KR20160112012A - Rapid dissolve tablet compositions for vaginal adminstration - Google Patents

Abstract

A pharmaceutically acceptable swallowable vaginally tablet composition comprising one or more active pharmaceutical ingredients suitable for topical or systemic absorption therapy and methods of making and using such compositions are disclosed herein. In some embodiments, the present invention provides pharmaceutical compositions comprising one or more active pharmaceutical ingredients suitable for the vaginal administration route, as well as methods of making and using such compositions for therapy via local action or systemic absorption as well as uterine targeting . In certain embodiments, the present invention provides a pharmaceutical composition comprising one or more active pharmaceutical ingredients suitable for the vaginal administration route, one or more polymeric excipients having a biocompatible double-acting as a biocompatible material as a binder, one or more sugar alcohols or sugars, And at least one disintegrant.

Description

[0001] RAPID DISSOLVE TABLET COMPOSITIONS FOR VAGINAL ADMINSTRATION [0002]

This application claims priority from U.S. Serial No. 61 / 481,582, filed May 2, 2011, the entire contents of which are incorporated by reference for all purposes.

Vaginal drug delivery is a potential route for topical or systemic absorption therapy as well as uterine targeting of active pharmaceutical ingredients. This provides the following benefits:

- Large surface area

- Avoidance of hepatic first-pass effects which may lead to significant improvement in bioavailability or reduction of dosage strength or side effect profile

- dense network of blood vessels

- High permeability even in large molecular weight drugs such as peptides and proteins

- low systemic drug exposure (ie, for products used in local conditions)

- low enzyme activity and the possibility of preferential transfer of drugs absorbed into the uterus (referred to as " primary uterine transit effect ");

- ease of removal if required

Despite these advantages, vaginal administration routes for drug delivery have been used to a limited extent. Traditional drug delivery systems, such as tablets, are traditionally used to deliver contaminants to treat contraceptives and vaginal infections. Vaginal tablets, rings, creams and viscous gels containing a wide range of drugs (such as steroids, prostaglandins, antimicrobial agents, proteins and peptides) have been developed and in vitro, in vitro and in vivo performance evaluations of such vaginal drug delivery systems have been studied . Such as those containing one or more non-toxic, non-irritating or biocompatible materials that can easily incorporate into the vaginal formulation and theoretically extend the bioactive residence time within the vagina and reduce the dosage administered as well as the dosage frequency Studies of drug delivery systems are as follows: Lehr, 2000. J. Control. Rel. 65, 19-29; Mandal et al . 2000. J. 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. Pharm. Biopharm. 69, 622-632; Ndesendo et al ., 2009. Int. J. Pharm. 370, 151-159; Poelvoorde et al ., 2009. J. Pharm. Biopharm. 71, 280-284-343; Perioli et al ., 2009. Int. J. Pharm. 377, 120-127; Yellanki et al ., 2010. Int. J. PharmTech Res. 2; 1746-1750; And Wang et al ., 2002. J. Contr. Rel. 82, 39-50.

Most bioadhesive gels, creams and tablets used as vaginal delivery systems are rapidly ineffective after application to the vagina and have minimal bioadhesion to the vaginal mucosa. This complexity may be due to miscibility with water, or due to a lack of physical stability at body temperature, which results in limited therapeutic efficacy. (i) at least one microsphere stabilizing polymer (such as HPMC, polyvinyl alcohol or pegylated lipids) and (ii) a therapeutically active drug; Drugs approved or used for the treatment, prevention, cure or alleviation of diseases of the vagina, urinary tract, cervical or other female reproductive organs; Contraceptive agents; Or systemic drug therapies have been developed.

U.S. Patent Application No. 20030180366 (U.S. Patent No. 6,899,890) discloses a novel, microemulsion intrinsically pH-neutral vaginal delivery system suitable for the modified delivery of a therapeutically active substance in the vaginal cavity. U.S. Patent Application No. 20050276836 discloses a method of coating a therapeutic or health promoting agent delivery vaginal device with a mucoadhesive composition. International Patent Application Publication No. WO 2008133928 discloses a method of treating a pain associated with a disease of epithelial lesion and damaged mucin function by treating a pharmaceutical composition containing mucin glycoprotein in combination with a therapeutic agent such as trefoil polypeptide, A method of treating a patient having a disease of epithelial lesion or impaired mucin function is disclosed. International Patent Application Publication No. WO 2010061284 discloses a controlled-release in vaginal pharmaceutical formulation consisting of at least one pharmaceutically active ingredient mixed with a combination of biocompatible and biodegradable polymers and having a shape for insertion into a patient's vagina . Intra-vaginal administration of controlled-release opioids such as oxycodone has proved to be a safe, effective, and simple means of dealing with cancer pain in patients who can not tolerate adverse events caused by oral administration (X. Zhang, XJ. Ruan, C. Liu, and ZH Yu, Effects of intrathecal administration of oxycodone on controlled release types on cancer pain. Chin, J. Cancer J. Cancer, 2009, 28 (7) 1-4; F. Acarturk, Adhesive quality drug delivery system. Recent patents on drug delivery and formulation, 2009, 3 , 193-205) ("Acarturk 2009"). Acarturk 2009 recently summarized the development of an improved formulation for transmucosal vaginal delivery and in vitro / in vivo evaluation.

Disintegration or distribution / diffusion as well as retention times of bioadhesive vesicles (e.g., conventional tablets, multiparticulates, adhesive gel preparations) have been extensively evaluated. Conventional tablets or even bioadhesive tablets are easy to administer individually by the user; However, such formulations are too slow to disintegrate and diffuse and are too rapidly removed from the vagina, failing to provide any significant improvement in therapy. The level of patient acceptance is weak and is generally believed to be influenced by a limited dosage regimen, the need to consume multiple combination oral drug products, patient suspicion of the efficacy of vaginal therapy, discomfort associated with leakage or administration. In addition, gel formulations require the use of a vaginal applicator, resulting in an increase in packaging materials and manufacturing costs.

One area in which vaginal administration has been studied is in the context of the treatment of acquired immunodeficiency syndrome (AIDS), as the impact of human immunodeficiency virus (HIV) continues to significantly affect a large number of global populations. HIV is a retrovirus that primarily infects and directly or indirectly destroys key components of the human immune system, such as CD4 ⁺ T cells (a small group of T cells required for proper functioning of the human immune system), macrophages and dendritic cells. AIDS is a collection of syndromes and infections resulting from the specific damage of the immune system by HIV in humans. AIDS through sexually transmitted infections (STIs) affects more than 13 million men and women each year in the United States. Although there are treatments for AIDS and HIV to slow the progression of the virus, there is no known cure now. Despite a recent report from the United Nations Joint Program on HIV / AIDS claiming stabilization of HIV prevalence (UN AIDS / World Health Organization 2008 - Report on Global AIDS Prevalence, Geneva: United Nations AIDS, page 362) Over the past year, HIV-1 infections have infected 2,700,000 people and more than two million have died.

In HIV-infected patients, the efficacy of highly active antiretroviral (ARV) therapy through blocking of different steps of the retroviral life cycle is now well understood. Because HIV is a retrovirus that replicates in the cells of the immune system, intracellular drug concentration is important in determining ARV drug efficacy and toxicity. Some ARV agonists used for oral administration are prodrugs that require intracellular anabolic phosphorylation to be converted to the active form of triphosphorylated metabolites . These active metabolites, which have longer plasma half-lives than parent compounds, have been used in vaginal administration routes.

Some studies in the field of vaginal administration and HIV therapy are as follows. In vitro and in vitro testing of tenofovir (TFV) as a vaginal preparation containing 1% TFV and 2% hydroxyethyl cellulose (HEC) as bioadhesive polymers is as effective as HIV-1 disinfectant in vitro and in vitro (Mayer et al ., 2006. AIDS 20 , 543-551; Rohan et al ., PLoS One February 2010, 5, 1-12). A new generation of vaginal gels containing 1% TFV in combination with 5% emeticcitabine (FTC) protected macaque monkeys from ape HIV exposure (Parikh et al ., 2009. J. Virology. 83 , 10358-10364 ). (i) dual segment polyurethane vaginal rings that maintain the release of two oral antiviral agonists tenofovir and dapivirine, or (ii) thiocarboxanilide ) Results of studies using vaginal gels containing UC781 were investigated for antiretroviral activity (Friend, 2000. Pharm. Develop. Technol. 1-20; Mahalingam et al ., 2010. Pharm Res., 27 , 2478-2491).

Despite the promising qualities of quality for pharmacotherapy, the following development and commercialization issues exist:

- Lack of adequate in vitro / in vitro testing methods

- Lack of adequate retention time of the vaginal preparation

- lack of proper diffusion properties of the vaginal preparation

Other limitations include menstrual cycle-related quality changes, reproductive health problems, local side effects, coitus interference, and variable drug permeability

- Social taboos, unawareness, and gender-specificity are also significant barriers to the use and development of quality drug delivery.

- Lack of quality agents with ease of administration without causing discomfort to improve patient acceptance.

Surprisingly, the present inventors have discovered a method of providing a vaginal form, an " easy-to-use tablet preparation ", which is easy to administer personally and which will meet the unmet medical need for a vaginal formulation rapidly disintegrating / . This formulation produces a viscous suspension that spreads rapidly and broadly across the vaginal mucosa and is maintained long enough to provide therapeutic efficacy through topical or systemic absorption. Unlike gel formulations, these tablets do not require the use of a vaginal dispenser, so that based on the potential reduction in packaging material (i.e., increased portability) and the potential reduction in manufacturing costs, . This formulation can be used in the context of HIV therapy as well as other therapeutic applications.

In some embodiments, the present invention relates to a fastidious tablet composition comprising at least one active pharmaceutical ingredient for the treatment of a disease state via local action or systemic absorption upon vaginal administration, and to a method of making and using such a composition will be.

In some embodiments, the present invention provides pharmaceutical compositions comprising one or more active pharmaceutical ingredients suitable for the vaginal administration route, as well as methods of making and using such compositions for therapy via local action or systemic absorption as well as uterine targeting . In certain embodiments, the present invention provides a pharmaceutical composition comprising one or more active pharmaceutical ingredients suitable for the vaginal administration route, one or more polymeric excipients having a biocompatible double-acting as a biocompatible material, one or more sugar alcohol Pharmaceuticals which rapidly dissolve in the vaginal cavity rapidly and extensively diffusing to form a viscous suspension that coats the vaginal mucosa with a drug suspension / solution for topical or systemic absorption therapy, including aqueous suspensions or sugars and one or more disintegrants ≪ / RTI >

The pharmaceutical composition of the present invention may contain, for vaginal administration, an antifungal agent; Antimicrobial agents; Antimicrobial agents; Antiviral agents; Anti-infective agents; Spermicide; hormone; Antibiotic; Antiviral agents; painkiller; Antitrichomonial agents; Antigen challenge; Antimycoplasm agents; Antiretroviral agents; Nucleoside analogs; Reverse transcriptase inhibitors; Protease inhibitors; Contraceptive; Anorexics and appetite suppressants; steroid; helminthic; anesthetic; Antiarthritics; Anti-asthmatics; Anticonvulsants; Antidepressants; Antidiabetic agents; Governance system; Antihistamines; Anti-inflammatory agents; Migraine treatment; Antimotion sickness agents; Antinociceptive agents; Antitumor agents; Antiparkinsonism agents; Appealing agent; Antipsychotic; fever remedy; Anticonvulsants; Anticholinergics; Sympathetic stimulants; Xanthine derivatives; Cardiovascular preparations; Calcium channel blockers; Beta blockers; Antiarrhythmics; Hypotensive agents; diuretic; Systemic, coronary, peripheral and cerebral vasodilators; Erectile dysfunction treatment; Central nervous system stimulants; Cough and cold remedies; Decongestants; Diagnostics; hormone; soporific; Immunosuppressants; Muscle relaxant; Parasympathomimetics; Parasympathic stimulants, stimulants, sedatives, orally active drugs with significant first-pass effects; A protein / peptide comprising a growth promoting hormone and a luteinizing hormone-releasing hormone (LHRH); Nerve stabilizers; Antioxidants; vitamin; mineral; And at least one drug selected from the group consisting of herbal extracts and preparations, or combinations thereof.

According to the present invention, polymeric excipients such as low-substituted hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl (Ethylene glycol 6000-vinylcaprolactam-vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide, poly (lacticco-glycolic acid), polyamide, alginates, carrageenan, chitosan and cellulosic gum) Will enhance bioadhesion to the mucosal surface of the active ingredient (drug) and increase retention time for improved therapy through local action or systemic absorption.

In certain embodiments, the pharmaceutical composition further comprises a surfactant and / or lipid to enhance bioadhesion or enhance / maintain systemic absorption of the active ingredient on the mucosal surface, thereby enhancing local action or systemic absorption ≪ / RTI > and more specifically, the drug will have reduced water solubility to provide reduced side effects.

In some other embodiments, the present invention provides a viscous suspension that rapidly disintegrates upon insertion into the patient ' s vagina and rapidly and broadly diffuses and coats the vaginal mucosa with a drug suspension / solution for topical or systemic absorption therapy To a pharmaceutical composition in the form of a fast-dissolving tablet.

In addition, in some other embodiments, the present invention is directed to a fast tablet comprising rapidly expanding microgranules comprising at least one sugar alcohol and at least one disintegrant. These tablets can form a viscous drug suspension that rapidly disintegrates upon insertion into the patient ' s vagina and rapidly and broadly diffuses to coat the vaginal mucosa with the drug suspension / solution.

Figure 1 shows a schematic diagram of a " readily available tablet " as contemplated in certain embodiments of the invention.
Figure 2 shows average Tenofovir plasma concentration-time profiles after vaginal administration of a single Tenofovir < RTI ID = 0.0 > fasted < / RTI > Purified Tablets (RDT) in female rabbits.
Figure 3 shows average Tenofovir plasma concentration-time profiles after multiple doses of administration of tenofovir fluids tablets (RDTs) (seven daily doses once daily) to the quality of female rabbits.
Figure 4 shows the mean free and total tenofovir contents of abdominal and vaginal tissues in doses 2 hours and 24 hours after intravaginal administration of single Tenofovir fluids tablet (RDT) to female rabbits.
Figure 5 shows the average free and abundance of abdominal and vaginal tissues in doses 2 hours and 24 hours after administration of multiple doses (once daily dosing for 7 days) of tenofovir fluids tablets (RDTs) to the quality of female rabbits The contents of tenofovir are shown.
Figure 6 shows the mean postdose and postdose doses at Weck-Cel ^® in doses 2 hours and 24 hours after vaginal administration of single Tenofovir fluids tablet (RDT) to female rabbits. ≪ / RTI >
Figure 7 is administered average drug in tenofovir in soluble tablets of (RDTs) multi-dose (7 days once a day dose) 2 hours after the administration, and 24 in the time after dosage Weck-Cel ^® of the quality of the female rabbits And tenofovir concentrations after drug administration.

The following description includes information that may be useful for understanding the present invention. None of the information provided herein is prior art or any publications specifically or implicitly referred to are prior art.

All documents cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. As used hereinabove and throughout the specification, unless otherwise indicated, the following terms are to be understood to have the following meanings:

The terms "drug", "active", "bioactive substance", "active agent" or "active pharmaceutical ingredient" as used herein means a pharmaceutically acceptable and therapeutically effective compound, a pharmaceutically acceptable salt, Mixtures of stereoisomers and stereoisomers, solvates (including hydrates), homogeneous anomalies, or prodrugs thereof. Unless indicated otherwise, when referring to a drug in the description of various embodiments of the present invention, the reference should be understood to include mixtures of basic drugs, pharmaceutically acceptable salts, stereoisomers and stereoisomers, solvents (including hydrates) Cargoes, homogeneous anomalies, or prodrugs thereof.

The term " salt " refers to a product formed by reacting a suitable inorganic or organic acid with the " free base " form of the drug. Suitable acids include acids with sufficient acidity to form stable salts, for example, acids which are less toxic, 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 drugs such as metronidazole or tenofovir include inorganic acids such as HF, HCl, HBr, HI, H ₂ SO ₄ and H ₃ PO ₄ ; Non-limiting examples of organic acids include organic sulfonic acids such as C _6-16 arylsulfonic acids, C _6-16 heteroarylsulfonic acids and C _1-16 alkylsulfonic acids, such as phenyl, α-naphthyl, β-naphthyl Methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, pentyl and hexylsulfonic acids; Non-limiting examples of organic acids include carboxylic acids such as C _1-16 alkyl, C _6-16 aryl carboxylic acids and C _4-16 heteroaryl carboxylic acids such as acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid , Glutaric acid, tartaric acid, citric acid, fumaric acid, malic acid, malic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and 2-phenoxybenzoic acid; Non-limiting examples of organic acids include amino acids such as naturally occurring amino acids, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like. Other suitable salts are described, for example, in SM Birge et al ., J. Pharm. Sci., 1977, 66 , pp. 1-19. In most embodiments, " salts " refers to biocompatible or pharmaceutically acceptable or non-toxic salts, especially for mammalian cells. Salts of drugs useful in the present invention may be crystalline or amorphous, or mixtures of different crystalline forms or mixtures of crystalline and amorphous forms.

The term " prodrug " means a form of the compound which is suitable for administration to a patient without undue toxicity, irritation, allergic response, etc., and which is effective for its intended use, including ketals, esters and zwitterionic forms. Prodrugs are modified by hydrolysis in the body, e. G., In the blood. A thorough discussion of this is provided in T. Higuchi and V. Stella's ACS Symposium Series, Volume 14, Prodrugs as a New Delivery System, and Edward B. Roche Edition, Bioreversible Carriers in Drug Design, American Pharmacological Society and Pergamon Press, 1987 / RTI >

The term " fast-dissolving tablet ", " quick-release tablet ", or " RDT "refers to a tablet that rapidly disintegrates after about 8 minutes, about 6 minutes, about 4 minutes, or about 2 minutes in the patient's vagina after administration / The disintegration rate may vary but may be slower than the disintegration rate of the oral disintegration tablet when tested as described herein (e. G., The US Pharmacopoeia Disintegration Time Test Method) It is faster than the disintegration rate.

The term " substantially disintegrable " refers to the level of disintegration that results in at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% disintegration. The term " disintegration " refers to the dissolution of a solid within a liquid (e. G., Dissolution of a drug in a solvent or gastric fluid), while " disintegration " refers to the degradation or loss of structural aggregation of constituent particles comprising a tablet, Is distinguished from the term " dissolution "

The term " water soluble polymer " refers to a polymer that is soluble (i. E., A significant amount dissolves) in an aqueous medium, regardless of pH.

The term " biocompatible material " refers to a polymer that improves adhesion to a mucosal or similar biological surface of a pharmaceutical composition containing a biocompatible material, as compared to adhesion of a pharmaceutical composition that does not contain the biocompatible material. Non-limiting examples of bioadhesive materials include bioadhesive polymers such as hydroxypropylcellulose.

The term " patient acceptance status " refers to the fact that patients prescribed to follow a particular dosage regimen of the particular needing drug do not adhere to the dosage regimen. The non-availability of dosing schedules or adherence is a significant medical problem that requires billions of dollars worldwide and affects the lifestyle of millions of people.

The term " about " as used herein in reference to a quantity includes not only the numbers close to the quantity but also the quantity indicated. For example, " about 60 seconds " includes exactly 60 seconds as well as values close to 60 seconds (e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.).

The use of the term " or " in the claims is used herein to mean " and / or " unless expressly indicated to refer to alternatives only or the alternatives are mutually exclusive. Any recitation of items using the term " or " is specifically contemplated to mean that any of the recited items may be specifically excluded from the related embodiments.

The term " work " and " one " when used in conjunction with the word " comprising " in the claims or the specification follow one or more of the following unless the context clearly dictates otherwise.

Unless otherwise stated, the amounts of the various pharmaceutically acceptable excipients or excipients included in the various pharmaceutical compositions in accordance with certain embodiments of the present invention are expressed as percentages by weight of the composition as granulate or RDT. Thus, 10% active agent in the RDT composition refers to the presence or amount of active agent in the RDT as much as 10% by weight.

In some embodiments, the present invention provides an anti-fungal agent suitable for intra-vaginal administration by topical or systemic absorption; Antimicrobial agents; Antimicrobial agents; Antiviral agents; Anti-infective agents; Spermicide; hormone; Antibiotic; Antiviral agents; painkiller; Antitricomonase; Antigen challenge; Antimicrobial plasma agents; Antiretroviral agents; Nucleoside analogs; Reverse transcriptase inhibitors; Protease inhibitors; Contraceptive; Anorexics and appetite suppressants; steroid; helminthic; anesthetic; Anti-arthritic agents; Anti-asthmatics; Anticonvulsants; Antidepressants; Antidiabetic agents; Governance system; Antihistamines; Anti-inflammatory agents; Migraine treatment; Antispasmodics; Antinociceptive agents; Antitumor agents; Parkinson's disease remedy; Appealing agent; Antipsychotic; fever remedy; Anticonvulsants; Anticholinergics; Sympathetic stimulants; Xanthine derivatives; Circulatory organ drug; Calcium channel blockers; Beta blockers; Antiarrhythmics; Hypotensive agents; diuretic; Systemic, coronary, peripheral and cerebral vasodilators; Erectile dysfunction treatment; Central nervous system stimulants; Cough and cold remedies; Decongestants; hormone; soporific; Immunosuppressants; Muscle relaxant; Parasympathomimetics; Nerve stabilizers; Antioxidants; vitamin; mineral; And herbal extracts or preparations; Parasympathetic stimulants; speed; sedative; An orally active drug exhibiting a significant first pass effect; Nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside / nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and combinations thereof. , An integrase inhibitor, a growth-promoting hormone and a luteinizing hormone-releasing hormone (LHRH), or a pharmaceutically acceptable salt, solvate or ester thereof.

In some embodiments, the present invention provides an anti-fungal agent suitable for intra-vaginal administration by topical or systemic absorption; Antimicrobial agents; Antimicrobial agents; Antiviral agents; Anti-infective agents; Spermicide; hormone; Antibiotic; Antiviral agents; painkiller; Antitricomonase; Antigen challenge; Antimicrobial plasma agents; Antiretroviral agents; Nucleoside analogs; Reverse transcriptase inhibitors; Protease inhibitors; Contraceptive; Anorexics and appetite suppressants; steroid; helminthic; anesthetic; Anti-arthritic agents; Anti-asthmatics; Anticonvulsants; Antidepressants; Antidiabetic agents; Governance system; Antihistamines; Anti-inflammatory agents; Migraine treatment; Antispasmodics; Antinociceptive agents; Antitumor agents; Parkinson's disease remedy; Appealing agent; Antipsychotic; fever remedy; Anticonvulsants; Anticholinergics; Sympathetic stimulants; Xanthine derivatives; Circulatory organ drug; Calcium channel blockers; Beta blockers; Antiarrhythmics; Hypotensive agents; diuretic; Systemic, coronary, peripheral and cerebral vasodilators; Erectile dysfunction treatment; Central nervous system stimulants; Cough and cold remedies; Decongestants; hormone; soporific; Immunosuppressants; Muscle relaxant; Parasympathomimetics; Nerve stabilizers; Antioxidants; vitamin; mineral; And herbal extracts or preparations; Parasympathetic stimulants; speed; sedative; An orally active drug exhibiting a significant first pass effect; Nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside / nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and combinations thereof. , An integrase inhibitor, a growth-promoting hormone and a luteinizing hormone-releasing hormone (LHRH), or a pharmaceutically acceptable salt, solvate or ester thereof.

Thus, in some embodiments, the present invention provides a method of treating HIV / AIDS carriers to treat or prevent HIV infection by administering NRTIs (e. G., Africitabine, entecavir, NNRTIs (such as nevirapine, delavirdine, epibilene, rilpivirin, UC-781, MKC-442, and the like), emtricitabine, tenofovir, abacavir, adefovir, Quinoxaline HBY 097, DMP 266, salts thereof and mixtures thereof), protease inhibitors (such as indinavir, amprenavir, darunavir, lotinavir, nelvinabear, ritonavir, A group of antiretroviral agents consisting of an inhibitor (e.g., quinabial, atazanavir, tifranavir, salts thereof and mixtures thereof) and an integrase inhibitor (e.g., Elvetegravir, MK-2048, salts thereof and mixtures thereof) Gt; It relates to pharmaceutical compositions containing one or more drugs. A variety of commercial vaginal creams, ointments, gels, inserts / loops and tablets are now available. For example, Dahl discloses the preparation of a pharmaceutical vaginal gel comprising tenofovir in European Patent No. 1773296. Because this formulation may suffer from limitations such as leakage, messiness, and short residence times, as with other similar gel preparations, it is recommended that AIDS carriers or those who wish to avoid the risk of HIV transmission or infection during sexual activity It may not help. However, it is 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 provides a pharmaceutical composition comprising a bisphosphonate (e.g., alendronate, claudonate, etidronate, pamidronate, tyluronate, ibandronate, neridronate, risedronate, zoledronic acid, Imidronate, minodronate and olefadronate); But are not limited to, ergotamine, erythromycin, ergotamine, dihydroergotamine, ergostine, buccal slab, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, Razatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isomethapentene, chloromethoxazole, isomethapentene, Migraine treatment drugs such as those selected from the group consisting of promazine, diazepam, droperidol, valproic acid, gabapentin, topiramate and divalproex sodium; But are not limited to, methotrexate, metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolassetron, nevallone, dronabinol, levonan tradol, coprecipitant, cyclolin, promethazine, sildenafil, oxytocin, Oximetidine, oxytocin, oxybutynin, bromocriptine, rifamycin, azithromycin; Steroids used in hormone replacement therapy or for contraception; Calcitonin; LHRH and analogs; insulin; And human growth hormone, and combinations thereof. The present invention also relates to pharmaceutical compositions in the form of inert microgranules or tablets comprising one or more drugs suitable for vaginal administration. (E. G., Carbomers, chitosan, hydroxyethylcellulose), a surfactant (e. G., Glyceryl palmitostearate) or a lipid < / RTI > (For example, glyceryl palmitostearate, phospholipids) may be employed.

In certain embodiments, the present invention provides a pharmaceutical composition comprising at least one drug suitable for vaginal administration, at least one sugar alcohol such as mannitol, a saccharide such as lactose, and at least one polymeric binder such as low-substituted hydroxyethylcellulose ≪ RTI ID = 0.0 > microgranules. ≪ / RTI > Such compositions may be used, for example, for topical or systemic absorption therapy when inserting a medicinal composition into the vagina of a patient / subject in need thereof.

In certain embodiments of the present invention, the pharmaceutical composition in the form of the ready-to-use microgranules further comprises a disintegrant such as crospovidone. This disintegration can promote rapid disintegration of the readily available microgranules to form a viscous drug-containing suspension within the vagina of the patient / subject in need thereof.

In certain other embodiments of the invention, the pharmaceutical composition in the form of the readily available microgranules further comprises at least one bioadhesive polymer, such as a low-substituted hydroxyethylcellulose. The bioadhesive polymer is provided at a desired concentration that can coat the vaginal mucosa at the time of formation of the viscous drug-containing suspension in the vagina of the patient / subject so that the biocompatible polymer can be sustained for longer periods of time for local action or systemic absorption, The efficacy can be improved.

Examples of sugar alcohols / saccharides include mannitol, sorbitol, xylitol, arabitol, erythritol, glycerol, hydrogenated starch hydrolyzate, isomalt, lactitol, lactose, maltitol, sucrose, maltose and combinations thereof. It does not.

Examples of suitable binders include polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropylmethylcellulose or hypromellose (e.g., Methocel E5 or E15 or PharmacoatTM 603), hydroxypropylcellulose (such as Klucel ^® LF ), Low-substituted hydroxyethylcellulose, and polysaccharides, but are not limited thereto. The binder may be present in an amount of, for example, from about 0.5 to 3% by weight, based on the readily available microgranule.

Examples of disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, starch, cross-linked carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, gums (such as gellan gum) . The disintegrant may be in the form of a pharmaceutical composition in the form of the inert microgel to about 1% to about 10%, about 3% to about 7%, about 5%, including all ranges and subranges therebetween May be present in the composition.

Non-limiting examples of suitable bioadhesive polymers include, but are not limited to, hydroxypropylcellulose, hypromellose, low-substituted hydroxyethylcellulose, hydroxyethylethylcellulose, polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone- polyvinylacetate copolymers (e.g., BASF Corporation Kollidon ^® VA 64), polyvinyl alcohol, polyethylene oxide, carbomers acids ^{(CARBOPOL ® 974P, 941, 940} , 934, G70), poly (lactic co-glycolic acid), poly Amide, carrageenan, chitosan, and various cellulose gums (e.g., xanthan gum), but are not limited thereto. The bioadhesive polymer may be in the form of an inert microgel, for example, in the range of about 3% to about 10%, about 4% to about 8%, about 5%, including all ranges and subranges therebetween. May be present in the composition.

Non-limiting examples of suitable surfactants that may be employed include DL-alpha tocopherol, surfactants such as CAPTEX 200, Tween 20, Tween 80, Vitamin E TPGS, Capryol 90, CREMOPHOR EL, CARBITOL, PEG 400, 92, LABRASOL, triacetin, sodium lauryl sulfate, ethylene glycol monostearate, polysorbate acids and Pollock four meoryu ^{®, GELUCIRE ®, LABRAFIL ®,} LABRASOL ®, IMWITOR ®, lauryl acid, sodium dodecyl sulfate, sodium) , And mixtures thereof.

Non-limiting examples of suitable lipids that may be employed include lecithins; Hydrogenated lecithins; Lyso lecithin, hydrogenated lyso lecithins; Lysophospholipids and derivatives thereof; Phospholipids and derivatives thereof; Salts of alkyl sulfates; Salts of fatty acids; Docusate sodium; Stearyl alcohol, glyceryl palmitostearate (PRECIROL ^® ATO 5); Mixtures of mono-, di- and triesters 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 readily available tablet is a combination of a disintegrant prepared according to co-pending U.S. Patent Application Serial No. 10 / 827,106 (published as US 2005/0232988) And further comprises rapidly dispersing microgranules containing one saccharide or sugar alcohols. Further, in another specific embodiment of the present invention, the readily available tablet composition comprises a sugar alcohol such as mannitol, a super-disintegrant such as low-substituted hydroxypropylcellulose and starch, a modified starch and a binder, and a hydroxypropyl It may further comprise rapidly expanding microgranules including disintegrant polyfunctional additives such as cellulose.

Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, starch, crosslinked carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, gum (e.g., gellan gum) . Exemplary sugars or sugar alcohols are selected from the group consisting of arabitol, erythritol, glycerol, hydrogenated starch hydrolyzate, isomalt, lactitol, lactose, maltitol, mannitol, sorbitol, xylitol, sucrose, maltose and combinations thereof . The saccharide or sugar alcohol may be supplemented or replaced with an artificial sweetener such as sucralose. The ratio of disintegrant to saccharide or sugar alcohol in the rapidly expanding microgranules is generally from about 1:99 to about 10:90 or from about 5:95 to about 10:90, inclusive, by weight, It reaches about 10:90. In some embodiments, the disintegrant or saccharide or sugar alcohol, or both, may have an average of less than about 30 占 퐉 according to co-pending U.S. Patent Application Serial No. 10 / 827,106 (published as US 2005/0232988) When present in the form of particles having a particle size and the composition has a polyfunctional additive, the saccharide or sugar alcohol is present in the form of particles having an average particle size of about 60 쨉 m or less. The polyfunctional additive may be present, for example, in an amount of from 1 to 2.5% by weight in the rapidly expanding microgel composition. The ratio of the drug-containing granules to the rapidly expanding granules may range from about 5: 1 to about 1: 5, from about 3: 1 to about 1: 3, or from about 2: 1 to about 1: 1: 2 or 1: 1.

The in vitro dissolution test of the pharmaceutical compositions of the present invention can be carried out using the US Pharmacopoeia I (paddle at 100 rpm) or II (paddle at 50 rpm) and the appropriate dissolution medium (900 mL) (HPLC method) according to the drug .

The disintegration of the RDTs of the present invention is tested according to the US Pharmacopoeia disintegration test. Alternatively, the disintegration time of the pharmaceutical composition prepared with the RDT tablet may be determined by the vaginal fluid stimulant prepared according to the disclosure by Owen and Katz (Owen and Katz, 1999. Contra. 59. 91 to 95) . ≪ / RTI > In view of the small volume of fluid available in the vagina, dissolution tests were performed with a small amount of buffer (e.g., 3.5 mL) of ammonium acetate buffer at a pH of about 6 at appropriate times when centrifuging at 4,000 rpm for 2 minutes and HPLC By dropping the compatible tablets into test tubes containing the test specimens filtered through a 0.45 [mu] m PTFF filter.

In one particular embodiment, the readily-soluble tablet of the present invention comprises a therapeutically effective amount of tenofovir or a pharmaceutically acceptable salt thereof, alone or in combination with emtricitabine, in a ratio of about 2: 1 to 1:10, 1: 8 or from about 1: 2 to about 1: 6 or about 1: 5. The ready-to-use tablet, after insertion into the vagina, provides a viscous, easily spreading suspension that substantially disintegrates in the patient's vagina and spreads / coats into the vaginal mucosa to provide efficacy through topical or systemic absorption. In addition to the rapidly expanding microgranules, the ready-to-use tablets of the present invention may be formulated as tablets containing low-substituted hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polycarboxylic acids, polyvinylpyrrolidone, Polyvinyl acetate copolymer (e.g., Kollidon ^占 VA 64 from BASF), SOLUPLUS ^占 poly (ethylene glycol 6000-vinyl caprolactam-vinyl acetate from BASF) (13:57:30 copolymer), polyvinyl alcohol, A pharmaceutically acceptable bioadhesive polymer, such as one selected from the group consisting of polyethylene oxide, poly (lactic-co-glycolic acid), polyamides, alginates, carrageenan, chitosan and various cellulosic gums .

In some embodiments, the readily available tablet comprises about 50 mg or more; For example, 100 mg or more; 200 mg or more; 300 mg or more; Or 500 mg or more. In some other embodiments, the affirmative tablet comprises about 2,000 mg or less; For example, 1,600 mg or less; Not more than 1,400 mg; 1,200 mg or less; 1,000 mg or less; 800 mg or less; Or 500 mg or less. In another embodiment, the readily available tablet has a weight of about 800 mg or less. In another embodiment, the readily available tablet has a weight of about 600 mg or less. In another embodiment, the readily available tablet has a weight of 500 mg or less. The formulations of the present invention may include two or more populations of antibiotic drug containing particles, such as, for example, comprising at least one population of metronidazole particles as described herein. The formulations may comprise, for example, one or more populations of emtricitabine particles as described herein for AIDS prevention, such as Tenofovir, nucleoside reverse transcriptase inhibitors, one population of fastidious particles and, in addition,

In one embodiment, the treatment as described herein targets two specific viral enzymes: a reverse transcriptase (e.g., using NRTIs or NNRTIs) and a protease (e.g., using a protease inhibitor).

A pharmaceutical composition of the present invention in the form of a fast-dissolving tablet for vaginal administration may contain a therapeutically effective amount of propranolol, a non-selective beta-blocker that undergoes extensive initial-pass (hepatic) metabolism upon oral administration, And mixtures thereof.

A pharmaceutical composition of the present invention which is in the form of a fast-dissolving tablet for vaginal administration comprises a therapeutically effective amount of metronidazole and, optionally, clarithromycin, sulfonamides, erythromycin, azithromycin, doxycycline, quinolones, Antibiotics selected from the group consisting of cetriaxone cifrofloxacin, doxycycline, vancomycin, clindamycin, rifaximin and metronidazole.

A pharmaceutical composition of the invention in the form of a fast-dissolving tablet for vaginal administration may contain a therapeutically effective amount of clotrimazole and optionally an antifungal agent selected from the group consisting of nystatin, ketoconazole, itraconazole and clotrimazole.

In certain embodiments, the present invention provides a pharmaceutical composition comprising at least one sugar alcohol, saccharide or mixture thereof, a polymeric binder, optionally a superdisintegrable or bioadhesive polymer, and an antifungal, antimicrobial, antimicrobial, Antitumor agents, antimetabolites, antiretroviral agents, nucleoside analogs, reverse transcriptase inhibitors, protease inhibitors, contraceptives, proteins, peptides, steroids, growth factors, Or a pharmaceutically acceptable salt, solvate or ester thereof, is first prepared, and then the drug-containing easy-to-use micro-granule composition comprising a therapeutically effective amount of at least one drug selected from the group consisting of a drug- The granules are described in co-pending U.S. Patent Application Serial No. 10 / 827,106 (US 200 (RDTs) containing therapeutically effective doses and mixing with rapidly spreading microgranules prepared according to the specifications of WO-A-5/0232988, the disclosure of which is hereby incorporated by reference. The readily available tablet rapidly disintegrates in the vagina of the patient / subject and rapidly and broadly spreads to form a viscous drug-containing suspension which is expected to coat the vaginal mucosa for the treatment of diseases via local action or systemic absorption.

In certain other embodiments, the present invention provides a method of treating HIV / AIDS carriers, in addition to treating HIV / AIDS carriers, such as for inhibiting or eliminating the growth or severity of AIDS, (S) selected from the group consisting of alcohols, sugars or mixtures thereof, polymeric binders, optionally a deodorizing or bioadhesive polymer, and NRTIs such as africitabine, entecavir, emtricitabine, tenofovir, avacavir, adefovir, NNRTIs (e.g., nevirapine, delavirdine, epibatidine, UC-781, MKC-442, quinoxaline HBY 097, DMP 266, salts thereof and mixtures thereof), protease inhibitors (Such as indinavir, amprenavir, darunavir, rotinavir, nelfinavir, ritonavir, saquinavir, atazanavir, tifranavir, salts thereof and mixtures thereof) and an integrase inhibitor for example , Elvetegravir, MK-2048, salts thereof, and mixtures thereof), and thereafter administering a pharmaceutically-effective amount of at least one medicament selected from the group of anti-retroviral agents, Containing ready-to-use micro-granules with rapidly expanding micro-granules, and tabletting with readily available tablets containing therapeutically effective doses. A variety of commercial vaginal creams, ointments, gels, inserts / loops and tablets are now available. For example, Dahl discloses the preparation of a pharmaceutical vaginal gel comprising tenofovir in European Patent No. 1773296. This formulation is not helpful to AIDS carriers or those who want to avoid the risk of HIV transmission or infection during sexual activity, as gel / applicators can experience limitations such as leakage, jam and short residence times, like other similar gel preparations . However, it is 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 present invention provides a composition comprising at least one sugar alcohol such as mannitol, a polymeric binder such as a low-substituted hydroxypropylcellulose, optionally a disintegrant such as crospovidone, One NRTI alone, such as tabin, or one or more NRTIs, such as emtricitabine or tenofovir in combination with dapiviren, is then prepared and then the ready-to-use micro-granules, rapidly spreading Microcrystalline cellulose, a superdisintegrant such as crospovidone, and a lubricant such as sodium stearyl fumarate to form the fast-pacifying tablets.

In another embodiment, the method of making readily available microgranules is a biodegradable bioadhesive polymer for improving bioadhesion of the viscous drug suspension on the surface of the vaginal mucosa upon insertion of the RDT into the vaginal cavity (e. G., A biosubstituted ≪ / RTI > hydroxyethylcellulose), as described herein.

The granulation method is not limited; A fluidized bed or high shear granulation method using a solution of a polymeric binder dissolved in purified water, ethanol, isopropanol, acetone or a mixture thereof is an embodiment of the present invention. In accordance with the present invention, at least one sugar alcohol and, optionally, a disintegrating or low-viscosity sugar in a top spray fluidized bed granulator such as, for example, Glatt GPCG 3, GPCG 5, GPCG 120, or Fluid Air FA0300, A solution containing a polymeric binder and a drug dissolved or homogeneously suspended in solution is sprayed onto a powder mixture comprising a bioadhesive polymer such as substituted hydroxyethylcellulose and the granulation is dried in the same fluid bed dryer Granulation can be carried out. The granulation may be carried out by drying in the Glatt using a high shear granulator such as GMX 25 (batch size: 4 to 7 kg), GMX 65 or GMX 600 (batch size: 140 to 160 kg) . The dry granules thus produced can be recovered from ready-to-use drug-containing microgranules having a desired particle size distribution by milling / re-milling large granules by discarding the fine powder by passing the granules through a suitable container have.

The drug-containing microparticles, which have been granulated with one or more bioadhesive polymers to improve bioadhesive properties in the vaginal mucosa, may have a median particle size in the range of about 100 to 400 [mu] m. In some embodiments, at least 90% of the microparticles are less than 600 microns in order to incorporate into the readily available tablet.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising the readily available drug-containing microgranules prepared as described herein and the rapidly expanding microgranules, and for the therapeutic efficacy via topical or systemic absorption on a rotary tablet press, To a ready-to-use tablet for administration to the vaginal cavity of a patient in need thereof.

The readily available tablets of the present invention may be produced by, for example, an internal lubrication method in which the tablet mix is further mixed with lubricant prior to tableting. Alternatively, the readily available tablet may be produced by an external lubrication method that is not externally applied to the punch of the rotary tablet press and to the material in contact with the surfaces of the die, although the lubricant is not included in the tablet formulation. Lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and the like may be used to lubricate the granules, or may be used to lubricate the granules or to contact the die and punch surfaces of rotary tablet presses used to tablet the tablets Can be applied externally onto the material.

Another embodiment according to the present invention is a pharmaceutical composition comprising an antifungal agent, an antimicrobial agent, an antimicrobial agent, an antiviral agent, a spermicide, a hormone, an anticholinergic agent, an anticholinergic agent, an anticholinergic agent, an antiretroviral agent, a nucleoside analogue, a reverse transcriptase inhibitor, A pharmaceutical composition comprising at least one therapeutically effective amount of a medicament selected from the group consisting of an inhibitor, a contraceptive, a steroid, an orally active drug exhibiting a significant first-pass effect, a protein / peptide comprising a growth promoting hormone and a luteinizing hormone-releasing hormone (LHRH) The present invention relates to a method of treating a patient or a subject comprising administering the composition of the present invention as a fast-dissolving tablet by inserting it into the vaginal cavity of a patient in need thereof.

Example

The invention is explained in more detail in the following sections. Many of the examples provided below for illustrating the present invention include Tenofovir alone or Tenofovir in combination with emtricitabine. It should be understood that the embodiments and embodiments described herein are for illustrative purposes only and that various modifications or changes will be apparent to those of ordinary skill in the art and are included within the spirit and scope of the present application.

Example  One

A: RD microgranules containing Tenofovir , crospovidone and Klucel :

Sodium bicarbonate (54 g) was slowly added to the purified water (2,800 g) in a stainless steel vessel with continued stirring to dissolve. The pH of the bicarbonic acid solution is adjusted to about 6.0 by adding hydrochloric acid if necessary. Hydroxypropylcellulose (Clucel LF; 125 g) was added slowly to dissolve during stirring; Thereafter, Tenofovir (180 g) was added and dissolved. Preheated Glatt GPCG 3, equipped with a top spray insert, a granulation air distribution bottom plate, a 200 mesh product retention screen, and a 1.0 mm spray nozzle, had an average particle size of less than 30 μm (781 g) and crospovidone (60 g). Both mannitol and crospovidone are passed through Comil, and the lumps are pulverized. The readily available microgel composition is granulated continuously to fluidize the fill and maintain the process parameters under the following conditions: production temperature - 34 +/- 1 DEG C; Fluidizing air flow - 10 CFM; Injection rate - 10 to 16 mL / min. At the completion of spraying, the RD microgranules are dried to produce a drying loss of about 1% by weight.

B: RD microgranules containing tenofovir , crospovidone and L- HEC :

Sodium bicarbonate (54 g) is slowly added to the purified water (2,500 g) in a stainless steel vessel with continued stirring to dissolve. The pH of the bicarbonic acid solution is adjusted to about 6.0 by adding hydrochloric acid if necessary. Low-substituted hydroxyethylcellulose (L-HEC; 20 g) was added slowly to dissolve during stirring; Thereafter, Tenofovir (180 g) was added and dissolved. The preheated Glatt GPCG 3 is filled with lumpy milled mannitol (781 g) and crospovidone (60 g) and fluidized. The RD microgranules were prepared by spraying a solution as described in Experiment 1A above.

C: RD microgranules containing Tenofovir , crospovidone and HPMC :

Sodium bicarbonate (39.1 g) is slowly added to the purified water (2,500 g) in a stainless steel vessel with continued stirring to dissolve. The pH of the bicarbonic acid solution is adjusted to about 6.0 by adding hydrochloric acid if necessary. Hypromellose (HPMC; 18.1 g) was added slowly to dissolve during stirring; Thereafter, Tenofovir (183.2 g) was added and dissolved. The preheated Glatt GPCG 3 is filled with bulk crushed mannitol (637.4 g) and crospovidone (43.1 g) and fluidized. The RD microgranules were prepared by spraying a solution as described in Experiment 1A above.

D: Rapidly spreading micro-granules :

Rapidly expanding microgranules are described in co-pending U.S. Patent Application Publication No. U.S. Pat. 2003/0215500. Specifically, D-mannitol (152 kg) (Pearlitol 25 from Roquette, France) having an average particle size of about 20 microns or less was crosslinked in a high shear granulator (Vector, GMX 600) (Crospovidone XL- 10), granulated with purified water (approximately 32 kg), wet milled using a Quadro Comil, and finally tray dried to yield microgranules with an LOD (loss on drying) of less than about 0.8% to provide. The dried granules are milled and the larger sized materials are milled again to produce rapidly expanding microgranules with an average particle size in the range of approximately 175 to 300 mu m.

E: Tenofovir Fast-acting tablets ( crospovidone ) :

RDT tablet formulations containing the Tenofovir (TFV) RD microgranules of Experiments 1A, 1B and 1C were fitted with partial tooling at 15 RPM mold-to-turret speed Tablets are pressed on a Hata tablet press (see Table 1 for composition). Half of the rapidly expanding microgranules were filled with a 0.25 square foot V mixer and then the remaining half of the crospovidone, microcrystalline cellulose (Avicel PH101), TFV RD granules and the rapidly expanding microgranules were filled and mixed for 10 minutes do. Sodium stearyl fumarate (Pruv) passed through a 35 mesh screen is added to the tablet mix and mixed for 2 minutes. The Hata refinement press is set to a passive mode of filling weight of 150 mg and a hardness of 10 to 50 N. Once the setting is completed, the tablet press is operated at a compression force of 3, 4 and 5 kN in the 'automatic' mode. The tablets are recovered in the steady state for each tack force for testing of weight, thickness, hardness and degree of shrinkage. The mean values tested for each batch of tablets are shown in Table 1. The disintegration time tested according to the US Pharmacopoeia Method < 701 > 60 to 90 seconds, 30 to 60 seconds for the Tenofovir RDT tablet batches of 1AD (TFV RDG: Experiment 1A), Experiment 1BD (TFV RDG: Experiment 1B) and Experiment 1CD (TFV RDG: Experiment 1C) Second, and 30 to 60 seconds. The readily soluble tablets of these preparations tableted at 4 kN are observed to disintegrate within 30-60 seconds when tested by the US Pharmacopoeia method < 701 >, and more than 80% when tested for dissolution in test tubes at 30 minutes Lt; / RTI >

Table 1: Composition of Tablet Tablets

Example  2

A: RD microgranules containing Tenofovir :

Sodium bicarbonate (67.5 g) is slowly added to the purified water (2,010 g) in a stainless steel vessel with continued stirring to dissolve. The pH of the bicarbonic acid solution is measured to be about 6.8. Hippromelose (Methocel, 62.5 g) was slowly added to dissolve in the stirring; Then, Tenofovir (190 g) is added and dissolved. The preheated Glatt GPCG 3 is packed and fluidized with lumpy milled mannitol (890 g). The readily available microgranules are prepared by spraying the fill and maintaining process parameters at the following conditions: production temperature - 34 + - 1 [deg.] C; Fluidized air flow - 5 to 15 CFM; Injection rate - 4 to 16 mL / min. At the completion of spraying, the RD microgranules are dried to produce a drying loss of about 1% by weight.

B: RD microgranules containing Tenofovir :

Sodium bicarbonate (57 g) is slowly added to the mixture of ethanol (540 g) and purified water (1,260 g) in a stainless steel vessel with continued stirring to dissolve. The pH of the bicarbonic acid solution is measured to be about 6.2. Next, tenofovir (200 g) is added and dissolved, and then low-substituted hydroxyethylcellulose (L-HEC; 20 g) is added and dissolved with stirring. The preheated Glatt GPCG 3 is packed and fluidized with lumpy milled mannitol (1,023 g). The RD microgranules are prepared by spraying the solution under the following conditions. Production temperature - 34 ± 1 ° C; Fluidized air flow - 4 CFM; Injection rate - 8 to 12 mL / min. At the completion of spraying, the RD microgranules are dried to produce a drying loss of about 1% by weight.

C: RD microgranules containing Tenofovir :

Sodium bicarbonate (54 g) was added slowly to the mixture of ethanol (540 g) and purified water (1,260 g) in a stainless steel vessel with constant stirring to dissolve. The pH of the bicarbonic acid solution is measured to be about 6.15. Next, tenofovir (200 g) was added and dissolved, and then low-substituted hydroxyethylcellulose (L-HEC; 30 g) was added and dissolved with stirring. The preheated Glatt GPCG 3 is packed and fluidized with lumpy milled mannitol (1,023 g). The RD microgranules are prepared by spraying a solution as described in Experiment 2B above. Upon completion of the spray, the drying loss of the RD microgranule is about 1.5 wt%.

D: Tenofovir RDT :

RDT tablet formulations (Experiment 2BD and Experiment 2CD formulations) containing the Tenofovir (TFV) RD microgranules of Experiment 2B and Experiment 2C were prepared with a 4 kN tack force and a partial tooling at 15 RPM mold- And mounted on a Hata tablet press (see Table 2 for composition). Recover samples at the start, middle and end of operation for in-process refinement characterization testing. The results are shown in Table 2. In Experiment 2AD, tablets are tableted using a Carver press.

Table 2: Composition of Tablet Tablets

E: Tenofovir injected into the vagina of rabbits Single and multi-dose PK studies of RDT :

The aim of this study was to assess the drug-induced decline in female rabbits with a minimum body weight of 2.5 kg after single or 7-day daily dosing in the form of a fast-paced tablet (n = 0, 0.5, 1, 2, 4, 8 and 24 hours after dosing of 1 or 7 days in group 1 and group 3 and 1 or 7 days of dosing in group 2 and group 4, 0.5, 1.0, 1.5 and 2 hours). Prior to administration of the test article, maleic acid proges- mar (0.3-0.5 mg / kg or effect) was administered via subcutaneous administration to gently sedate the animal. Once sedated, a single tablet was inserted into the abdominal cavity of each animal (approximately 8 cm) using an 18 catheter. Lubricants were not used because they could affect tablet uptake. Detailed clinical investigations of each animal were performed daily during the course of the study. Observations include autonomic nerve effects such as skin, fur, eyes, ears, nose, mouth, thorax, abdomen, vulva, limb and foot, respiratory and circulatory effects, salivary secretion, Including, but not limited to, evaluation of the effects of the nervous system, including behavior. For groups 1 and 3 under yellow illumination, using the procedure approved by a number of pathologists for all deaths, deaths, euthanasia or euthanasia in each planned autopsy according to the current standard work instructions (SOP), 1 A complete autopsy was performed 2 hours after dosing on days or 7 days or 24 hours after dosing for groups 2 and 4. The iliac lymph nodes were recovered under yellow illumination for measuring Tenofovir total concentration. The Weck-Cel ^® sponge samples were prepared by placing each Weck-Cel ^® sponge on the vagina to absorb the vaginal secretion of the Tenofovir total concentration.

Figure 2 shows average Tenofovir plasma concentration-time profiles after inserting a single Tenofovir RDT (i.e., RDTs of Experiment 2CD) into the vaginal glands of female rabbits, while Figure 3 shows the results of multiple dose (7 days 1 Lt; / RTI > dosing once daily). Figure 4 shows the mean free and total tenofovir contents of abdominal and vaginal tissues in doses 2 and 24 hours after the insertion of a single Tenofovir RDT into the vaginal glands of female rabbits, Once a day for 7 days). ≪ / RTI > Figure 6 shows the mean tissue permeate concentrations before and after drug administration in Weck-Cel < ( ^R) > in doses 2 hours and 24 hours after insertion of single Tenofovir RDT into the vitals of female rabbits, 7 shows Tenofovir concentrations before and after drug administration in Weck-Cel ^® after multiple doses (once daily dosing for 7 days).

According to another preclinical comparative PK study in rabbits dosing 40 mg as 40 mg versus 40 mg as 1% tenofovir gel (4 mL) as fast-acting tablets (4 10 mg tablets), the fast- Suggests that they provide equivalent tissue concentrations compared to 1% TFV gels. Unlike gel formulations, which require the use of a vaginal applicator and accompanying packaging, the readily available tablet technology makes its use very attractive in terms of increased portability and potential reduction in manufacturing costs. Additionally, the technique provides privacy and convenience of drug administration.

Example  3

A: RD microgranules containing Tenofovir :

The high shear granulator GMX-25 was prepared by mixing a mixture of tenofovir (TFV; 829.2 g), mannitol (Pearlitol 25 with an average particle size of less than 30 μm, 7,829.2 g), hydroxyethylcellulose (NITROSOL-HEC 250L; 91.6 g) And filled with crospovidone (200 g). The contents of the product bowl are mixed well for 2 minutes at an impeller speed set to 150 RPM. The powder mixture is granulated by spraying purified water at an injection rate of about 100 g / min at the following process parameters: injection nozzle pore size 0.085 "; Impeller setting: speed - 325 RPM, time - 5.5 minutes; Chopper Setup Speed - High, Time - 5.5 minutes. After 5 minutes, the spraying is stopped and the granulation is continued to be mixed for 30 seconds before stopping the granulator, and the plate, chopper blade and impeller blades are scraped off. Continue spraying to spray about 630 g of water and mix for two more minutes before releasing the contents of the product dish. The product plate of the preheated Glatt GPCG 5 is filled with moisture granules that dry at a loss of less than 2% on drying as measured using a Computrac Moisture Analyzer at 85 ° C. The drying conditions in the Glatt are as follows: Product support screen - 200 mesh; Inlet air temperature - 42 ° C; Inlet air volume - 40 cfm; Desiccant Wheel - operating.

B: RD microgranules containing Tenofovir :

Emtricitabine (FTC, 682.9 g) is slowly added to the mixture of ethanol (3,974 g) and purified water (995 g) in a stainless steel vessel with continued stirring to dissolve. Subsequently, low-substituted hydroxyethylcellulose (Natrosol HEC-250L; 80.1 g) was added with stirring to disperse / dissolve. The preheated Glatt GPCG 3 is filled with bulk crushed mannitol (2,737 g) and fluidized. The RD microgranules were prepared by spraying the solution under the following conditions: Product support screen - 200 mesh; Nozzle tip size - 1.2 mm; Atomizing pressure - 2 bar; Inlet air temperature - 72 ° C; Product temperature -38 占 1 占 폚; Fluidizing air flow - 40 cfm; Spray Rate - 40 mL / min; Dehumidifier wheel - in operation. At the completion of spraying, the FTC RD microgranules were dried at an input air temperature set to 42 DEG C resulting in a dry loss of about 1 wt%.

C: RDTs (40-mg TFV / 40-mg FCT)

The RDT tablet formulation containing the TFV RD microgranules of Experiment 3A and the Experiment 3B alone FCT RD microgranules or mixtures thereof was first mixed with a lubricant, other pharmaceutical excipients including sodium stearyl fumarate, and mixed with 4 to 6 kN Tableting on a Beta tablet press with partial tooling at a rotational speed of 15 RPM (see Table 3 for composition). The samples are recovered at the beginning, middle, and end of each operation for the in-process purification characterization test.

Manesty Beta presses with eight 12 mm round, diamond shaped tooling without embossing are set with the following parameters for 40 mg TFV / 40 mg FCT RDTs.

Tablet weight : total (10) - 5.00 g; Nominal: 500 mg; Range: 460 to 540 mg

Weight setting Fill: 8 mm (or 6 mm for TFV); Pre-setting: 6 mm

Main tabletting: 3.3 mm (or 2.85 mm for TFV) Force Feeder Settings: 3.

The press was set to operate at 25 rpm, and after several die table / mold revolutions, ten tablets were withdrawn before stopping the operation of the press. Ten tablets are withdrawn to check the weight of the 10 tablets and the appearance of the tablets (picking, capping, etc.) is checked. The tablet press is adjusted if necessary to produce tablets that meet the above listed specifications for weight, thickness and hardness, and the results are recorded in the production batch record. If necessary, the parameters are readjusted as necessary to produce tablets that meet the above listed fray specifications.

At the beginning, middle, and end of process operation, 35 tablets are sampled for in-process testing. Ten tablets are tested for weight, hardness, and thickness, and the margins are tested for 6.5 g tablets. Results are recorded in production batch records. The remaining specimens are combined in a suitably labeled container as part of a composite specimen. Each of the process test points will use a separate container for analysis testing.

Using similar settings, rapidly disintegrating tablets of 40-mg TFV / 20-mg FCT, 20-mg TFV / 40-mg FCT, 40-mg TFV or 40-mg FCT are titrated from individual tablet mixes.

The composition of RDTs (40 mg TFV; 40 mg FCT; 40 mg TFV / 40 mg FCT; 40 mg TFV / 20 mg FCT; 20 mg TFV / 40 mg FCT)

Example  4

A: RD microgranules containing metronidazole :

Vinylpyrrolidone-vinyl acetate copolymer (for example, BASF Corporation Kollidon ^® VA 64; 50 g) with continued stirring and dissolved by slow addition to a mixture of ethanol and purified water in a stainless steel vessel. Next, metronidazole (180 g) was added and dissolved with stirring. The preheated Glatt GPCG 3 is filled with lumpy milled mannitol (770 g) and crospovidone (50 g) and fluidized. The RD microgranules are prepared by spraying the solution under the following conditions: production temperature - 34 +/- 1 DEG C; Fluidized air flow - 4 CFM; Injection rate - 8 to 12 mL / min. Upon completion of the spray, the RD microparticles are dried to a loss of drying of about 1% by weight.

B: RD microgranules containing clotrimazole :

Hydroxyethylcellulose (50 g) is slowly added to the mixture of ethanol and purified water in a stainless steel vessel with continued stirring to dissolve. Next, metronidazole (180 g) was added and dissolved with stirring. The preheated Glatt GPCG 3 is filled with bulk crushed mannitol (720 g) and crospovidone (50 g) and fluidized. The RD microgranules are prepared by spraying the solution under the following conditions: production temperature - 34 +/- 1 DEG C; Fluidized air flow - 4 CFM; Injection rate - 8 to 12 mL / min. Upon completion of the spray, the RD microparticles are dried to a loss of drying of about 1% by weight.

C: RD microgranules containing propranolol HCl :

Polyvinyl pyrrolidone-polyvinyl acetate copolymer (for example, BASF Corporation Kollidon ^® VA 64; 50 g) with continued stirring and dissolved by slow addition of purified water in a stainless steel vessel. Next, propranolol HCl (240 g), a non-specific beta-blocker exhibiting extensive hepatic metabolism, is added and dissolved while stirring. The preheated Glatt GPCG 3 is packed and fluidized with lumpy milled mannitol (560 g) and low-substituted hydroxyethylcellulose (50 g). The RD microgranules are prepared by spraying the solution under the following conditions: production temperature - 38 +/- 2 DEG C; Fluidizing air flow - 10 CFM; Injection rate - 10 to 20 mL / min. Upon completion of the spray, the RD microparticles are dried to a loss of drying of about 1% by weight.

D: RDTs containing metronidazole, clotrimazole or propranolol HCl

The required amount of the metronidazole RD microgranules of Experiment 4A, the clotrimazole RD microgranules of Experiment 4B or the propranolol HCl RD microgranules of Experiment 4C, the rapidly dispersing microgranules of Experiment 1D, 5 to 15 weight%, microcrystalline cellulose (Avicel PH101 5 to 10% by weight), RDT tablets containing 2 to 5% by weight of low-substituted hydroxypropylcellulose, 1% by weight of sodium stearyl fumarate (Experiment 4AD: Metronidazole RDTs, Experiment 4BD: Clotrimazole RDTs And Experimental 4CD formula: Propranolol HCl RDTs) are tableted on a Hata tablet press equipped with tooling suitable for different tacking forces and different mold-to-rotational speeds. The samples are collected at the start, middle and end of each operation for the in-process purification characterization test to establish the robustness of the manufacturing process of each tablet formulation.

Those skilled in the art will appreciate that the above procedures and compositions may be suitably modified to provide for the appropriate dosage of the drug (s) for which buccal tablets for vaginal administration are required.

While the present invention has been described in connection with specific embodiments thereof, it is evident that further modifications are possible and that the present application is generally based on the principles of the present invention and originates from known or conventional practice in the art to which this invention pertains, It is to be understood that the invention is applicable to the essential features described and that it is intended to encompass any variations, uses, or modifications of the invention including modifications from this disclosure, as in accordance with the scope of the appended claims.

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

Claims (13)

(a) a therapeutically effective amount of a vaginally active drug or a pharmaceutically acceptable salt thereof, or a mixture or combination thereof;
(b) a low-substituted hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl acetate copolymer, poly (ethylene glycol 6000- A biocompatible material selected from the group consisting of polyvinyl alcohol, polyethylene oxide, poly (lactic-co-glycolic acid), polyamide, alginate, carrageenan, chitosan and various cellulose gums as well as binders From 4 to 10% by weight of a polymeric excipient having dual properties;
(c) sugar alcohols, saccharides, or mixtures thereof; And
(d)
, ≪ / RTI > and
(1) disintegrating and
(2) sugar alcohols or saccharides having an average particle size of 30 mu m or less
Lt; RTI ID = 0.0 > and / or < / RTI > less than 400 microns,
Wherein said vaginal tablets rapidly disintegrate upon insertion into the vagina of a patient or subject to form a rapidly and widely diffusing viscous drug-containing suspension coating vaginal mucosa. The method according to claim 1,
DL-alpha tocopherol, CAPTEX 200, Tween 20, Tween 80, Vitamin E TPGS, Capryol 90, CREMOPHOR EL, CARBITOL, PEG 400, Lecithin, BRIJ 92, LABRASOL, Triacetin, Sodium Lauryl Sulphate, Ethylene Glycol Monostearate, Characterized in that it further comprises at least one surfactant selected from the group consisting of polysorbates PLURONIC ^® , GELUCIRE ^® , LABRAFIL ^® , LABRASOL ^® , IMWITOR ^® , sodium laurylsalicylate and sodium dodecyl sulfate or mixtures thereof. Fast-acting tablets. The method according to claim 1,
The present invention relates to a process for the preparation of a medicament for the treatment and / or prophylaxis of a disease or condition selected from the group consisting of lecithins, hydrogenated lecithins, lysolecithin, hydrogenated lyso lecithins, lysophospholipids and derivatives thereof, phospholipids and derivatives thereof, At least one lipid selected from the group consisting of monostearate, mixtures of mono-, di- and tri-esters of glycerol, mono- and di-esters of PEG, free PEG, or mixtures thereof Featured, fast-paced, quality tablet. The method according to claim 1,
Characterized in that the rapidly expanding microgranules comprise a disintegrant selected from the group consisting of cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked carboxymethylcellulose of sodium and low-substituted hydroxypropylcellulose or mixtures thereof Lt; / RTI > tablet. The method according to claim 1,
Characterized in that the rapidly expanding microgranules comprise sugar alcohols selected from the group consisting of arabitol, erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol and xylitol, Quality purification. The method according to claim 1,
Wherein said fastfatible tablet disintegrates within 60 seconds when tested according to the US Pharmacopoeia disintegration time. The method according to claim 6,
The ready-to-
i) a degree of warpage of 1% or less by weight; And
ii) has a sufficient tablet hardness to be packaged in a blister or bottle for storage, transport, commercial distribution and end use. The method according to claim 1,
A therapeutically effective amount of a tablet, comprising therapeutically effective amounts of tenofovir and emtricitabine. The method according to claim 1,
Wherein said vaginal active drug is selected from the group consisting of tenofovir, emtricitabine, metronidazole, clotrimazole and propanol roll HCl. a) i. At least one therapeutically effective drug or a pharmaceutically acceptable salt thereof, or a mixture or combination thereof, selected from the group consisting of tenofovir, emtricitabine, metronidazole, clotrimazole and propanol roll HCl;
ii. Mannitol; And
iii. Polyvinyl pyrrolidone-polyvinylacetate copolymers, poly (ethylene glycol 6000-vinylcaprolactam, polyvinylpyrrolidone-polyvinylacetate copolymer, polyvinylpyrrolidone-polyvinylacetate copolymer, polyvinylpyrrolidone- Polymeric excipient selected from the group consisting of polyvinyl alcohol, polyethylene oxide, poly (lactic-co-glycolic acid), polyamide, alginates, carrageenan, chitosan and cellulose gum;
Granulating the microcrystalline granules to produce readily available microgranules;
b) i. At least one sugar alcohol, saccharide, or mixture thereof having an average particle size of 30 탆 or less; And
ii. One or more disintegrants;
≪ / RTI > to produce drug-free rapidly expanding microgranules;
c) mixing the readily available micro-granules from step a) and the rapidly expanding micro-granules from step b) in a weight ratio of from 5: 1 to 1: 2; And
d) titrating the mixture of step c) with an affinity purification tablet;
A method for producing an easily available tablets according to claim 1,
The vaginal tablets form a viscous drug-containing suspension which rapidly and broadly diffuses, which rapidly disintegrates upon insertion into the vaginal cavity of a patient or subject in need thereof, thereby coating the vaginal mucosa. A method for producing a fast - dissolving tablet. 11. The method of claim 10,
a) granulating the tenofovir, mannitol, low-substituted hydroxyethylcellulose, and optionally crospovidone and chitosan to produce swallowable microgranules;
b) granulating mannitol and crospovidone, each having an average particle size of 30 mu m or less, to produce rapidly spreading microgranules;
c) mixing the readily available microgranules of step a) and the rapidly expanding microgranules of step b) with microcrystalline cellulose, crospovidone and sodium stearyl fumarate to form a mixture; And
d) titrating the mixture of step c) with a readily available tablet using a rotary tablet press;
Wherein each readily available tablet disintegrates within 60 seconds when tested by the US Pharmacopoeia disintegration time. 12. The method of claim 11,
Step d) further comprises the step of calibrating the mixture of step c) with the fast-spinning tablet using a rotary tablet press equipped with an external lubrication system to lubricate the die and punches prior to tableting with magnesium stearate Wherein the method comprises the steps of: 12. The method of claim 11,
Step a) comprises preparing compatible microgranules comprising emtricitabine, mannitol, low-substituted hydroxyethylcellulose and optionally crospovidone and carbobole, and administering to both treatment of both Tenofovir and emtricitabine ≪ / RTI > wherein the method further comprises the step of producing readily available vaginal tablets containing an effective amount of the active ingredient.

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