of the invention comprises a therapeutically effective amount of tenofovir or a pharmaceutically acceptable salt thereof, alone or from about 2: 1 to about 1:10, from about 1: 1 to about 1: 8. Or in combination with emtricitabine at a ratio of about 1: 2 to about 1: 6, or about 1: 5. After insertion into the vagina, the RDT substantially disintegrates in the patient's vaginal cavity, forming a diffusible, sticky suspension that diffuses / coats on the vaginal mucosa, local action or systemic absorption The effect by. In addition to rapidly dispersible microgranules, the RDT of the present invention may optionally be low substituted hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polycarboxylic acid, polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl acetate copolymer (eg, manufactured by BASF). Kollidon® VA 64), SOLUPLUS®, poly (ethylene glycol 6000-vinyl caprolactam-vinyl acetate) (13:57:30) copolymer, polyvinyl alcohol, polyethylene oxide, poly ( Lactic acid-glycolic acid) copolymers, polyamides, alginates, carrageenans, chitosan, and those selected from the group consisting of various cellulose gums (eg, xanthan gum) Including the sex polymer.

  In some embodiments, the weight of the RDT is about 50 mg or more; such as 100 mg or more; 200 mg or more; 300 mg or more; or 500 mg or more. In some other embodiments, the weight of the RDT is about 2000 mg or less; such as 1600 mg or less; 1400 mg or less; 1200 mg or less; 1000 mg or less; In another embodiment, the RDT has a weight of about 800 mg or less. In another embodiment, the RDT has a weight of about 600 mg or less. In another embodiment, the weight of RDT is 500 mg or less. The dosage form of the present invention can comprise a population of two or more antibiotic-containing particles, for example comprising at least one population of metronidazole particles as described herein. Dosage forms can include, for example, a population of tenofovir, a nucleoside reverse transcriptase inhibitor, a rapidly soluble particle as described herein, and a further population of emtricitabine particles for AIDS prophylaxis.

  In one embodiment, the treatments described herein target two specific viral enzymes: reverse transcriptase (eg, use of NRTI or NNRTI) and protease (eg, use of a protease inhibitor). .

  A pharmaceutical composition of the invention in the form of a fast dissolving tablet intended for vaginal administration is a therapeutically effective amount of propranolol, a non-selective beta blocker that undergoes extensive first-pass (liver) metabolism when administered orally, or These pharmaceutically acceptable salts or mixtures can be included.

  A pharmaceutical composition of the present invention in the form of a fast dissolving tablet intended for vaginal administration comprises a therapeutically effective amount of metronidazole and, optionally, clarithromycin, sulfonamide, erythromycin, azithromycin, doxycycline, quinolone, cefoxitin An antibiotic selected from the group consisting of: ceftriaxone ciflfloxacin, doxycycline, vancomycin, clindamycin, rifaximin, and metronidazole.

  A pharmaceutical composition of the present invention in the form of a fast dissolving tablet intended for vaginal administration comprises a therapeutically effective amount of clotrimazole, and optionally from the group consisting of nystatin, ketoconazole, itraconazole, and clotrimazole. Selected antifungal agents can be included.

  In certain embodiments, the invention first comprises at least one sugar alcohol, saccharide, or mixture thereof, a polymeric binder, optionally a super disintegrant or bioadhesive polymer, and an antifungal agent, an antibacterial agent , Antimicrobial, antiviral, spermicidal, hormonal, antitrichomonas, antiprotozoal, antimycoplasma, antiretroviral, nucleoside analog, reverse transcriptase inhibitor, protease inhibitor, contraceptive, protein, Administration by the vaginal route comprising a therapeutically effective amount of at least one drug selected from the group consisting of peptides, steroids, growth promoters, etc., or pharmaceutically acceptable salts, solvates, or esters thereof. A fast-dissolving microgranule composition suitable for the treatment, and then co-pending rice with drug-containing fast-dissolving microgranules Rapid blending with rapidly dispersible microgranules prepared according to patent application No. 10 / 827,106 (published as US Patent Application Publication No. 2005/0232988) to contain a therapeutically effective dose The present invention relates to a method for compression into a soluble tablet (RDT). RDT is a sticky drug for the treatment of diseases by local action or systemic absorption that is expected to disintegrate rapidly in the vaginal cavity of the patient / subject and diffuse rapidly and extensively to coat the vaginal mucosa A containing suspension is formed.

  In certain other embodiments, the present invention first comprises at least one sugar alcohol, saccharide, or mixture thereof, a polymeric binder, optionally a super disintegrant or a bioadhesive polymer, and NRTI (eg, Aplicitabine, entecavir, emtricitabine, tenofovir, abacavir, adefovir, salts thereof, and mixtures thereof), NNRTI (eg, nevirapine, delavirdine, efavirenz, UC-781, MKC-442, quinoxaline HBY 097, salts thereof) , And mixtures thereof), protease inhibitors (eg, indinavir, amprenavir, darunavir, rotinavir, nelfinavir, ritonavir, secinavir, atazanavir, tipranavir, their salts, and them And a therapeutically effective amount of at least one drug selected from the group of antiretroviral drugs consisting of integrase inhibitors (eg, elbitegravir, MK-2048, salts thereof, and mixtures thereof) Individuals with HIV / AIDS, such as preparing a soluble microgranule composition and then blending drug-containing rapidly dissolving microgranules with rapidly dispersible microgranules to reduce or eliminate the progression or severity of AIDS In addition to the treatment of these, it relates to a method of compression into RDT tablets containing a therapeutically effective amount for the prevention of their initial infection. A variety of commercial vaginal creams, ointments, gels, inserts / rings, and tablets are currently available. For example, Dahl discloses in EP 1773296 the preparation of a pharmaceutical vaginal gel containing tenofovir. Because the gel / applicator may be subject to limitations such as leakage, dirt, and low residence time, as with other similar gel formulations, this dosage form is suitable for individuals with AIDS or HIV during sexual activity. May not be useful for individuals who want to avoid the risk of transmission or infection. However, it would be highly desirable to provide improved compositions and methods that reduce the risk of HIV transmission and / or infection during sexual activity.

  In certain other embodiments, the invention relates to at least one sugar alcohol such as mannitol, a polymeric binder such as low substituted hydroxypropylcellulose, optionally a disintegrant such as crospovidone, and one such as tenofovir or emtricitabine. A rapidly dissolving tablet composition comprising only one NRTI, or one or more NRTIs such as tenofovir in combination with emtricitabine or dapivirene is prepared, and then said rapidly dissolving microgranules, rapidly dispersible microgranules, The present invention relates to a method for compressing a formulation comprising a super disintegrant such as crystalline cellulose, crospovidone and a lubricant such as sodium stearyl fumarate on a rotary tableting machine to form a rapidly dissolving tablet.

  In another embodiment, a method of preparing rapidly dissolving microgranules is incorporated into an RDT that improves the bioadhesiveness of an adhesive drug suspension to the vaginal mucosal surface upon insertion of the RDT into the vaginal cavity Granulating the composition described herein further comprising a bioadhesive polymer (eg, low substituted hydroxyethyl cellulose).

  Granulation methods are not limited; fluidized bed or high shear granulation methods using a solution of a polymeric binder dissolved in purified water, ethanol, isopropanol, acetone, or mixtures thereof are embodiments of the present invention. . According to the present invention, for example, the granulation is carried out in an upper spray fluid bed granulator such as Glatt GPCG 3, GPCG 5, GPCG 120, or Fluid Air FA0300 in a polymeric binder and suspended or homogeneously suspended therein. The sprayed drug is sprayed onto a powder mixture containing at least one sugar alcohol, optionally a disintegrant such as low-substituted hydroxyethyl cellulose or a bioadhesive polymer, and the granules are dried in the same fluid bed dryer be able to. Granulation can also be done using a high shear granulator such as GMX 25 (batch size: 4-7 kg), GMX 65, or GMX 600 (batch size: 140-160 kg) from Vector and dried in Glatt. It can also be implemented. The dry granules thus produced are sieved through a suitable sieve, the fine particles are discarded, and in some cases, the oversized granules are crushed / re-screened to quickly dissolve with the desired particle size distribution. Sexual drug-containing microgranules can be collected.

  Drug-containing microparticles granulated with one or more bioadhesive polymers to improve bioadhesion properties to the vaginal mucosa can have a median particle size in the range of about 100-400 μm. In some embodiments, 90% or more of the microparticles are less than 600 μm due to their incorporation into rapidly dissolving tablets.

  In yet another embodiment, the present invention blends rapidly dissolving drug-containing microgranules and rapidly dispersible microgranules prepared as described herein to provide therapeutic effects via local action or systemic absorption. It may also relate to a method for preparing rapidly dissolving tablets by compressing on a rotary tablet press into rapidly dissolving tablets for administration into the vaginal cavity of a patient in need of such drugs.

  For example, the fast dissolving tablet of the present invention can be produced, for example, by an internal lubrication method in which the compression mixture is further blended with a lubricant prior to compression. Alternatively, fast-dissolving tablets may be manufactured by an external lubrication method in which the lubricant is not included in the tablet formulation but is applied externally on the material contacting surface of the punch and die of the rotary tablet press. Can do. Lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate may be used to smooth the granules and are used to compress tablets It may be applied externally on a material that contacts the die and punch surface of the rotary tablet press.

  Another embodiment of the present invention is an antifungal agent, an antibacterial agent, an antimicrobial agent, an antiviral agent, a spermicide, a hormonal agent, an antitrichomonas agent, an antiprotozoal agent, an antimycoplasma agent, an antiretroviral agent, a nucleoside analog, Selected from the group consisting of proteins / peptides including reverse transcriptase inhibitors, protease inhibitors, contraceptives, steroids, orally active agents with significant first pass effects, growth promoting hormones and luteinizing hormone releasing hormone (LHRH) A patient or subject comprising administering the composition of the present invention as a rapidly dissolving tablet containing a therapeutically effective amount of one or more drugs by insertion into the vaginal cavity of the patient in need thereof It relates to a method of treatment.

  The invention is described in more detail in the following sections. Many of the examples provided below to illustrate the present invention include tenofovir alone or in combination with emtricitabine. The examples and embodiments described herein are for illustrative purposes only, and various modifications and alterations will be suggested to one skilled in the art in light of this, and they are not It should be understood that it should be included within the spirit and scope of

Example 1
A: RD microgranules containing tenofovir, crospovidone, and Klucel:
Sodium bicarbonate (54 g) is gradually added and dissolved in purified water (2800 g) in a stainless steel container with constant stirring. If necessary, add hydrochloric acid to adjust the pH of the bicarbonate solution to about 6.0. Hydroxypropyl cellulose (Klucel LF; 125 g) is slowly added and dissolved with stirring; then tenofovir (180 g) is added and dissolved. Average particle size, deagglomerated by passing Comil through a preheated Glatt GPCG 3, fitted with a top spray insert, granulated air distribution bottom plate, 200 mesh product retention screen, and 1.0 mm spray nozzle. Is filled with mannitol (781 g) and crospovidone (60 g) of less than 30 μm. The packing is continuously fluidized and rapidly dissolved microgranules while maintaining the processing parameters at the following conditions: product temperature -34 ± 1 ° C; fluidized airflow-10 CFM; spray rate-10-16 mL / min. Granulate the composition. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

B: RD microgranules containing tenofovir, crospovidone, and L-HEC:
Sodium bicarbonate (54 g) is gradually added and dissolved in purified water (2500 g) in a stainless steel container with constant stirring. If necessary, add hydrochloric acid to adjust the pH of the bicarbonate solution to about 6.0. Low substituted hydroxyethyl cellulose (L-HEC; 20 g) is slowly added and dissolved with stirring; then tenofovir (180 g) is added and dissolved. Preheated Glatt GPCG 3 is filled with fluidized mannitol (781 g) and crospovidone (60 g) and fluidized. RD microgranules are prepared by spraying the solution as disclosed in the process of Example 1A above.

C: RD microgranules containing tenofovir, crospovidone, and HPMC:
Sodium bicarbonate (39.1 g) is gradually added and dissolved in purified water (2500 g) in a stainless steel container with constant stirring. If necessary, adjust the pH of the bicarbonate solution to approximately 6 by adding hydrochloric acid. Hypromellose (HPMC; 18.1 g) is added and dissolved slowly with stirring; then tenofovir (183.2 g) is added and dissolved. Preheated Glatt GPCG 3 is filled with fluidized mannitol (637.4 g) and crospovidone (43.1 g) and fluidized. RD microgranules are prepared by spraying the solution as disclosed in the process of Example 1A above.

D. Rapidly dispersible microgranules:
Rapidly dispersible microgranules are prepared according to the procedure disclosed in co-pending US Patent Application Publication No. 2003/0215500. Specifically, D-mannitol (Pearlitol 25 manufactured by Roquette, France) (152 kg) having an average particle size of about 20 μm or less was mixed with 8 kg of crosslinked povidone (ISP) in a high shear granulator (GMX 600 manufactured by Vector). Crospovidone XL-10), granulated with purified water (about 32 kg), wet-milled using Quadro Comil, and finally tray dried to produce LOD (loss on drying). Microgranules of less than about 0.8% are obtained. The dried fruit granules are screened and the oversized material is ground again to produce rapidly dispersible microgranules with an average particle size in the range of about 175-300 μm.

E: Tenofovir RDT (Crospovidone):
RDT tablet formulations containing Tenofovir (TFV) RD microgranules of Example 1A, Example 1B, and Example 1C are compressed on a Hata tablet press equipped with a partial tooling with a turret speed of 15 RPM (Table for composition) 1). After filling half of the rapidly dispersible microgranules in a 0.25 cubic foot V blender, crospovidone, microcrystalline cellulose (Avicel PH101), TFV RD granules, and the other half of the rapidly dispersible microgranules Fill and blend for 10 minutes. Sodium stearyl fumarate (Pruv) passed through a 35 mesh screen is added to the compression mixture and blended for 2 minutes. The Hata tablet press is set up in manual mode with a fill weight of 150 mg and a hardness of 10-50N. When setup is complete, the tablet press is operated in “auto” mode with compression forces of 3, 4, and 5 kN. Tablets at steady state for each compression force are collected for weight, thickness, hardness, and friability testing. The average value of the test is shown in Table 1 for each tablet batch. The disintegration time of the test according to the US Pharmacopoeia method <701> for DT is as follows: Formulation Example 1AD (TFV RDG: Example 1A), Formulation Example 1BD (TFV RDG: Example 1B), and Formulation Example 1CD (TFV) RDG: 60-90 seconds, 30-60 seconds, and 30-60 seconds for the Tenofovir RDT tablet batch of Example 1C), respectively. The RDT of these formulations compressed at 4 kN disintegrates in 30-60 seconds when tested according to US Pharmacopeia method <701>, and over 80% in 30 minutes when tested in a tube Is observed to elute.

Example 2
A: RD microgranules containing tenofovir:
Sodium bicarbonate (67.5 g) is gradually added and dissolved in purified water (2010 g) in a stainless steel container with constant stirring. The pH of the bicarbonate solution is measured at about 6.8. Hypromellose (Methocel; 62.5 g) is slowly added and dissolved with stirring; then tenofovir (190 g) is added and dissolved. Preheated Glatt GPCG 3 is filled with fluidized mannitol (890 g) and fluidized. Spray the packing and treat the rapidly dissolving microgranules while maintaining the processing parameters at the following conditions: Product temperature -34 ± 1 ° C; Fluidized airflow-5-15 CFM; Spray rate-4-16 mL / min. Prepare. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

B: RD microgranules containing tenofovir:
Sodium bicarbonate (57 g) is gradually added and dissolved in a mixture of ethanol (540 g) and purified water (1260 g) in a stainless steel container with constant stirring. The pH of the bicarbonate solution is measured at about 6.2. Next, tenofovir (200 g) is added and dissolved, and then low-substituted hydroxyethyl cellulose (L-HEC; 20 g) is added and dissolved while stirring. Preheated Glatt GPCG 3 is filled with fluidized mannitol (1023 g) and fluidized. RD microgranules are prepared by spraying the solution at the following conditions: product temperature -34 ± 1 ° C; fluidized airflow-4 CFM; spray rate-8-12 mL / min. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

C: RD microgranules containing tenofovir:
Sodium bicarbonate (54 g) is gradually added and dissolved in a mixture of ethanol (540 g) and purified water (1260 g) in a stainless steel container with constant stirring. The pH of the bicarbonate solution is measured at about 6.15. Next, tenofovir (200 g) is added and dissolved, and then low-substituted hydroxyethyl cellulose (L-HEC; 30 g) is added and dissolved while stirring. Preheated Glatt GPCG 3 is filled with fluidized mannitol (1023 g) and fluidized. RD microgranules are prepared by spraying the solution as disclosed in the process of Example 2B above. Upon completion of spraying, the loss on drying of the RD microgranules is about 1.5% by weight.

D. Tenofovir RDT:
RDT tablet formulations (Formulation Example 2BD and Formulation Example 2CD) containing the Tenofovir (TFV) RD microgranules of Example 2B and Example 2C were loaded onto a Hata tablet press equipped with a partial tooling with a compression force of 4 kN and a turret speed of 15 RPM. (See Table 2 for composition). Samples are collected at the beginning, middle, and end of processing to test tablet properties during processing. The results are shown in Table 2. In the case of Formulation Example 2AD, the tablets are compressed using a Carver press.

E: Single and multiple dose PK studies for tenofovir RDT administered vaginally to rabbits:
The purpose of this study was to evaluate the pharmacokinetics of tenofovir after a single dose or 7 daily doses when administered in the form of rapidly dissolving tablets to a female rabbit with a minimum body weight of 2.5 kg ( N = 6 in each group; blood was collected at 0, 0.5, 1, 2, 4, 8, and 24 hours after administration on days 1 or 7 for groups 1 and 3, and administered for groups 2 and 4 At 0, 0.5, 1.0, 1.5, and 2 hours after dosing on day 1 or 7). Prior to administration of the test substance, acepromazine maleate (0.3-0.5 mg / kg or until effective) was administered subcutaneously in order to lightly sedate the animals. When sedated, a single tablet was inserted with 18 catheters into the abdomen vagina of each animal (approximately 8 cm). Lubricants were not used because they can affect tablet absorption. Detailed clinical examination of each animal was performed daily during the study period. Observations include, but are not limited to, skin, hair, eyes, ears, nose, oral cavity, chest, abdomen, external genitals, extremities and feet, respiratory and circulatory effects, and autonomic nervous system such as salivation Effects, tremors, convulsions, responses to handling, and nervous system effects including abnormal behavior. A complete anatomical examination is performed using groups 1 and 4 using procedures approved by a veterinary pathologist for all animals of death at death, terminal euthanasia, or euthanasia at necropsy scheduled according to current SOP, respectively. For 3 performed 2 hours after dosing on day 1 or 7 or for groups 2 and 4 under 24 hours after dosing under yellow light. The iliac lymph nodes were collected under a yellow light for determination of total tenofovir concentration. In order to absorb secretions from the vagina for determination of total tenofovir concentration, each Weck-Cel® sponge was placed in the vagina to prepare a Weck-Cel® sponge sample.

  FIG. 2 shows the average tenofovir plasma concentration-time profile after a single tenofovir RDT (ie, RDT of Formulation 2CD) insertion into the vaginal cavity of a female rabbit, and FIG. 3 shows multiple doses (once daily) The corresponding tenofovir concentration after 7 doses) is shown. FIG. 4 shows the average abdominal and vaginal release and total tenofovir content at 2 and 24 hours after single tenofovir RDT insertion into the vaginal cavity of female rabbits, and FIG. 5 shows multiple doses (once daily). The corresponding fenofovir concentration after 7 doses) is shown. FIG. 6 shows mean pre-dose and post-dose tenofovir concentrations in Weck-Cel® at 2 and 24 hours after administration by single tenofovir RDT insertion into the vaginal cavity of female rabbits. The corresponding pre-dose and post-dose tenofovir concentrations in Weck-Cel® after a single dose (7 doses once daily) are shown.

  According to a further preclinical comparative PK study of 40 mg as a fast dissolving tablet (four 10 mg tablets) versus 40 mg rabbit as 1% tenofovir gel (4 mL), the fast dissolving tablet form is 1% TFV It is suggested that the same tissue concentration is imparted compared to the gel. Unlike gel dosage forms that require the use of a vaginal applicator and attached package, the fast dissolving tablet technology makes it extremely attractive in terms of increased portability and reduced manufacturing costs. In addition, this technology provides privacy and convenience for drug administration.

Example 3
A: RD microgranules containing tenofovir:
To high shear granulator GMX-25, Tenofovir (TFV; 829.2 g), Mannitol (Pearlitol 25; 789.2 g with an average particle size of less than 30 μm), Hydroxyethyl cellulose (NITROSOL-HEC 250L; 91.6 g), and Fill with crospovidone (200 g). Thoroughly mix the contents of the product bowl at 150 RPM with a 2 minute impeller speed setting. The powder mixture was about 100 g / at the following processing parameters: spray nozzle pore size -0.085 inch; impeller setting: speed -325 RPM, time -5.5 minutes; chopper setting speed -high, time -5.5 minutes. Granulate by spraying purified water at a spray rate of minutes. After 5 minutes, by stopping spraying, the granulation operation continues to mix for another 30 seconds before stopping the granulator, and the bowl, chopper blade, and impeller blade can be rubbed. Spraying continues to spray about 630 g of water, mixing the contents of the product bowl for an additional 2 minutes and then removing the contents of the product bowl. Preheated Glatt GPCG 5 is filled with wet granules and dried to a loss on drying of less than 2% measured at 85 ° C. using a Computrac Moisture Analyzer. Drying conditions in Glatt are as follows: Product Retention Screen—200 mesh; Inlet Air Temperature—42 ° C .; Inlet Air Volume—40 cfm; Drying Wheel—ON.

B: RD microgranules containing emtricitabine:
Emtricitabine (FTC, 682.9 g) is gradually added and dissolved in a mixture of ethanol (3974 g) and purified water (995 g) in a stainless steel container with constant stirring. Next, low substituted hydroxyethyl cellulose (Natrosol HEC-250L; 80.1 g) is added and dispersed / dissolved with stirring. Preheated Glatt GPCG 3 is filled with lumped mannitol (2737 g) and fluidized. The solution was subjected to the following conditions: product retention screen -200 mesh; nozzle tip size -1.2 mm; atomization pressure -2 bar; inlet air temperature -72 ° C; product temperature -38 ± 1 ° C; RD microgranules are prepared by spraying with 40 cfm; spray rate—40 mL / min; dry wheel—ON. At the completion of spraying, dry the FTC RD microgranules with an inlet air temperature setting of 42 ° C. until the loss on drying is about 1% by weight.

C. RDT (40mg TFV / 40mg FCT)
RDT tablet formulations containing the TFV RD microgranules of Example 3A and the FCT RD microgranules of Example 3B alone or as a mixture thereof, and other pharmaceutical excipients including the lubricant sodium stearyl fumarate Are first blended and compressed on a Beta tablet press equipped with a partial tooling with a compression force of 4-6 kN and a turret speed of 15 RPM (see Table 3 for composition). Samples are collected at the beginning, middle, and end of each process to test tablet properties during the process.

For a 40 mg TFV / 40 mg FCT RDT, a Manesty Beta press fitted with 8 circumferential 12 mm lozenge tooling without embossing is set to the following parameters:
Tablet weight: Total (10) -5.00 g; Nominal: 500 mg; Range: 460-540 mg
Fill weight setting: 8 mm (or 6 mm for TFV); Pre-compression setting: 6 mm
Main compression: 3.3 mm (or 2.85 mm for TFV) Force supply setting: 3.

  Set the press to operate at 25 rpm and after several die table / turret rotations, collect 10 tablets and stop the press. To determine the weight of 10 tablets, 10 tablets are collected and inspected for tablet appearance (picking, capping, etc.). In order to produce tablets that meet the specifications described above for weight, thickness, and hardness, the tablet press is adjusted as necessary and the results recorded in the production batch record. If necessary, the parameters are readjusted as necessary to produce tablets that meet the friability specifications described above.

  At the beginning, middle, and end of processing, 35 tablets are sampled for in-process inspection. Ten tablets are tested for weight, hardness, and thickness, and 6.5 g tablets are tested for friability. Record the results in the production batch record. The remainder of the sample is put together in a container that is appropriately labeled as part of the composite sample. Each point in the process uses a separate container for analytical testing.

Similar settings are used to compress 40 mg TFV / 20 mg FCT, 20 mg TFV / 40 mg FCT, 40 mg TFV, or 40 mg FCT fast disintegrating tablets from their respective compression mixtures.

Example 4
A: RD microgranules containing metronidazole:
A vinylpyrrolidone-vinyl acetate copolymer (for example, Kollidon® VA 64; 50 g, manufactured by BASF) is gradually added and dissolved in a mixture of ethanol and purified water in a stainless steel container with constant stirring. Next, metronidazole (180 g) is added and dissolved with stirring. Preheated Glatt GPCG 3 is filled with fluidized mannitol (770 g) and crospovidone (50 g) and fluidized. RD microgranules are prepared by spraying the solution at the following conditions: product temperature -34 ± 1 ° C; fluidized airflow-4 CFM; spray rate-8-12 mL / min. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

B: RD microgranules with clotrimazole:
Hydroxyethyl cellulose (50 g) is gradually added and dissolved in a mixture of ethanol and purified water in a stainless steel container with constant stirring. Next, metronidazole (180 g) is added and dissolved with stirring. Preheated Glatt GPCG 3 is filled with fluidized mannitol (720 g) and crospovidone (50 g) and fluidized. RD microgranules are prepared by spraying the solution at the following conditions: product temperature -34 ± 1 ° C; fluidized airflow-4 CFM; spray rate-8-12 mL / min. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

C: RD microgranules containing propranolol HCl:
Vinylpyrrolidone-polyvinyl acetate copolymer (for example, Kollidon® VA 64; 50 g manufactured by BASF) is gradually added and dissolved in purified water in a stainless steel container with constant stirring. Next, propranolol HCl (240 g), a non-specific β-blocker that exhibits extensive liver metabolism, is added and dissolved with stirring. Preheated Glatt GPCG 3 is filled with deagglomerated mannitol (560 g) and low substituted hydroxyethyl cellulose (50 g) and fluidized. RD microgranules are prepared by spraying the solution at the following conditions: product temperature -38 ± 2 ° C; fluidized airflow-10 CFM; spray rate-10-20 mL / min. At the completion of spraying, the RD microgranules are dried until the loss on drying is about 1% by weight.

D. RDT containing metronidazole, clotrimazole, or propranolol HCl
The required amount of metronidazole RD microgranules of Example 4A, clotrimazole RD microgranules of Example 4B, or propranolol HCl RD microgranules of Example 4C, 5-15 wt. Of rapidly dispersible microgranules from Example 1D above. % RDT tablets containing 5% by weight of microcrystalline cellulose (5-10% by weight of Avicel PH101), 2-5% by weight of low-substituted hydroxypropylcellulose and 1% by weight of sodium stearyl fumarate (Formulation Example 4AD: Metronidazole RDT, formulation) Example 4BD: Clotrimazole RDT, and Formulation Example 4CD: Propranolol HCl RDT) are compressed at various compression forces and various turret speeds on a Hata tablet press equipped with appropriate tooling. In order to test the tablet properties during processing, samples are collected at the beginning, middle and end of processing to prove the robustness of the manufacturing process for each tablet formulation.

  One of ordinary skill in the art will recognize that the above procedures and compositions can be appropriately modified to provide the appropriate dose of drug for which a rapidly dissolving tablet formulation for vaginal administration is required.

  Although the present invention has been described in connection with specific embodiments herein, the present invention is capable of further modifications and the present application is intended to cover any variation of the present invention that generally follows the principles of the present invention, Use or adaptation is also described within the scope of the technology to which the present invention pertains and is within the scope of known or customary practice, and is set forth herein above, and the following appended claims It will be understood that it is intended to encompass any deviations from the present disclosure that apply to basic features that are within the scope of the section.

  All documents, patents, patent applications, and publications cited herein are incorporated by reference in their entirety for all purposes.

Claims (21)

A pharmaceutical composition in the form of a fast dissolving vaginal tablet comprising:
(A) a therapeutically effective amount of a vaginal active agent;
(B) 4-10% polymeric excipients with dual properties that act both as binders and bioadhesive materials;
(C) sugar alcohols, sugars, or mixtures thereof;
(D) a rapidly soluble drug-containing microgranule comprising a disintegrant;
Each having an average particle size of about 400 μm or less, and (1) a disintegrant and (2) a sugar alcohol or saccharide,
A rapidly dispersible population of rapidly dispersible microgranules, wherein the sugar alcohol or saccharide each has an average particle size of about 30 μm or less,
The pharmaceutical composition rapidly disintegrates when inserted into the vaginal cavity of a patient or subject to form a sticky drug-containing suspension that diffuses rapidly and extensively to coat the vaginal mucosa;
The polymeric excipient is low-substituted hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polycarboxylic acid, polyvinyl pyrrolidone, vinyl pyrrolidone-polyvinyl acetate copolymer, ethylene glycol 6000-vinyl caprolactam-vinyl acetate copolymer, polyvinyl alcohol, Selected from the group consisting of polyethylene oxide, poly (lactic acid-glycolic acid) copolymer, polyamide, alginate, carrageenan, chitosan, and cellulose gum, and the sugar alcohol / sugar is mannitol, sorbitol, xylitol, arabitol, erythritol, glycerol , Hydrogenated starch hydrolyzate, isomalt, lactitol, lactose, maltitol, sucrose or maltose   The pharmaceutical composition according to claim 1, wherein the therapeutically effective drug is an antifungal agent, an antibacterial agent, an antimicrobial agent, an antiviral agent, an antiinfective agent, a spermicidal agent, a steroid agent, a hormonal agent, or a non-steroidal agent. Analgesics including cardiovascular anti-inflammatory drugs, cardiovascular agonists, calcium channel blockers, beta blockers, arrhythmia drugs, antihypertensives, diuretics, systemic, coronary, peripheral, and brain vasodilators, anti-fragment Headache drugs, erectile dysfunction drugs, central nervous stimulants, sedatives, hypnotics, immunosuppressants, muscle relaxants, orally active drugs with significant first-pass effects, β-adrenergic drugs, tranquilizers, antioxidants , Vitamins, antitrichomonas drugs, antiprotozoal drugs, antimycoplasma drugs, antiretroviral drugs, nucleoside analogs, reverse transcriptase inhibitors, protease inhibitors, contraceptives, sulfa drugs, sulfonamides, sulfones, Plastid, protein, growth hormone, and luteinizing hormone-releasing hormone, or a mixture or a pharmaceutical composition characterized in that it is selected from a combination thereof.   The pharmaceutical composition of claim 2, wherein the therapeutically effective drug is apricitabine, entecavir, emtricitabine, tenofovir, abacavir, adefovir, nevirapine, delavirdine, efavirenz, UC-781, MKC-442, quinoxaline HBY 097, DMP 266, indinavir, amprenavir, darunavir, rotinavir, nelfinavir, ritonavir, secinavir, atazanavir, tipranavir, elbitegravir, and MK-2048, or pharmaceutically acceptable salts, prodrugs, or mixtures or combinations thereof A reverse transcriptase inhibitor, a nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleotide reverse transcriptase inhibitor, or a protease inhibitor selected from the group consisting of A pharmaceutical composition characterized.   3. The pharmaceutical composition according to claim 2, wherein the therapeutically effective drug is butconazolenystatin, oxyconazole, fluconazole, posaconazole, clotrimazole, and ketoconazole, or a pharmaceutically acceptable salt thereof. Or an antifungal agent selected from the group consisting of mixtures or combinations thereof.   The pharmaceutical composition according to claim 2, wherein the therapeutically effective drug is clindamycin, sulfonamide, erythromycin, clarithromycin, azithromycin, doxycycline, metronidazole, macrolide antibiotics, quinolone, cephalosporin, A pharmaceutical composition characterized in that it is an antibacterial agent selected from the group consisting of cefoxitin, and ceftriaxone, or a mixture or combination thereof.   3. The pharmaceutical composition of claim 2, wherein the therapeutically effective drug is an antiviral selected from the group consisting of penciclovir, acyclovir, genciclovir, and valacyclovir, or a mixture or combination thereof. A pharmaceutical composition characterized by the above.   The cardiovascular agonist according to claim 2, wherein the therapeutically effective drug is selected from verapamil, propranolol, metoprolol, diltiazem, isoladipine, felodipine, nifedipine, and nicardipine, or mixtures or combinations thereof. A pharmaceutical composition characterized by the above.   3. The non-steroidal anti-inflammatory of claim 2, wherein the therapeutically effective drug is selected from the group consisting of aspirin, ibuprofen, indomethacin, sulindac, naproxen, and nebumetone, or mixtures or combinations thereof. A pharmaceutical composition characterized by being a medicine. In the pharmaceutical composition according to claim 1, DL-alpha-tocopherol, CAPTEX (TM) 200, Tween (R) 20, Tween (R) 80, Vitamin E TPGS, Capryol (TM) 90, CREMOPHOR (R ) EL, CARBITOL (TM), PEG 400, lecithin, BRIJ (R) 92, bets Riasechin, sodium lauryl sulfate, ethylene glycol monostearate, polysorbate PLURONIC (R), GELUCIRE (trademark), LABRAFIL (quotient ), LABRASOL (registered trademark), IMWITOR (registered trademark), sodium lauryl salicylate, and sodium dodecyl sulfate, or a mixture thereof, A pharmaceutical composition characterized in that it further comprises one surfactant.   The pharmaceutical composition according to claim 1, wherein lecithin, hydrogenated lecithin, lysolecithin, hydrogenated lysolecithin, lysophospholipid and derivatives thereof, phospholipid and derivatives thereof, alkyl sulfate, fatty acid salt, doxate sodium, stearyl alcohol, glyceryl Further comprising at least one lipid selected from the group consisting of palmitostearate, mixtures of mono-, di-, and tri-esters of glycerol, mono- and di-esters of PEG, and free PEG, or mixtures thereof. A pharmaceutical composition characterized by the above.   2. The pharmaceutical composition according to claim 1, wherein the ratio of rapidly dissolving drug-containing microgranules to rapidly dispersible microgranules is in the range of about 50: 1 to about 1: 2. .   The pharmaceutical composition of claim 1, wherein the rapidly dispersible microgranules are selected from the group consisting of crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethylcellulose, and low substituted hydroxypropylcellulose, or mixtures thereof. A pharmaceutical composition comprising a disintegrant.   2. The pharmaceutical composition of claim 1, wherein the rapidly dispersible microgranules are selected from the group consisting of arabitol, erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol, or combinations thereof. A pharmaceutical composition comprising a sugar alcohol.   11. The pharmaceutical composition of any one of claims 1-10, further defined as a rapidly dissolving tablet that disintegrates in about 60 seconds when tested by the United States Pharmacopeia method <701> disintegration time. A pharmaceutical composition characterized by the above. 15. The pharmaceutical composition according to claim 14, wherein the rapidly dissolving tablet has the following characteristics:
As a fast dissolving tablet that exhibits a friability of 1% by weight or less, and ii) sufficient tablet hardness suitable for packaging into blisters or bottles for storage, transportation, merchandise distribution, and end use A pharmaceutical composition characterized in that it is further defined. A method for preparing a pharmaceutical composition according to claim 1 comprising:
a) Quickly dissolving drug-containing microgranules
i. Antifungal, antibacterial, antimicrobial, antiviral, anti-infective, spermicidal, steroidal, hormonal, analgesic, including non-steroidal anti-inflammatory, cardiovascular, calcium channel blocker, Beta-blockers, antiarrhythmic drugs, antihypertensive drugs, diuretics, systemic, coronary arteries, peripheral and brain vasodilators, antimigraine drugs, erectile dysfunction drugs, central nervous stimulants, sedatives, hypnotics, immunity Inhibitors, muscle relaxants, orally active drugs with significant first-pass effects, β-adrenergic drugs, tranquilizers, antioxidants, vitamins, antitrichomonas drugs, antiprotozoal drugs, antimycoplasma drugs, antiretroviral drugs , Nucleoside analogs, reverse transcriptase inhibitors, protease inhibitors, contraceptives, sulfa drugs, sulfonamides, sulfones, peptides, proteins, growth hormone, and luteinizing hormone release Hormone or at least one therapeutically active drug selected from the group consisting of a mixture or combination thereof,
ii. With mannitol,
iii. Low substituted hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polycarboxylic acid, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, ethylene glycol 6000-vinyl caprolactam-vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide, poly (lactic acid- Preparing by granulating a polymeric excipient selected from the group consisting of (glycolic acid) copolymer, polyamide, alginate, carrageenan, chitosan, and cellulose gum;
b) rapidly dispersible microgranules free of drugs
i. At least one sugar alcohol, saccharide, or mixture thereof having an average particle size of about 30 μm or less;
ii. Preparing by granulating at least one disintegrant, wherein the sugar alcohol / saccharide is mannitol, sorbitol, xylitol, arabitol, erythritol, glycerol, hydrogenated starch hydrolysate, isomalt, lactitol, lactose, A step that is maltitol, sucrose or maltose;
c) blending rapidly dissolving microgranules from step a) with rapidly dispersible microgranules from step b);
d) compressing the product of c) into rapidly dissolving tablets. The method of claim 16, wherein
a) preparing rapidly soluble microgranules by granulating tenofovir, mannitol, low substituted hydroxyethylcellulose, and optionally crospovidone and chitosan;
b) producing rapidly dispersible microgranules by granulating mannitol and crospovidone each having an average particle size of about 30 μm or less;
c) Blending the rapidly dissolving microgranules from step a) with the rapidly dispersible microgranules from step b) with microcrystalline cellulose, crospovidone and sodium stearyl fumarate to form a blend. Steps,
d) compressing the blend of step c) into rapidly dissolving tablets using a rotary tablet press, each rapidly dissolving tablet being tested by US Pharmacopoeia method <701> disintegration time. A method that, when done, disintegrates in about 60 seconds.   18. The method of claim 17, wherein step d) uses a rotary tablet press equipped with an external lubrication device for smoothing the dies and punches before compression with magnesium stearate. The method further comprises the step of compressing the blend of The method of claim 17, step a), emtricitabine, mannitol, low-substituted hydroxypropyl cellulose, and optionally by preparing a rapidly dissolving microgranules containing crospovidone and mosquito Boporu, tenofovir and emtricitabine A method further comprising the step of preparing a rapidly dissolving tablet containing both therapeutically effective amounts.   Use of the pharmaceutical composition according to any one of claims 1, 9, 14, or 15 for the manufacture of a medicament for vaginal administration.   Use of a pharmaceutical composition according to any one of claims 1, 9, 14, or 15 comprising a therapeutically effective amount of tenofovir and emtricitabine for the manufacture of a medicament for the treatment of HIV infection.

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