EP2704694A1 - Compositions de comprimés à dissolution rapide pour administration vaginale - Google Patents

Compositions de comprimés à dissolution rapide pour administration vaginale

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Publication number
EP2704694A1
EP2704694A1 EP12779335.4A EP12779335A EP2704694A1 EP 2704694 A1 EP2704694 A1 EP 2704694A1 EP 12779335 A EP12779335 A EP 12779335A EP 2704694 A1 EP2704694 A1 EP 2704694A1
Authority
EP
European Patent Office
Prior art keywords
agents
pharmaceutical composition
microgranules
group
rapid dissolve
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12779335.4A
Other languages
German (de)
English (en)
Other versions
EP2704694A4 (fr
Inventor
Gopi Venkatesh
Vijaya Swaminathan
Jin-Wang Lai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adare Pharma Solutions Inc
Original Assignee
Aptalis Pharmatech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aptalis Pharmatech Inc filed Critical Aptalis Pharmatech Inc
Publication of EP2704694A1 publication Critical patent/EP2704694A1/fr
Publication of EP2704694A4 publication Critical patent/EP2704694A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P7/10—Antioedematous agents; Diuretics
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Vaginal drag delivery is a potential route for therapy via topical action or systemic absorption as well as uterine targeting of active pharmaceutical ingredients. It offers advantages such as:
  • Vaginal drug delivery systems such as conventional tablets are traditionally used to deliver contraceptives and microbicides to treat vaginal infection.
  • Vaginal tablets, rings, creams, and viscous gels containing a wide range of drugs e.g., steroids, prostaglandins, antimicrobials, proteins, and peptides
  • drugs e.g., steroids, prostaglandins, antimicrobials, proteins, and peptides
  • Emulsion based vaginal drag delivery systems have been developed, such as ones containing (i) one or more globule stabilizing polymers (e.g., HP C, polyvinyl alcohol, or a PEGylatecl lipid) and (ii) a therapeutically active drug; drags approved for or used for the treatment, prophylaxis, cure, or mitigation of diseases of the vagina, urinary tract, cervix, or other female reproductive organ; inducement of contraception; or systemic drug therapy.
  • globule stabilizing polymers e.g., HP C, polyvinyl alcohol, or a PEGylatecl lipid
  • a therapeutically active drug e.g., a therapeutically active drug
  • US 20030180366 discloses a novel, microemuision based, essentially pH neutral, vaginal drug deliver ⁇ ' system suitable for modified deliveiy of a therapeutically active material in the vaginal cavity.
  • US 20050276836 discloses a method of coating a vaginal device for delivering therapeutic or health-promoting agents with a miicoadhesive compositio .
  • WO 2008133928 discloses a method of treating a patient having an epithelial lesion, such as of the vagina, or disorder of impaired mucin function as well as methods of treating pain associated with epithelial lesions and disorders of impaired mucin function using a pharmaceutical composition containing mucin glycoproteins in combination with therapeutic agents, e.g. , trefoil polypeptides.
  • WO 2010061284 discloses a controlled release, intravaginal, pharmaceutical dosage form consisting of at least, one pharmaceutically active ingredient which is admixed with a combination of biocompatible and biodegradable polymers and shaped for insertion into the vagina of a patient.
  • vaginal administration of a controlied-release opioid such as oxycodone has been shown to be a safe, effective, and simple means of managing cancer pain in patients who cannot tolerate the adverse events caused by oral administration (X. Zhang, X-J. uan, C. Liu, and Z-H. Yu, Effect of vaginal administration of controlied-release oxycodone on cancer pain. Chin. J. Cancer J. Cancer, 2009, 28(7) 1-4; F. Acartiirk, Miicoadhesive Vaginal Drug Deli very Systems. Recent Patents on Drug Delivery & Formulation 2009, 3, 193-205)
  • Acartiirk 2009 recently summarized the development and in vitro/in vivo evaluations of improved formulations for transmucosal vaginal delivery.
  • bioadhesive vaginal dosage forms e.g., conventional tablet, multiparticulate, viscous gel formulations
  • Conventional or even bioadhesive vaginal tablets are easy to administer in privacy by the user; however these dosage forms may be too slow to disintegrate and spread and are cleared from the vagina too rapidly to provide any meaningful improvement in therapy.
  • the level of patient compliance is poor and is generally believed to be influenced by restrictive dosing regimens, a need to consume multiple combination oral drug products, patients' suspicions as to the effectiveness of vaginal therapy, leakage, or discomfort associated with administration.
  • gel dosage forms require the use of a vaginal applicator, thereby resulting in increased packaging materials and manufacturing costs.
  • HIV acquired immune deficiency syndrome
  • AIDS human immunodeficiency virus
  • STIs sexually transmitted infections
  • ARV anti-tadsorption virus
  • H IV is a retrovirus that replicates within cells of the immune system
  • intracel lular drug concentrations are important to determine ARV drug efficacy and toxicity.
  • Some ARV agents used for oral administration are prodrugs that require intracellular anabolic phosphorylation to be converted to their active form of triphosphorylated metabolites.
  • the active metabolites which have longer plasma half-lives than their parent compounds, have been used in the vaginal route of administration.
  • TFV tenofovir
  • HEC hydroxy ethylcellulose
  • the present inventors surprisingly found a way to provide a vaginal dosage form, a 'rapid dissolve tablet formulation,' which promises to meet the unmet medical need for a vaginal dosage form that is easy to administer in privacy and which rapidly disintegrates/dissolves upon insertion into the vaginal cavity.
  • This dosage form creates a viscous suspension that is spread rapidly and widely over the vaginal mucosa, and is retained for a sufficiently long time to provide therapeutic efficacy via topical action or systemic absoiption.
  • use of a vaginal applicator is not required for these tablets, thereby making them an attractive dosage form based on potential reductions in packaging materials ⁇ i.e., increased portability) and manufacturing costs.
  • This dosage form may be used in the context of HI V therapy as well as other therapeutic applications.
  • this invention relates to rapid dissolve tablet compositions comprising one or more active pharmaceutical ingredients for the treatment of disease states via topical action or systemic absorption upon vaginal administration, and methods of making and using such compositions.
  • this invention relates to pharmaceutical compositions comprising one or more active pharmaceutical ingredients suitable for vaginal route of administration, and methods of making and using such compositions for therapy via topical action or systemic absorption, as well as uterine targeting.
  • the present invention is related to a pharmaceutical composition comprising one or more active pharmaceutical ingredients suitable for vaginal route of administration, one or more polymeric excipients having a dual property of acting as a binder as well as a bioadbesive material, one or more sugar alcohols or saccharides, and one or more disintegrants, which rapidly disintegrates in the vaginal cavity forming a viscous suspension that rapidly and widely spreads to coat the vaginal mucosa with the drug suspension/solution for therapy via topical action or systemic absorption.
  • the pharmaceutical composition of the present invention may contain at least one drug selected from the group consisting of antifungal agents; antibacterial agents; antimicrobial agents; antiviral agents; anti-infectives; spermicides; hormones; antibiotics; antiviral agents; analgesics; antitrichomonial agents; antiprotozoal] agents; antimycoplasm agents; antiretro viral agents; nucleoside analogues; reverse transcriptase inhibitors; protease inhibitors; contraceptive agents; anorexics and appetite suppressants; steroids; anthelmintics; anesthetics; antiarthritics; antiasthma agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals;
  • antihistamines anti-inflammatory agents; antimigraine preparations; antimotion sickness agents; antinauseants; antineoplastics; antiparkinsonism agents; antipruritics; antipsychotics;
  • antipyretics antispasmodics
  • anticholinergics anticholinergics
  • sympathomimetics antixanthine derivatives
  • cardiovascular preparations calcium channel blockers; beta blockers; antiarrhythmics;
  • antihypertensives diuretics; general, coronary, peripheral and cerebral vasodilators; erectile dysfunction agents; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; hypnotics; immunosuppressives; muscle relaxants;
  • proteiiis/peptides including growth enhancing hormones and lutei izing-hormone-releasing hormone (LHRH); tranquilizers; antioxidants; vitamins:
  • the bioadhesive property of the polymer excipient e.g., low- substituted hydroxyethylcelluiose, hydroxypropylcellulose, hypromellose, polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone-polwinyl acetate copolymer, ethylene glycol 6000 - vinylcaprolactam - vinyl acetate copolymer, polyvinyl alcohol , polyethylene oxide, poly(lactic co-glycolic acid), polyaniide, alginic acid salts, carrageenan, chitosan, and cellulosic gum) will enhance bioadherence of the active ingredient (drug) to the mucosa surface, thereby increasing the retention time for improved therapy via topical action or systemic absorption.
  • the active ingredient drug
  • the pharmaceutical composition could further comprise a surfactant, and/or a lipid that will enhance bioadherence of the active ingredient to the mucosa surface or enhance/sustain systemic absorption, thereby providing improved therapy via topical action or systemic absorption, and reduced side effects; more particularly when the drug has poor water solubility.
  • the present invention is directed to a pharmaceutical composition in the form of a rapid dissolve tablet, which rapidly disintegrates upon insertion into the vagina of a patient, forming a viscous suspension that rapidly and widely spreads and coats the vaginal mucosa with the drug suspension/solution for therapy via topical action or systemic absorption.
  • the present invention is related to a rapid dissolve tablet comprising rapidly dispersing microgranules comprising at least one sugar alcohol and at least one disintegrant.
  • This tablet may rapidly disintegrate upon insertion into the vagina of a patient, forming a viscous drug suspension that rapidly and widely spreads to coat the vaginal mucosa with the drug suspension/solution.
  • FIG. 1 shows a schematic of a 'Rapid Dissolve Tablet' as conceived in certain embodiments of the present invention.
  • FIG. 2 shows mean tenofovir plasma concentration - time profiles following vaginal administration of a single tenofovir rapid dissolve tablet (RDT) in female rabbits.
  • RDT rapid dissolve tablet
  • FIG. 3 shows mean tenofovir plasma concentration - time profiles following a multi-dose (7 once-daily dosing) administration of tenofovir rapid dissolve tablets (RDTs) into the vagina, of female rabbits.
  • RDTs tenofovir rapid dissolve tablets
  • FIG. 4 shows mean free and total tenofovir contents of the abdominal and vaginal tissues at 2 and 24 hrs post dosing following vaginal administration of a single tenofovir rapid dissolve tablet (RDT) in female rabbits,
  • RDT rapid dissolve tablet
  • FIG. 5 shows mean free and total tenofovir contents of the abdominal and vaginal tissues at 2 and 24 hrs post dosing following a multi-dose (7 once-daily dosing) administration of tenofovir rapid dissolve tablets (RDTs) into the vagina of female rabbits.
  • RDTs tenofovir rapid dissolve tablets
  • FIG. 6 shows mean predose and postdose tenofovir concentrations in Weck-Cel ⁇ at 2 and 24 hrs post dosing following vaginal administration of a single tenofovir rapid dissolve tablet (RDT) in female rabbits.
  • RDT rapid dissolve tablet
  • FIG. 7 shows mean predose and postdose tenofovir concentrations in Weck-CeV 1 at 2 and 24 hrs post dosing following a multi-dose (7 once-daily dosing) administration of tenofovir rapid dissolve tablets (RDTs) into the vagina of female rabbits.
  • RDTs tenofovir rapid dissolve tablets
  • 'drug includes a pharmaceutically acceptable and therapeutically effective compound, pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, or prodrugs thereof.
  • pharmaceutically acceptable salts pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, or prodrugs thereof.
  • the reference encompasses the base drug, pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, or prodrugs thereof.
  • salts refers to the product formed by the reaction of a suitable inorganic or organic acid with the "free base” form of the drug.
  • Suitable acids include those having sufficient acidity to form a stable salt, for example acids with low toxicity, such as the salts approved for use in humans or animals.
  • acids that may be used to form salts of a vaginally active drug such as metronidazole or tenofovir include inorganic acids, e.g.
  • organic acids include organic sulfonic acids, such as Ce-16 aryl sulfonic acids, Ce-ie heteroaryl sulfonic acids, or Ci.1 ⁇ 2 alkyl sulfonic acids - e.g., phenyl, a-napbthyl, ⁇ -naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids; non-limiting examples of organic acids includes carboxylic acids such as C;_ i6 alkyl, Ce- e aryl carboxylic acids, and C4-16 heteroaryl carboxylic acids, e.g.
  • organic acids include amino acids, e.g. , the natural iy-occurring amino acids, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.
  • suitable salts can be found in, e.g., S. M. Birge et at, J.
  • salts refers to salts that are biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells.
  • the salts of drugs useful in the invention may be crystalline or amorphous, or mixtures of different crystalline forms or mixtures of crystalline and amorphous forms.
  • prodrug means a. form of a compound suitable for administration to a patient without undue toxicity, irritation, allergic response, and the like, and effective for an intended use, including ketal, ester, and zwitterionic forms.
  • a prodrug is transformed in vivo, for example by hydrolysis in blood.
  • rapidly dissolve tablet refers to a tablet that disintegrates rapidly, such as in about 8 min, about 6 min, about 4 min, or about 2 mm, in the vaginal cavity of a patient after administration/insertion into the vaginal cavity.
  • the rate of disintegration can vary, but is slower than the rate of disintegration of orally disintegrating tablets, or faster than the rate of disintegration of conventional or bioadhesive vaginal tablets, when tested as described herein (e.g., the USP ⁇ 701> disintegration time test method).
  • substantially disintegrates refers to a level of disintegration amounting to disintegration of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 1 00% d s ntegration.
  • disintegration is distinguished from the term “dissolution” in that “disintegration” refers to the breaking up of or loss of structural cohesion of the constituent particles comprising a tablet, whereas “dissolution” refers to the solubilization of a solid in a liquid (e.g., the solubilization of a drug in solvents or gastric fluids).
  • water-soluble polymer refers to a polymer that is soluble (i.e., a significant amount dissolves) in aqueous media, independent of pH.
  • bioadhesive material refers to a polymer that improves adherence of the pharmaceutical composition containing a bioadhesive material to mucosa or similar biological surface compared to the adherence of the pharmaceutical composition without the bioadhesive material.
  • bioadhesive materials include bioadhesive polymers such as hydroxypropylcellulose.
  • patient compliance refers to non-adherence to dosing regimens by patients who are prescribed to follow a certain dosing regimen of a particular medication in need. Noncompliance or adherence to a dosing regimen is a major medical problem in the world costing billions of dollars and affecting lifestyles of millions of people.
  • the amount of the various pharmaceutically acceptable actives or ex dpi en ts incorporated into various pharmaceutical compositions in accordance with certain embodiments of the present invention is expressed as the percen tage weight of the composi tion as granulate or RDT.
  • a 10% of an active in the RDT composition refers to the presence or content of the active in the RDT by 10 weight%.
  • the present invention is directed to a pharmaceutical composition
  • a drug selected from the group consisting of antifungal agents; antibacterial agents; antimicrobial agents; antiviral agents; anti-mfectives; spermicides; hormones; antibiotics;
  • antiviral agents analgesics; antitrichomonial agents; antiprotozoan agents; antim ooplasm agents; antireiroviral agents; nucleoside analogues; reverse transcriptase inhibitors; protease inhibitors; contraceptive agents; anorexics and appetite suppressants; steroids; anthelmintics; anesthetics; antiarthritics; antiasthma agents: anticonvulsants: antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents antimigraine preparations; antimotion sickness agents: antinauseants; antineoplastics; antiparkinsonism agents; antipruritics; antipsychotics: antipyretics; antispasmodics; anticholinergics: sympathomimetics; xanthine derivatives; cardiovascular preparations; calcium channel blockers; beta blockers;
  • antiarrhythmics antihypertensives; diuretics; vasodilators that are general, coronary, peripheral or cerebral; erectile dysfunction agents; centra) nervous system stimulants; cough and cold preparations; decongestants; hormones; hypnotics; immunosuppressives; muscle relaxants;
  • parasympatholytics tranquilizers; antioxidants; vitamins, minerals; and herbal extracts or preparations; parasympathomimetics; psychostimulants; sedatives; orally active drugs exhibiting significant first-pass effects; or combinations thereof, proteins/ eptides, reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non- nucleoside/nucleotide reverse transcriptase inhibitors (N TIs), protease inhibitors (Pis), integrase inhibitors, growth enhancing hormones and luteinizing-hormone-releasing hormone (LHRH), and the like, or a pharmaceutically acceptable salt, solvate, or ester thereof, suitable for therap by vaginal administration via topical action or systemic absorption.
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • N TIs non- nucleoside/nucleotide reverse transcriptase inhibitors
  • Reverse transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit the activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.
  • the mode of action of NRTIs is essentially the same; they are analogues of naturally occurring deoxynucleotides needed to synthesize virai DNA.
  • NNRTIs are compounds that are specifically inhibitory to HIV-1 replication and target HIV-1 reverse transcriptase and have, in addition to the N RTIs and protease inhibitors, gained a definitive place in the treatment of HIV-1 infections. Pis are a class of drags used to treat or prevent infection by viruses, including HIV and Hepatitis C.
  • Integrase inhibitors are a class of antiretroviral drugs designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of a host cell.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more drugs selected from the group of antiretroviral agents consisting of NRTls (e.g., apricitabiiie , eiitecavir, emtricitabine, tenofovir, abacavir, adefovir, their salts and mixtures thereof), NNRTIs (e.g., nevirapine, delavirdine, efavirenz, rilpivirine, UC-781 , MKC-442, quinoxaline HBY 097, DMP 266, their salts and mixtures thereof), protease inhibitors (e.g., indinavir, amprenavir, darunavir, lotinavir, nelfmavir, ritonavir, sequinavir, atazanavir, tipranavir, their salts and mixtures thereof), and integrase inhibitors (e.g., N
  • vaginal creams ointments, gels, inserts/rings, and tablets are currently available.
  • Dahl discloses in EP 1773296 the preparation of a pharmaceutical vaginal gel comprising tenofovir.
  • This dosage form may not benefit individuals with AIDS or those who want to avoid the risk of HIV transmission or infections during sexual activity, as the gel/applicator- like other similar gel formulations-may suffer from limitations such as leakage, messmess, and low residence time.
  • compositions and methods which reduce the risk of HIV transmission or infections during sexual activity.
  • the present invention is directed to a pharmaceutical
  • composition in the form of rapid dissol ve microgranules or tablets comprising at least one drug suitable for vaginal administration selected from the group consisting of a bisphospbonate [e.g., alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, neridronate, risedronate, zoledronic acid, incadronate, minodronate, and olpadronate); an anti-migraine drug, such as one selected from the group consisting of ergotamine, dihydroergotamine, ergostine, butalbital, pheno barbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol,
  • a bisphospbonate e
  • meperidine methadone, sumatriptan, naratriptan, razatriptan, zoimitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chiorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate and divalproex sodium; an anti-nausea drug, such as one selected from the group consisting of metoclopramide, prochlorperazine,
  • domperidone ondansetron, tropisetron, dolasetron, nabilone, dronabinol, ievonantradol. aprepitant, cyelizine, promethazine, sildenafil, oxytocin, oxytoci , oxybutynin, bromocriptine, rifamycin, azithromycin; steroids used in hormone replacement therapy or for contraception: calcitonin; LHRH and analogues; insulin; and human growth hormones, and combinations thereof.
  • V aginally adm.inistrata.ble dosage forms may be employed, such as those including suppositories that contain poorly soluble/bioavailable drugs and effervescent agents as penetration enhancers, and one or more mucoadhesive polymers (e.g., carbomers, chitosan, hydroxyethylcellulose), surfactants (e.g., glyceryl palmitostearate), or lipids (e.g., glyceryl palmitostearate, phospholipid).
  • mucoadhesive polymers e.g., carbomers, chitosan, hydroxyethylcellulose
  • surfactants e.g., glyceryl palmitostearate
  • lipids e.g., glyceryl palmitostearate, phospholipid
  • the present invention is directed to a pharmaceutical composition in the form of rapid dissolve niicrogranules comprising at least one drug suitable for vaginal administration, at least, one sugar alcohol, such as mannitol or a saccharide such as lactose, and at least one polymeric binder such as low-substituted hydroxyethylcellulose.
  • a pharmaceutical composition in the form of rapid dissolve niicrogranules comprising at least one drug suitable for vaginal administration, at least, one sugar alcohol, such as mannitol or a saccharide such as lactose, and at least one polymeric binder such as low-substituted hydroxyethylcellulose.
  • Such compositions may be used, for example, for therapy via topical action or systemic absorption upon insertion of the medicinal composition into the vaginal cavity of a patient/subject in need thereof.
  • the pharmaceutical composition in the form of rapid dissolve microgranules further comprises a disintegrant such as crospovidone.
  • This disintegrant may facilitate rapid disintegration of rapid dissolve niicrogranules to form a viscous drug-containing suspension in the vaginal cavity of a patient/subject in need thereof.
  • the pharmaceutical composition in the form of rapid dissolve microgranules further comprises at least one bioadhesive polymer, such as low-substituted hydroxyethylcellulose,
  • This bioadhesive polymer may be provided at a desired concentration, which may, upon forming a viscous drug-containing suspension in the vaginal cavity of a patient/subject, coat the vaginal mucosa, thereby improving its bioadherence and therapeutic efficacy via longer retention for topical action or systemic absorption.
  • sugar alcohols/saccharides include, but are not limited to, mannitol, sorbitol, xylitol, arabitol, erythritoL glycerol, hydro genated starch hydrolysate, isomalt, lactitol, lactose, maititol, sucrose, maltose, and combinations thereof.
  • binders include, but are not limited to, polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose or hypromellose (e.g., Methocei E5 or E l 5, or PharmacoatTM 603), hydroxypropylcelluiose (e.g., Klucel* 1 LF), low-substituted
  • PVP polyvinylpyrrolidone
  • polyethylene oxide e.g., hydroxypropyl methylcellulose or hypromellose
  • hydroxypropylcelluiose e.g., Klucel* 1 LF
  • hydroxypropylcelluiose e.g., Klucel* 1 LF
  • the binder can be present in an amount ranging from, e.g., about 0.5 - 3 weight. % based on the rapid dissolve microgranules.
  • disintegraiits include, but are not limited to crospovidone, sodium starch glycolate, starch, crosslinked sodium carboxymethylcellulose, low-substituted
  • the disintegrant can be present in the pharmaceutical composition in the form of rapid dissolve microgranules, for example, from about 1 % to about, 1 0%, from about 3% to about 7%, to about 5%, inclusive of all ranges and subranges there between.
  • bioadhesive polymers include, but are not limited to, hydroxypropylcelluiose, hypromellose, low-substituted hydroxyethylcellulose,
  • hydroxyethylethyleelluiose polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone- poly inyl acetate copolymer (e.g., Kollidon " VA 64 from. BASF), polyvinyl alcohol, polyethylene oxide, carbomers (CARBOPOL ® 974P, 941 , 940, 934, G70), poly(lactic co- glycolic acid), poiyamide, carrageenan, chitosan, and various cellulosic gums (e.g., xanthan gum).
  • polyvinylpyrrolidone vinylpyrrolidone- poly inyl acetate copolymer
  • polyvinyl alcohol polyethylene oxide
  • carbomers CARBOPOL ® 974P, 941 , 940, 934, G70
  • poly(lactic co- glycolic acid) poiyamide
  • carrageenan chitosan
  • various cellulosic gums e
  • the bioadhesive polymer can be present in the pharmaceutical composition in the form of rapid dissolve microgranules, from, for example, about 3% to about 10%, from about 4% to about 8%, to about 5%, inclusive of all ranges and subranges there between.
  • Non-limiting examples of suitable surfactants that may be employed include DL-alpha tocopherol, surfactants (e.g., CAPTEX 200, Tween 20, Tween 80, Vitamin E TPGS, Capryol 90, CREMOPi !OR EL, CARBMOL, PEG 400, lecithin, Brij 92, LABRASOL, triacetin, sodium lauryl sulfate, ethylene glycol monostearate, polysorbates and poloxamers* ' , GELIJCIRE ® , LABRAF1L ® , LABRASOL*, IMWITOR ® , sodium lauryl salicylate, sodium dodecyl sulfate), and mixtures thereof.
  • surfactants e.g., CAPTEX 200, Tween 20, Tween 80, Vitamin E TPGS, Capryol 90, CREMOPi !OR EL, CARBMOL, PEG 400, lecithin, Brij 92,
  • Non-limiting examples of suitable lipids that may be employed include lecithins;
  • a pharmaceutical composition in the form of a rapid dissolve tablet further comprises rapidly dispersing microgranules comprising a saccharide or a sugar alcohol in combination with a dismtegrant, produced in accordance with the specifications co-pending U.S. Patent Application Ser. No. 10/827,106 (published as US 2005/0232988).
  • the rapid dissolve tablet composition can further comprise rapidly dispersing microgran les comprising a sugar alcohol such as mannitol, a super dismtegrant such as low-substituted hydroxypropylcellulose, and an additive with multi-functionality of a binder and dismtegrant such as starch, modified starch and hydroxypropylcellulose.
  • a sugar alcohol such as mannitol
  • a super dismtegrant such as low-substituted hydroxypropylcellulose
  • an additive with multi-functionality of a binder and dismtegrant such as starch, modified starch and hydroxypropylcellulose.
  • Suitable disintegrants include, but, are not limited to, crospovidone, sodium starch glycolate, starch, crosslinked sodium carboxymethylceliulose, low-substituted
  • hydroxypropylcellulose gums (e.g., gellan gum), and combinations thereof.
  • exemplary saccharides or sugar alcohols may be selected from the group consisting of arabitol, erythritol, glycerol hydrogenated starch hydrolysate, isomalt lactitol, lactose, maltitol, mannitol, sorbitol, xylitol, sucrose, maltose, and combinations thereof.
  • the saccharide or sugar alcohol may also be supplemented or replaced with artificial sweeteners such as sucralose.
  • the ratio of the dismtegrant to the saccharide or sugar alcohol in the rapidly dispersing microgranules typically ranges from about 1 :99 to about 10:90, or from about 5:95 to about 10:90 on a weight basis and inclusive, of all ranges and subranges there between.
  • the disintegrant or the saccharide or sugar alcohol, or both are present in the form of particles having an average particle size of about 30 ⁇ or less in accordance with the specifications in co-pending U.S. Patent Application Ser. No. 10/827,106 (published as US 2005/0232988) and where the composition has a multifunctional additive the saccharide or sugar alcohol, are present in the form of particles having an average particle size of about 60 um or less.
  • the multifunctional additive may be present in the rapidly dispersing mierogranule composition at 1 -2,5% by weight, for example.
  • the ratio of the drug-containing granules to the rapidly disintegrating granules can range from about 5: 1 to about 2 :5, from about 3: 1 to about 1 :3, or from about 2: 2 to about 1 :2, or about 1: 1, inclusive of all ranges and subranges there between.
  • the in vitro dissolution testing of pharmaceutical compositions of the present invention is performed using United States Pharmacopeia I (paddles at 100 rpm) or II (paddles at 50 rpm) and an appropriate dissolution media (900 mL) (HPLC method) depending on the drug(s).
  • Disintegration of the RDTs of the invention is tested according to the USP ⁇ 701> Disintegration Test.
  • disintegration time of pharmaceutical compositions prepared as RDT tablets may be determined using a vaginal fluid stimulant prepared in accordance with the disclosure by Owen and Katz (Owen and Katz, 1999. Contraception. 59, 91 -95).
  • dissolution testing may be performed by- dropping RDTs in test tubes containing a small amount of buffer (e.g., 3.5 mL) of ammonium acetate buffer at a pH of about 6, and at appropriate time points centrifuging at 4000 rpm for 2 min, and testing samples filtered through 0,45 ⁇ PTFF filters by HPLC,
  • buffer e.g., 3.5 mL
  • ammonium acetate buffer at a pH of about 6
  • an RDT of the invention comprises a therapeutically effective amount of tenofovir, or pharmaceutically acceptable salts thereof, alone or in combination with emitricita ine at a ratio of from about 2: 1 to about 1 : 10, from about 1 : 1 to about 1 :8, or from about 1 :2 to about 1 :6, or about 2 :5.
  • the RDT substantially disintegrates in the vaginal cavity of a patient, forming a viscous, eas -to-spread suspension that spreads/coats the vaginal mucosa to provide efficacy via topical action or systemic absorption.
  • an RDT of the invention optionally includes a pharmaceutically acceptable bioadhesive polymer, such as one selected from the group consisting of low-substituted hydroxyethylcellulose,
  • vinylpyrrolidone-polyvinyl acetate copolymer e.g., ollidon* 1 VA 64 from BASF
  • SOLUPLUS 3 ⁇ 4 poiy(ethylene glycol 6000 - vinylcaprolactam - vinyl acetate) (13:57:30) copolymer from BASF), polyvinyl alcohol, polyethylene oxide, poly(lactic co-glycolic acid), polyamide, alginic acid salts, carrageenan, chitosan, and various cellulosic gums (e.g., xanthan gum).
  • an RDT weighs not less than about 50 mg; for example, 100 mg or more; 200 mg or more; 300 mg or more; or 500 mg or more. In some other embodiments, the RDT weighs not more than about 2000 mg; for example, 1600 mg or less: 1400 mg or less; 1200 mg or less; 1000 mg or less; 800 mg or less; or 500 mg or less. In another embodiment, the RDT weighs not more than about 800 mg. In another embodiment, the RDT weighs not more than about 600 mg. In another embodiment, the RDT weights not more than 500 mg.
  • the dosage forms of the invention can, for example, comprise two or more populations of antibiotic drug- containing particles, such as including at.
  • a dosage form can, for example, comprise a population of tenofovir, a nucleoside reverse transcriptase inhibitor, rapid dissolve particles as described herein, and in addition, a population of emitricitabine particles, for the prevention of AIDS.
  • a treatment as described herein targets two specific viral enzymes: reverse transcriptase (e.g., using NRTIs or NNRTIs) and protease (e.g., using protease inhibitors).
  • reverse transcriptase e.g., using NRTIs or NNRTIs
  • protease e.g., using protease inhibitors
  • a pharmaceutical composition of the present invention in the form, of a. rapid dissolve tablet for vaginal admin stration may comprise a therapeutically effective amount of propranolol, a non-selective beta blocker undergoing extensive first-pass (hepatic) metabolism upon oral administration, or pharmaceutically acceptable salt or a mixture thereof.
  • metronidazole and optionally an antibiotic selected from the group consisting of clarithromycin, sulfonamides, erythromycin, azithromycin, doxycycSine, quinofones, cefoxitin, ceftriaxone cifrofloxacin, doxyclycline, vancomycin, clindamycin, rifaximin, and metronidazole.
  • an antibiotic selected from the group consisting of clarithromycin, sulfonamides, erythromycin, azithromycin, doxycycSine, quinofones, cefoxitin, ceftriaxone cifrofloxacin, doxyclycline, vancomycin, clindamycin, rifaximin, and metronidazole.
  • a pharmaceutical composition of the present invention in the form of a rapid dissolve tablet for vaginal administration may comprise a therapeutically effective amount of clotrimazole, and optionally an antifungal agent selected from the group consisting of nystatin, ketoeonazole, itraconazole, and clotrimazole.
  • the present invention is directed to a method of preparing first a rapid dissolve rnicrogranule composition
  • a rapid dissolve rnicrogranule composition comprising at least one sugar alcohol, saccharide, or mixture thereof, a polymeric binder, optionally a super disintegrant or bioadhesive polymer, and a therapeutically effective amount of at least one drug selected from the group consisting of antifungal agents, antibacterial agents, antimicrobial agents, antiviral agents, spermicides, hormone agents, antitrichornonial agents, antiprotozoal!
  • the present invention is directed to a method of preparing first a rapid dissolve rnicrogranule composition
  • a rapid dissolve rnicrogranule composition comprising at least one sugar alcohol, saccharide, or mixture thereof, a polymeric binder, optionally a super disintegrant or bioadhesive polymer, and a therapeutically effective amount of at least one drug selected from the group of
  • antiretroviral agents consisting of NRTls (e.g. , apricitabine , enteeavir, emtricitabine, tenofovir, ahacavir, adefovir, their salts and mixtures thereof), NNRTls (e.g., nevirapine, deiavirdine, efavirenz, UC-781 , MKC-442, quinoxaline HBY 097, DMP 266, their salts and mixtures thereof), protease inhibitors (e.g., indinavir, amprenavir, darunavir, lotinavir, nelfinavir, ritonavir, sequinavir, atazanavir, tipranavir, their salts and mixtures thereof), and integrase inhibitors (e.g., elvitegravir, MK-2048, their salts and mixtures thereof), next blending drug- containing rapid dissolve microgranules with rapidly dis
  • vaginal creams ointments, gels, inserts/rings, and tablets are currently available.
  • Dahl discloses in EP 1 773296 the preparation of a pharmaceutical vaginal gel comprising tenofovir.
  • This dosage form may not benefit individuals with AIDS or those who want to avoid the risk of HTV transmission or infections during sexual activity, as the gel/applicator-like other similar gel formulations-may suffer from limitations such as leakage, messiness, and low residence time.
  • the present invention is related to a method of preparing a rapid dissolve tablet composition
  • a rapid dissolve tablet composition comprising at least one sugar alcohol such as mannitol, a polymeric binder such as low-substituted hydroxypropyiceilulose, optionally a disintegrant such as crospovidone, and one NRTI alone, such as tenofovir or emtricitabine, or one or more NRTIs, such as tenofovir in combination with emtricitabine or dapivirene, and then form rapid dissolve tablets by compressing a formulation comprising said rapid dissolve microgranules, rapidly dispersing microgranules, macrocrystalline cellulose, a super disintegrant such as crospovidone, and a lubricant such as sodium stearyl fumarate on a rotary tablet press.
  • a method of preparing a rapid dissolve microgranules comprises granulating a composition as described herein, further comprising a bioadhesive polymer (e.g., low-substituted hydroxyethylceliulose) for incorporation into an RDT, which improves bioadherence of the viscous drug suspension to the surface of the vaginal mucosa upon insertion of the RDT into the vaginal cavity.
  • a bioadhesive polymer e.g., low-substituted hydroxyethylceliulose
  • the granulation method is not limited; a fluid 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.
  • granulation may be performed by spraying a solution comprising a polymeric binder and a.
  • a top spray fluid bed granulator such as Glatt GPCG 3, GPCG 5, GPCG 120, or Fluid Air FA0300, and drying the granulation in the same fluid-bed dryer.
  • the granulation may also be performed 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 drying in the Glatt.
  • the dried granulation thus produced may be sieved by passing through appropriate sieves to collect rapid dissolve drug-containing microgramiles with a desired particle size distribution by discarding fines and optionally milling resieving oversized granules.
  • the drug-containing microparticles granulated with one or more bioadhesive polymers to improve hioadherence characteristics to the vaginal mucosa may have a median particle size in the range of about 100-400 um. In some embodiments, not less than 90% of the microparticles are smaller than 600 pm for their incorporation into a rapid dissolve tablet.
  • the invention may be directed to a method of preparing a rapid dissolve tablet by blending rapid dissolve drug-containing microgramiles and rapidly dispersing microgranules prepared as described herein and compressing on a rotary tablet press into rapid dissolve tablets for administration into vaginal cavity of a patient in need of such a medication for therapeutic efficac via topical action or systemic absorption.
  • a rapid dissolve tablet of the present in vention can be produced by an internal lubrication method, for example, wherein the compression mix is further blended with a lubricant prior to compression.
  • a rapid dissolve tablet can be produced by an external lubrication method wherein a lubricant is not included in the tablet formulation, but is externally applied onto the material contacting surfaces of punches and dies of a rotary tablet press.
  • Lubricants such as magnesium stearate, calcium stearate, zinc stearate, stearic aid, sodium stearyl fumarate, glyceryl behenate, and the like may be used for lubricating the granules, or may be externally applied onto material contacting die and punch surfaces of a rotary tablet press used to compress tablets.
  • Another embodiment according to the invention is directed to a method of treating a patient or subject comprising administering a composition of the invention as a rapid dissolve tablet containing a therapeutically effective amount of one or more drugs selected from the group consisting of antifungal agents, antibacterial agents, antimicrobial agents, antiviral agents, spermicides, hormones, antiteichomonial agents, antiprotozoan agents, antimycopiasm agents, antiretroviral agents, nucleoside analogues, reverse transcriptase inhibitors, protease inhibitors, contraceptive agents, steroids, orally active drugs exhibiting significant first-pass effects, proteins/peptides including growth enhancing hormones and luteinizing-hormone-releasing hormone (LHRH), by insertion into the vaginal cavity of a patient in need thereof.
  • drugs selected from the group consisting of antifungal agents, antibacterial agents, antimicrobial agents, antiviral agents, spermicides, hormones, antiteichomonial agents, antiprotozoan agents
  • Sodium bicarbonate (54 g) is slowly added to purified water (2800 g) in a stainless steel container while continuously stirring to dissolve.
  • the pH of the bicarbonate solution is adjusted to about 6.0 if needed by adding hydrochloric acid, Hydroxypropylcellulose (Klucel LF; 12.5 g) is slowly added while stirring to dissolve; then tenofovir (180 g) is added to dissolve.
  • Preheated Glatt GPCG 3 equipped with top spray insert, granulation air distribution bottom plate, 200 mesh product retention screen, and 1 ,0 mm spray nozzle is charged with mannitol with an average particle size of less than 30 ⁇ (781 g) and crospovidone (60 g), both deagglomerated by passing through Comil.
  • the rapid dissolve micro granule composition is granulated while fluidizing the charge continuously and maintaining the process parameters at the following conditions: product temperature - 34.-i-.l°C; fiuidization air flow - 10 CFM; spray rate
  • the RD niicrograniiies are dried for a loss on drying to about 1 % by weight.
  • Sodium bicarbonate 54 g is slowly added to purified water (2500 g) in a stainless steel container while continuously stirring to dissolve.
  • the pH of the bicarbonate solution is adjusted to about 6.0 if needed by adding hydrochloric acid.
  • Low-substituted hydroxyethylcellulose 20 g is slowly added while stirring to dissolve: then tenofovir (180 g) is added to dissolve.
  • Preheated Glatt GFCG 3 is charged with deagglomerated mannitol (781 g) and crospovidone (60 g) and fluidized.
  • the RD microgranules are prepared by spraying the solution as disclosed in step Ex. I A above.
  • Sodium bicarbonate 39,1 g is slowly added to purified water (2500 g) in a stainless steel container while continuously stirring to dissolve.
  • the pH of the bicarbonate solution is adjusted to about 6. if needed by adding hydrochloric acid, Hypromellose (HPMC; 18.1 g) is slowly added while stirring to dissolve; then tenofovir (183.2 g) is added to dissolve.
  • Preheated Glatt GPCG 3 is charged with deagglomerated mannitol (637.4 g) and crospovidone (43.1 g) and fluidized.
  • the RD microgranules are prepared by spraying the solution as disclosed in step Ex.1 A above
  • Rapidly dispersing microgranules are prepared following the procedure disclosed in copending US Patent Application Publication No. U.S. 2003/0215500. Specifically, D-mannitol (152 kg) with an average particle size of approximately 20 ⁇ ⁇ ⁇ or less (Pearlitol 25 from
  • the disintegration times tested in accordance with USP method ⁇ 701 > for DT are 60-90 sec, 30-60 sec, and 30-60 sec, respectively for tenofovir RDT tablet batches of Formula Ex. I AD (TFV RDG: Ex. l A), Formula Ex. ! BD (TFV RDG: Ex. I B), and Formula Ex. 1 CD (TFV RDG: Ex. 1C).
  • RDTs of these formulations compressed at 4 kN are observed to disintegrate in 30-60 sec when tested by the USP method ⁇ 701 > and not less than 80% dissolved at 30 min when tested for dissolution in test tubes.
  • Sodium bicarbonate (67.5 g) is slowly added to purified water (2010 g) in a stainless steel container while continuously stirring to dissolve. The pH of the bicarbonate solution is measured to be about 6.8.
  • Hypromellose (Methocel; 62.5 g) is slowly added while stirring to dissolve; then tenofovir (190 g) is added to dissolve.
  • Preheated Glatt GPCG 3 is charged with deagglomerated mannitol (890 g) and fiuidized.
  • the rapid dissolve microgranules are prepared while spraying the charge and maintaining the process parameters at the following conditions: product temperature - 34 ⁇ 1°C; tluidization air flow - 5 to 15 CFM; spray rate - 4-16 mL/min.
  • the RD microgranules are dried for a loss on drying to about 1 % by weight.
  • Sodium bicarbonate (57 g) is slowly added to a mixture of ethanol (540 g) and purified water (1260 g) in a stainless steel container while continuously stirring to dissolve.
  • the pH of the bicarbonate solution is measured to be about 6.2.
  • tenofovir 200 g is added to dissolve followed by the addition of Low-substituted hydro xyethylcelluiose (L-HEC; 20 g) to dissolve while stirring.
  • Preheated Giatt GPCG 3 is charged with deagglomerated mannitoi (1023 g) and fluidized.
  • the RD microgranules are prepared by spraying the solution at the following conditions: product temperature - 34 ⁇ 1°C; fluidization air flow - 4 CFM; spray rate - 8-12 mUmin. Upon completion of spraying, the RD microgranules are dried for a loss on drying to about 1 % by weight.
  • Sodium bicarbonate (54 g) is slowly added to a mixture of ethanol (540 g) and purified water (1260 g) in a stainless steel container while continuously stirring to dissolve.
  • the pH of the bicarbonate solution is measured to be about 6.1 5.
  • tenofovir (200 g) is added to dissolve followed by the addition of Low-substituted hydroxyethylcellulose (L-HEC; 30 g) to dissolve while stirring.
  • Preheated Glatt GPCG 3 is charged with deagglomerated mannitoi (1023 g) and fluidized.
  • the RD microgranules are prepared by spraying the solution as disclosed in step Ex.2B above. Upon completion of spraying, the loss on drying of RD microgranules is about 1 .5% by weight.
  • RDT tablet formulations (Formula Ex. 2BD and Formula Ex. 2CD) containing tenofovir (TFV) RD microgranules of Ex, 2B and Ex. 2C are compressed (see Table 2 for compositions) on a Plata tablet press equipped with partial tooling at the compression force of 4 kN and turret speed of 15 RPM. Samples are collected at the start, mid, and end of the run for testing for in- process tablet properties. The results are presented in Table 2. In case of Formula Ex. 2 AD, tablets are compressed using a Carver press.
  • the objective of this study was to evaluate the pharmacokinetics of tenofovir after a single dose or seven daily doses when administered in rapid dissolve tablet form in female rabbits with a minimum body weight of 2.5 kg (n 6 in each group; blood sampled at 0, 0.5, 1 , 2, 4, 8, and 24 hrs post dosing day 1 or 7 in group 1 & 3 and at 0, 0.5, 1 .0, 1 .5, and 2 hrs post dosing day 1 or 7 in group 2 & 4).
  • acepromazine maleate 0.3- 0.5 mg/kg or to effect was administered via subcutaneous administration to mildly sedate the animal.
  • a single tablet was inserted into the abdominal vagina of each animal (approximately 8 cm) with an 18 catheter. No lubrication was used as this may affect tablet absorption, A detailed clinical examination of each animal was performed daily during the study. Observations included, but was not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, respiratory and circulatory effects, autonomic effects such as salivation, nervous system effects including tremors, convulsions, reactivity to handling, and atypical behavior.
  • Figure 2 shows the mean tenofovir plasma concentration - time profiles following insertion of a single tenofovir RDT (i.e. , RDTs of Ex. 2 CD) into the vaginal cavity of female rabbits while Figure 3 shows the corresponding tenofovir concentrations following multi-dose (7 once-daily dosing) administration.
  • Figure 4 shows the mean free and total tenofovir contents of the abdominal and vaginal tissues at 2 and 24 hrs pos dosing following insertion of a single tenofovir RDT into the vaginal cavity of female rabbits while Figure 5 shows the corresponding fenofovir concentrations following multi-dose (7 once-daily dosing) administration.
  • Figure 6 shows the mean predose and postdose tenofovir concentrations in eck-Cel ® at 2 and 24 hrs post dosing following insertion of a single tenofovir RDT into the vaginal cavity of female rabbits while Figure 7 shows the corresponding predose and postdose tenofovir concentrations in Weck-Cel ''8 ' following multi-dose (7 once-daily dosing) administration.
  • the high shear granulator GMX-25 is charged with tenofovir (TFV; 829.2 g), mannitol (Pearlitol 25 with a mean particle size of less than 30 ⁇ ; 7829.2 g), hydroxyethylcellulose
  • the contents of the product bowl are well mixed with the impeller speed set at 150 RPM for 2 minutes.
  • the powder mixture is granulated by spraying purified water at a spray rate of about 100 g/miri at. the following processing parameters: spray nozzle pore size - 0.085"; impeller setting: speed - 325 RPM, time
  • Emtricitabine (FTC, 682.9 g) is slowly added to a mixture of ethanol (3974 g) and purified water (995 g) in a stainless steel container while continuously stirring to dissolve.
  • Low-substituted hydrox ethylcellulose (Natrosoi HEC-250L; 80. i g) is added to
  • Preheated Glatt GPCG 3 is charged with deagglonierated mannitol (2737 g) and fiuidizcd.
  • the RD microgranules are prepared by spraying the solution at the following conditions: product support screen - 200 mesh; nozzle tip size - 1.2 mm;
  • the FTC RD microgranules are dried at the inlet air temperature set at 42°C for a. loss on drying to about 1% by weight.
  • RDT tablet formulations containing TFV RD microgranules of Ex. 3 A and FCT RD microgranules of Ex. 3B alone, or their mixtures thereof are first blended with other
  • compositions including the lubricant, sodium stearyl fumarate and are compressed (see Table 3 for compositions) on a Beta tablet press equipped with, partial tooling at a compression force of 4 - 6 kN and turret speed of 15 RPM. Samples are collected at the start, mid, and end of each run for testing for in-process tablet properties.
  • the Manesty Beta press equipped with eight (8) 12 mm round, lozenge tooling having no embossing is set. up to the following parameters for 40 mg TFV / 40 mg FCT RDTs:
  • Tablet weight total(l O) - 5.00 g; Nominal: 500 mg; Range: 460-540 mg
  • Main compression 3.3 mm (or 2.85 mm for TFV) Force feeder setting; 3.
  • the press was set to run at 25 rpm and after a few die table/turret rotations, 10 tablets are collected before stopping the press. Ten tablets are collected for determining the weight of 10 tablets and are inspected for tablet's appearance (picking, capping, etc).
  • the tablet press is adjusted, as necessary, in order to produce tablets that meet the specifications listed above for weight, thickness and hardness, and results are recorded on the production batch record. If required, the parameters are readjusted as necessary to produce tablets that meet the friability specifications listed above
  • Table 3 Compositions of RDTs (40 mg TFV; 40 mg FCT; 40 mg TFV/40 mg FCT;
  • Vinylpyrrolidone- vinyl acetate copolymer e.g., Kollidon ⁇ VA 64 from. BASF; 50 g
  • a mixture of ethanol and purified water in a stainless steel container while continuously stirring to dissolve.
  • metronidazole 180 g
  • Preheated Glatt GPCG 3 is charged with deagglomerated rnannitol (770 g) and crospovidone (50 g) and fiuidized.
  • the RD microgranules are prepared by spraying the solution at the following conditions: product temperature - 34 ⁇ 1°C; fluidization air flow - 4 CFM; spray rate - 8-12 mL/rain. Upon completion of spraying, the RD microgranules are dried for a loss on drying to about 1 % by weight.
  • HydroxyethykelMose 50 g is slowly added to a mixture of ethanol and purified water in a stainless steel container while continuously stirring to dissolve.
  • metronidazole 180 g is added to dissolve while stirring.
  • Preheated Glatt GPCG 3 is charged with deagglomerated rnannitol (720 g) and crospovidone (50 g) and fiuidized.
  • the RD microgranules are prepared by spraying the solution at the following conditions: product temperature - 34 ⁇ 1 °C; fluidization air flow - 4 CFM; spray rate - 8- 12 mL/min. Upon completion of spraying, the RD microgranules are dried for a loss on drying to about 1% by weight,
  • Vinyipyrrolidone -polyvinyl acetate copolymer e.g., Kollidon*' VA 64 from BASF; 50 g
  • Vinyipyrrolidone -polyvinyl acetate copolymer e.g., Kollidon*' VA 64 from BASF; 50 g
  • propranolol HCI 240 g
  • Preheated Glatt GPCG 3 is charged with deagglomerated mannitol (560 g) and low-substituted hydroxyethylcellulose (50 g) and fluidized.
  • the RD microgranules are prepared by spraying the solution at the following conditions: product temperature - 38 ⁇ 2°C; fluidization air flow - 1 0 CFM; spray rate - 10-20 mL/min. Upon completion of spraying, the RD microgranules are dried for a loss on drying to about 1 % by weight.
  • RDT tablets (Formula Ex. 4 AD: Metronidazole RDTs, Formula Ex. 4BD: Clotrimazole RDTs, and Formula Ex. 4CD: Propranolol HCI RDTs) containing required amounts of
  • Metronidazole RD microgranules of Ex. 4A, Clotrimazole RD microgranules of Ex. 4B, or Propranolol HCI RD microgranules of Ex. 4C rapidly dispersing microgranules from Ex. I D above at 5- 15% by weight, microcrystallinecellulose (Avicel PH101 at 5-10% by weight), low- substituted hydroxypropylcellulose at 2-5%o by weight, sodium stearyl fumarate, at 1 % by weight are compressed on a Hata tablet press equipped with appropriate tooling at different compression forces and at different turret speeds. Samples are col lected at the start, mid, and end of the run for testing for in-process tablet properties to establish the robustness of the manufacturing processes of each tablet formulation.
  • compositions can be suitably modified to provide the appropriate dose of drug(s) whose rapid dissolve tablet formulations for vaginal administration are required.

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Abstract

La présente invention concerne des compositions de comprimés vaginaux à dissolution rapide, de qualité pharmaceutique, qui comportent un ou plusieurs principes pharmaceutiques actifs, appropriés pour une thérapie par l'intermédiaire d'une action topique ou d'une absorption systémique. L'invention concerne également des procédés de fabrication et d'utilisation de telles compositions. Dans certains modes de réalisation, cette invention concerne des compositions pharmaceutiques qui comportent un ou plusieurs principes pharmaceutiques actifs, appropriés pour une voie d'administration vaginale, et des procédés de fabrication et d'utilisation de telles compositions pour une thérapie par l'intermédiaire d'une action topique ou d'une absorption systémique, ainsi que d'un ciblage utérin. Dans certains modes de réalisation, la présente invention concerne une composition pharmaceutique qui comporte un ou plusieurs principes pharmaceutiques actifs, appropriés pour une voie d'administration vaginale, un ou plusieurs excipients polymères ayant une double propriété d'action en tant que liant et matière bioadhésive, un ou plusieurs alcools de sucres ou saccharides et un ou plusieurs agents délitant.
EP12779335.4A 2011-05-02 2012-05-02 Compositions de comprimés à dissolution rapide pour administration vaginale Withdrawn EP2704694A4 (fr)

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AP2013007268A0 (en) 2013-11-30
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WO2012151237A1 (fr) 2012-11-08
MX2013012745A (es) 2014-12-05
AU2012250862B2 (en) 2015-07-09
SG194725A1 (en) 2013-12-30
AU2012250862A1 (en) 2013-05-02
EP2704694A4 (fr) 2014-11-19
CA2839790A1 (fr) 2012-11-08
JP2014513124A (ja) 2014-05-29
RU2013150323A (ru) 2015-06-10
KR20140014264A (ko) 2014-02-05
IL229170A0 (en) 2013-12-31
TW201247240A (en) 2012-12-01
JP6154803B2 (ja) 2017-06-28
KR20160112012A (ko) 2016-09-27
CN103596556A (zh) 2014-02-19
AR086249A1 (es) 2013-11-27
CL2013003161A1 (es) 2014-08-01

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