WO2012151237A1 - Compositions de comprimés à dissolution rapide pour administration vaginale - Google Patents
Compositions de comprimés à dissolution rapide pour administration vaginale Download PDFInfo
- Publication number
- WO2012151237A1 WO2012151237A1 PCT/US2012/036055 US2012036055W WO2012151237A1 WO 2012151237 A1 WO2012151237 A1 WO 2012151237A1 US 2012036055 W US2012036055 W US 2012036055W WO 2012151237 A1 WO2012151237 A1 WO 2012151237A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- agents
- pharmaceutical composition
- microgranules
- group
- rapid dissolve
- Prior art date
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- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
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- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
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- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
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- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
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- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
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- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
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- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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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:
- 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.
- 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.
- antipyretics antispasmodics
- anticholinergics anticholinergics
- sympathomimetics antixanthine derivatives
- 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 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. 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
- '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.
- 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.
- 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).
- 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.
- 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;
- 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.
- 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.
- 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 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.
- 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
- 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.
- 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).
- 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
- 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 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 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.
- 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.
- 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.
- 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.
- 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 (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.
- 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 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
- 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.
- 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.
- 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
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Abstract
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
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RU2013150323/15A RU2013150323A (ru) | 2011-05-02 | 2012-05-02 | Композиции в форме быстрорастворимых таблеток для вагинального введения |
SG2013080882A SG194725A1 (en) | 2011-05-02 | 2012-05-02 | Rapid dissolve tablet compositions for vaginal administration |
MX2013012745A MX2013012745A (es) | 2011-05-02 | 2012-05-02 | Composiciones en forma de comprmido de disolución rápida para administración vaginal. |
KR1020137031788A KR20140014264A (ko) | 2011-05-02 | 2012-05-02 | 질내 투여용 속용성 정제 조성물 |
JP2014509373A JP6154803B2 (ja) | 2011-05-02 | 2012-05-02 | 膣投与のための迅速溶解性錠剤組成物 |
NZ617376A NZ617376B2 (en) | 2011-05-02 | 2012-05-02 | Rapid dissolve tablet compositions for vaginal administration |
CN201280026286.XA CN103596556A (zh) | 2011-05-02 | 2012-05-02 | 用于阴道给药的快速溶解片剂组合物 |
AP2013007268A AP2013007268A0 (en) | 2011-05-02 | 2012-05-02 | Rapid dissolve tablet compositions for vaginal administration |
EP12779335.4A EP2704694A4 (fr) | 2011-05-02 | 2012-05-02 | Compositions de comprimés à dissolution rapide pour administration vaginale |
AU2012250862A AU2012250862B2 (en) | 2011-05-02 | 2012-05-02 | Rapid dissolve tablet compositions for vaginal administration |
CA2839790A CA2839790A1 (fr) | 2011-05-02 | 2012-05-02 | Compositions de comprimes a dissolution rapide pour administration vaginale |
KR1020167025256A KR20160112012A (ko) | 2011-05-02 | 2012-05-02 | 질내 투여용 속용성 정제 조성물 |
IL229170A IL229170A0 (en) | 2011-05-02 | 2013-10-31 | Preparations in the form of tablets that dissolve quickly for vaginal administration |
US14/069,712 US20180177733A9 (en) | 2011-05-02 | 2013-11-01 | Rapid dissolve tablet compositions for vaginal administration |
US15/879,806 US20180147152A1 (en) | 2011-05-02 | 2018-01-25 | Rapid dissolve tablet compositions for vaginal administration |
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US14/069,712 Continuation US20180177733A9 (en) | 2011-05-02 | 2013-11-01 | Rapid dissolve tablet compositions for vaginal administration |
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WO2012151237A1 true WO2012151237A1 (fr) | 2012-11-08 |
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EP (1) | EP2704694A4 (fr) |
JP (1) | JP6154803B2 (fr) |
KR (2) | KR20140014264A (fr) |
CN (1) | CN103596556A (fr) |
AP (1) | AP2013007268A0 (fr) |
AR (1) | AR086249A1 (fr) |
AU (1) | AU2012250862B2 (fr) |
CA (1) | CA2839790A1 (fr) |
CL (1) | CL2013003161A1 (fr) |
CO (1) | CO6940408A2 (fr) |
IL (1) | IL229170A0 (fr) |
MX (1) | MX2013012745A (fr) |
RU (1) | RU2013150323A (fr) |
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TW (1) | TW201247240A (fr) |
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WO2015070072A1 (fr) * | 2013-11-07 | 2015-05-14 | Evofem, Inc. | Procédés de fabrication de microbicides contraceptifs ayant des propriétés antivirales |
WO2015095793A1 (fr) * | 2013-12-19 | 2015-06-25 | Evofem, Inc. | Compositions et méthodes pour l'inhibition d'une inflammation et de maladies à l'aide d'un composé antimicrobien à base d'acide alginique |
EP2968127A4 (fr) * | 2013-03-15 | 2016-09-07 | Conrad | Préparations à faible taux de glycérol destinées au traitement et à la prévention du vih |
JP2017510655A (ja) * | 2014-04-11 | 2017-04-13 | シノセラピューティクス インコーポレイテッドSinotherapeutics Inc. | ポサコナゾール医薬組成物並びにその調製方法、使用及び医薬製剤 |
US9918702B2 (en) | 2014-08-12 | 2018-03-20 | Nextgen Jane, Inc. | System and method for monitoring health based on collected bodily fluid |
US11026883B2 (en) | 2016-10-13 | 2021-06-08 | Catalent U.K. Swindon Zydis Limited | Lyophilized pharmaceutical compositions for vaginal delivery |
US11253501B2 (en) | 2015-06-01 | 2022-02-22 | Lupin Inc. | Secnidazole formulations and use in treating bacterial vaginosis |
EP3870167A4 (fr) * | 2018-10-23 | 2022-07-27 | Eastern Virginia Medical School | Compositions pharmaceutiques et procédés de préparation de formulations posologiques solides à la demande |
US11419835B2 (en) | 2016-10-04 | 2022-08-23 | Evofem, Inc. | Method of treatment and prevention of bacterial vaginosis |
US11439610B2 (en) | 2012-06-13 | 2022-09-13 | Evofem, Inc. | Compositions and methods for enhancing the efficacy of contraceptive microbicides |
US11446011B2 (en) | 2016-04-13 | 2022-09-20 | Nextgen Jane, Inc. | Sample collection and preservation devices, systems and methods |
RU2810844C2 (ru) * | 2018-07-31 | 2023-12-28 | Мьюкоузе Инновейшнз, С.Л. | Композиция для применения в предупреждении и/или лечении патологий слизистой оболочки мочеполовой системы |
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CN104434992B (zh) * | 2014-12-21 | 2018-06-08 | 昆明赛诺制药股份有限公司 | 一种美洲大蠊提取物生物粘附性阴道片及其制备方法 |
US20220072138A1 (en) * | 2018-12-21 | 2022-03-10 | The University Of Liverpool | Nrti therapies |
WO2020213983A1 (fr) * | 2019-04-19 | 2020-10-22 | 한양대학교 산학협력단 | Composition thermosensible contenant de l'acide phosphatidique et son utilisation |
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- 2012-05-02 EP EP12779335.4A patent/EP2704694A4/fr not_active Withdrawn
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EP2968127A4 (fr) * | 2013-03-15 | 2016-09-07 | Conrad | Préparations à faible taux de glycérol destinées au traitement et à la prévention du vih |
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AU2020202835B2 (en) * | 2013-12-19 | 2021-12-02 | Evofem, Inc. | Compositions and methods for inhibiting inflammation and diseases using an alginic acid-based antimicrobial compound |
RU2691950C1 (ru) * | 2013-12-19 | 2019-06-19 | Ивофем, Инк. | Композиции и способы ингибирования воспаления и заболеваний с применением антимикробного соединения на основе альгиновой кислоты |
WO2015095793A1 (fr) * | 2013-12-19 | 2015-06-25 | Evofem, Inc. | Compositions et méthodes pour l'inhibition d'une inflammation et de maladies à l'aide d'un composé antimicrobien à base d'acide alginique |
US11337989B2 (en) | 2013-12-19 | 2022-05-24 | Evofem, Inc. | Compositions and methods for inhibiting inflammation and diseases using an alginic acid-based antimicrobial compound |
US10022373B2 (en) | 2014-04-11 | 2018-07-17 | Sinotherapeutics Inc. | Posaconazole pharmaceutical compositions and preparation methods, uses and pharmaceutical formulations thereof |
JP2017510655A (ja) * | 2014-04-11 | 2017-04-13 | シノセラピューティクス インコーポレイテッドSinotherapeutics Inc. | ポサコナゾール医薬組成物並びにその調製方法、使用及び医薬製剤 |
US9918702B2 (en) | 2014-08-12 | 2018-03-20 | Nextgen Jane, Inc. | System and method for monitoring health based on collected bodily fluid |
US11253501B2 (en) | 2015-06-01 | 2022-02-22 | Lupin Inc. | Secnidazole formulations and use in treating bacterial vaginosis |
US11864740B2 (en) | 2016-04-13 | 2024-01-09 | Nextgen Jane, Inc. | Sample collection and preservation devices, systems and methods |
US11446011B2 (en) | 2016-04-13 | 2022-09-20 | Nextgen Jane, Inc. | Sample collection and preservation devices, systems and methods |
US11419835B2 (en) | 2016-10-04 | 2022-08-23 | Evofem, Inc. | Method of treatment and prevention of bacterial vaginosis |
RU2753864C2 (ru) * | 2016-10-13 | 2021-08-24 | Каталент Ю.Кей. Суиндон Зайдис Лимитед | Лиофилизированные фармацевтические композиции для вагинальной доставки |
US11026883B2 (en) | 2016-10-13 | 2021-06-08 | Catalent U.K. Swindon Zydis Limited | Lyophilized pharmaceutical compositions for vaginal delivery |
RU2810844C2 (ru) * | 2018-07-31 | 2023-12-28 | Мьюкоузе Инновейшнз, С.Л. | Композиция для применения в предупреждении и/или лечении патологий слизистой оболочки мочеполовой системы |
EP3870167A4 (fr) * | 2018-10-23 | 2022-07-27 | Eastern Virginia Medical School | Compositions pharmaceutiques et procédés de préparation de formulations posologiques solides à la demande |
Also Published As
Publication number | Publication date |
---|---|
CA2839790A1 (fr) | 2012-11-08 |
AU2012250862B2 (en) | 2015-07-09 |
AP2013007268A0 (en) | 2013-11-30 |
NZ617376A (en) | 2016-03-31 |
EP2704694A4 (fr) | 2014-11-19 |
IL229170A0 (en) | 2013-12-31 |
AU2012250862A1 (en) | 2013-05-02 |
MX2013012745A (es) | 2014-12-05 |
CL2013003161A1 (es) | 2014-08-01 |
EP2704694A1 (fr) | 2014-03-12 |
KR20140014264A (ko) | 2014-02-05 |
JP6154803B2 (ja) | 2017-06-28 |
CN103596556A (zh) | 2014-02-19 |
CO6940408A2 (es) | 2014-05-09 |
RU2013150323A (ru) | 2015-06-10 |
AR086249A1 (es) | 2013-11-27 |
KR20160112012A (ko) | 2016-09-27 |
JP2014513124A (ja) | 2014-05-29 |
SG194725A1 (en) | 2013-12-30 |
TW201247240A (en) | 2012-12-01 |
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