CN103596556A - Rapid dissolve tablet compositions for vaginal administration - Google Patents

Rapid dissolve tablet compositions for vaginal administration Download PDF

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Publication number
CN103596556A
CN103596556A CN201280026286.XA CN201280026286A CN103596556A CN 103596556 A CN103596556 A CN 103596556A CN 201280026286 A CN201280026286 A CN 201280026286A CN 103596556 A CN103596556 A CN 103596556A
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China
Prior art keywords
agent
group
mixture
comprised
pharmaceutical composition
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CN201280026286.XA
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Chinese (zh)
Inventor
戈皮·文卡特施
维贾雅·斯瓦米纳坦
赖金旺
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Adare Pharmaceuticals Inc
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Aptalis Pharmatech Inc
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • 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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    • A61K31/66—Phosphorus compounds
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    • A61K9/0012—Galenical forms characterised by the site of application
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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
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    • 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
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    • A61P15/18—Feminine contraceptives
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Abstract

Disclosed herein are pharmaceutically acceptable rapid dissolve vaginal tablet compositions comprising one or more active pharmaceutical ingredients suitable for therapy via topical action or systemic absorption, and methods of making and using such compositions. In some embodiments, 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. In certain embodiments, 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 bioadhesive material, one or more sugar alcohols or saccharides, and one or more disintegrants.

Description

Fast dissolving tablet agent compositions for vagina administration
the cross reference of related application
The application requires the priority of the U. S. application serial number 61/481,582 submitted on May 2nd, 2011, for all objects by it by reference with its combination in full.
background of invention
It is the potential approach that local action or systemic Absorption via active pharmaceutical ingredient are used for the treatment of together with uterus targeting that intravaginal drug is sent.It provides for example following advantage:
High surface area
Avoid the first pass effect of liver, this can cause the remarkable enhancing of biological availability or the reduction of dose intensity or side effect overview
Intensive blood vessel network
Even for example, for the high osmosis of macromolecule medicine (peptide and albumen)
Low systemic drug exposes (if for the product of local condition)
Low enzymatic activity and the medicine absorbing are preferentially transferred to the probability (being called " uterus first pass effect ") in uterus
If desired, easily remove
Although there are these advantages, for the intravaginal of drug delivery, give approach and only in limited range, utilized.Intravaginal drug delivery system (for example conventional tablet) is traditionally for sending contraceptive and the microbicide that is used for the treatment of vaginal infection.Develop the vaginal tablet, ring, emulsifiable paste and the viscogel agent that contain broad range medicine (for example steroid, prostaglandin, antibiotics, albumen and peptide), and studied the external, in vitro of these intravaginal drug delivery systems and the interior performance evaluation of body.The research of intravaginal drug delivery system (for example comprising one or more is easy to be attached in vagina dosage form and can extends in theory the intravaginal biological activity holdup time and reduce administration frequency together with these of nontoxic, the nonirritant of dosage or bioadhesive material) comprising: Lehr(Lai Er), 2000.J.Control.Rel.(controlled release magazine) 65,19-29; Mandal(Mandal) people such as, 2000, J.Pharm.Biopharm.(pharmacy and bio-pharmaceuticals magazine) 50,337-343; Garg(adds lattice) etc. people, 2001.Pharma.Tech.(pharmaceutical technology) 14-23; Ceschel(Qie Sikaier) people such as, 2001.Drug Del.Ind.Pharm.(drug development and industrial pharmaceutics) 6,541-547; Bilensoy(is than Lun Suoyi) etc. people, 2006.AAPS PharmSciTech.(AAPS pharmacy science and technology) 7,19-29; Valenta(Wahlen tower), 2005.Advanced Drug Del.Rev.(advanced drugs is carried comment) 57,1692-1712; Bonferoni(Bang Fulangni) people such as, 2006.AAPS Pharm.SciTech.(AAPS pharmacy science and technology) 7, El-E8; Neves(Nei Weisi) people such as, 2008.Eur.J.Pharm.Biopharm.(Europe pharmacy and bio-pharmaceuticals magazine) 69,622-632; Ndesendo(grace is worn sendoh) etc. people, the international pharmacy magazine of 2009.Int.J.Pharm.() 370,151-159; Poelvoorde(Bo Weide) people such as, 2009.J.Pharm.Biopharm.(pharmacy and bio-pharmaceuticals magazine) 71,280-284-343; Perioli(pendant Liao Li) people such as, the international pharmacy magazine of 2009.Int.J.Pharm.() 377,120-127; Yellanki(Ye Lanka) people such as, the international pharmaceutical technology research of 2010.Int.J.PharmTech Res.(magazine) 2,1746-1750; And Wang(king) people such as, 2002.J.Contr.Rel.(controlled release magazine) 82,39-50.
Most bioadhesive gel agent, emulsifiable paste and tablets as vaginal delivery system decompose rapidly after in being applied to vaginal canal and have a minimum bioadhesion with vaginal mucosa.These complex situations may, owing to the miscibility with water or owing to lack physical stability under body temperature, make only to represent limited curative effect.Develop the intravaginal drug delivery system based on emulsion, for example, contained (i) one or more bead stabilization of polymer (for example, HPMC, vinyl alcohol or Pegylation lipid) and (ii) a kind of therapeutic activity medicine; Through checking and approving for or be used for the treatment of, prevent, cure or alleviate the medicine of the disease of vagina, urinary tract, cervix uteri or other female genital organs; Induction contraception; Or systemic drug therapy.
US20030180366(US6,899,890) disclosed that the improvement of applicable therapeutic active substance in vaginal canal send novel, based on microemulsion, the intravaginal drug delivery system of pH neutrality substantially.US20050276836 has disclosed the method that is coated with the vagina device that is applied to delivery of therapeutic or health promotion medicament by mucosa-adherent compositions.WO2008133928 has disclosed and has used the pharmaceutical composition that contains mucin Glycoprotein binding therapeutic agent (for example Herba Trifolii Pratentis polypeptide), treat and suffer from epithelial lesion the patient's of (for example vagina) or impaired mucin functional disorder method, together with the method for the treatment pain relevant with impaired mucin functional disorder to epithelial lesion.WO2010061284 disclosed by least one pharmacy activity component, mixed mutually with biocompatible and combination Biodegradable polymeric form and for inserting the control of patient's vagina, discharge intravaginal drug dosage form through being shaped.The vagina administration that control to discharge OPIOIDS (for example oxycodone) has been depicted as the safety managing not tolerating the patient's of the adverse events that oral administration causes cancer pain, effective and simple means (X.Zhang(opens chivalrous), Ruan X-J.uan(is newly-built), C.Liu(Liu Chang), with Z-H.Yu(in loyal and), the effect of Effect of vaginal administration of controlied-release oxycodone on cancer pain(oxycodone controlled release tablets vagina administration treatment cancerous pain) .Chin.J.Cancer J.Cancer(cancer), 2009, 28(7) 1-4, F.Acart ü rk, Mucoadhesive Vaginal Drug Delivery Systems(mucosal adhesive material intravaginal drug delivery system), the Recent Patents on Drug Delivery recent drug delivery of and Formulation(and preparation patent) 2009 3, 193-205) (" Acart ü rk2009 ").Acart ü rk2009 has summed up exploitation and the in vitro/in vivo evaluation of the improvement preparation of sending for transmucosal vaginal recently.
The disintegrate of bioadhesion vagina dosage form (for example conventional tablet, many granules, viscogel preparation) or distribution/diffusion, together with the holdup time extensive evaluation.Routine or even bioadhesion vaginal tablet are easy to by the ground administration of user secret; Yet these dosage forms possibility disintegrates and diffusion are too slow, and from vagina, remove too fast so that any significant treatment improvement can not be provided.Patient's compliance level is not good, and it has been generally acknowledged that being restricted property dosage regimen, need to consume multiple combination oral drugs product, patient is about the suspecting of vagina therapy effectiveness, seepage or the uncomfortable impact relevant to administration.In addition, gel dosage form need to be used vagina applicator, causes thus packaging material and manufacturing cost to increase.
A field having probed into vagina administration is in the background for the treatment of acquired immune deficiency syndrome (AIDS) (AIDS), because the impact of HIV (human immunodeficiency virus) (HIV) continues appreciable impact, a large amount of population in the worlds.HIV is a kind of retrovirus, and main infection also directly and indirectly destroys the important component of human immunity system, for example CD4 +t cell (the required T cell subsets of the normal operation of human immunity system), macrophage and dendritic cell.AIDS is the series of symptoms that immune special damage is caused and the infection being caused by mankind HIV.In the U.S., the annual impact of AIDS obtaining via the infection (STI) that spreads through sex intercourse surpasses 1,000 3 hundred ten thousand masculinity and femininities.Although there is AIDS and HIV treatment that virus progress is slowed down, as far as is known still can not be cured.Although the nearest report from UNAIDS (UNAIDS/WHO2008-Report on the Global AIDS Epidemic(whole world AIDS report of infectious disease), Geneva(Geneva): UNAIDS, the 362nd page) declare that HIV epidemic diseases is stable, but in this last year, there is the new infection that 2,700,000 HIV-1 infect and had again 2 million peoples to die.
In the patient of infected by HIV, the effect of Effective Anti retrovirus (ARV) therapy of being undertaken by the different phase of blocking-up retrovirus life cycle is fully understood now.Because HIV is the retrovirus copying in immune system cell, so drug concentration is very important for definite ARV efficacy of drugs and toxicity.Some ARV medicaments for oral administration are to need to assimilate phosphorylation to be converted into the prodrug of the triphosphoric acid metabolite of its activity form in cell.Compare with its parent compound, the active metabolite with longer plasma half-life has been used in vagina administration approach.
At vagina administration, comprise following with some researchs in HIV treatment field: the external and in vitro test of tenofovir (TFV) (for containing the vaginal jellies preparation of 1%TFV and 2% hydroxyethyl-cellulose (HEC) (for bioadhesive polymer)) is by external and test and illustrate and the same people such as effective (Mayer(mayer) of HIV-1 microbicide in vitro, 2006.AIDS(acquired immune deficiency syndrome (AIDS)) 20, 543-551; Sieve's Rohan(writing brush) people such as, PLoS One(Public science library is comprehensive) in February, 2010, 5,1-12).Comprise 1%TFV the people such as the protection that exposes for ape HIV (in Parikh(handkerchief gram), 2009.J.Virology(Journal of Virology be provided in macaque in conjunction with the vagina gel of new generation of 5% emtricitabine (FTC)), 83, 10358-10364).Active for antiretroviral, to using (i) to maintain two kinds of oral antiretroviral agent tenofovirs and the two section polyurethane pessaries that reach the release of a Wei Lin (dapivirine), or the result of study of the vagina gel that (ii) contains formyl sulfide aniline (thiocarboxanilide) UC781 is investigated (Friend(Fleder), 2000.Pharm.Develop.Technol.(drug development and technology) 1-20; Mahalingam(Ma Halingan) people such as, 2010.Pharm.Res.(drug research) 27, 2478-2491).
Although the feature likely that vagina has for pharmacotherapy, exploitation and commercialization problem still exist, for example:
Lack suitable external/in vitro method of testing
The abundant holdup time that lacks vagina preparation
The abundant diffusion characteristic that lacks vagina preparation
Other restrictions comprise vagina variation, genitals hygienic issues, local side effects, sexual intercourse interference and the variable drug permeability that menstrual cycle is relevant
Social taboo, do not understand and sex-specific is also to use and develop the powerful obstacle that intravaginal drug is sent
Lack and to there is administration simplification and can not cause that thereby discomfort improves the vagina preparation of patient's compliance.
Ladies and gentlemen inventor of the present invention finds to provide the mode of vagina dosage form (a kind of ' fast dissolving tablet agent preparation ') surprisingly, this preparation is hopeful to meet unsatisfied medical science needs, for being easy to the administration of secret ground and the needs of the vagina dosage form of disintegrate/dissolving rapidly after inserting vaginal canal.This dosage form produces viscous suspension, is also spread in vaginal mucosa widely rapidly, and is detained the sufficiently long time to provide therapeutic efficiency via local action or systemic Absorption.Be different from gel dosage form, these tablets do not need to use vagina applicator, owing to reducing potentially packaging material (increasing portability) and manufacturing cost, become thus attractive dosage form.This dosage form can be for HIV treatment in the situation together with other treatment application.
summary of the invention
In certain embodiments, the present invention relates to comprise one or more for treating the fast dissolving tablet agent compositions of the active pharmaceutical ingredient of disease condition via local action or systemic Absorption when the vagina administration, and manufacture and use the method for such composition.
In certain embodiments, the pharmaceutical composition of the active pharmaceutical ingredient that the present invention relates to comprise one or more applicable vagina administration approach, and the method for manufacturing and use this type of compositions being used for the treatment of together with uterus targeting via local action or systemic Absorption.In certain embodiments, the active pharmaceutical ingredient that the present invention relates to comprise one or more applicable vagina administration approach, one or more have and serve as binding agent together with the pharmaceutical composition of polymeric excipient, one or more sugar alcohols or saccharide and one or more disintegrating agents of the double attribute of bioadhesive material, it is disintegrate rapidly in vaginal canal, form viscous suspension, and spread rapidly and widely so that by medicine suspension/solution coating vaginal mucosa, for treating via local action or systemic Absorption.
Pharmaceutical composition of the present invention can contain at least one medicine that is selected from lower group, and this group is comprised of the following: antifungal; Antibacterial agent; Antimicrobial; Antiviral agent; Anti-infective; Spermicide; Hormone; Antibiotic; Antiviral agent; Analgesic; Anti-trichomonal agent; Antiprotozoan agent; Anti-mycoplasma agent; Antiretroviral agent; Nucleoside analog; Reverse transcriptase inhibitors; Protease inhibitor; Contraceptive; Apositia and appetite suppressant; Steroid; Anthelmintic; Anesthetics; Anti-arthritic; Antiasthmatics; Anticonvulsant; Antidepressants; Antidiabetic; Diarrhea; Hydryllin; Antiinflammatory; Migraine preparation; Anti-motion sickness agent; Antinauseant; Antitumor drug; The agent of Kang Pajinsenshi disease; Pruritus; Psychosis; Antipyretic; Spasmolytic; Anticholinergic agent; Sympathomimetic; Xanthine derivative; Cardiovascular preparation; Calcium channel blocker; Beta receptor blockers; Antiarrhythmic drug; Antihypertensive drug; Diuretic; Generally, crown, around with cerebral blood vessel expander; Erection disturbance agent; Central nervous system stimulant; Cough and cold-treating preparation; Decongestant; Diagnostic agent; Hormone; Hypnotic; Immunosuppressant; Muscular flaccidity agent; The parasympathetic nervous that disappears is done medication; Parasympathomimetic agent, analeptic, tranquilizer, represent the Orally active medicine of remarkable first pass effect; Albumen/peptide, comprises growth promoting hormones and luteinising hormone-releasing hormo (LHRH); Tranquilizer; Antioxidant; Vitamin; Mineral; With herb extracts or preparation or its combination, for vagina administration.
According to the present invention, polymeric excipient (for example, low replacement hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polycarboxylic acids, polyvinylpyrrolidone, vinyl pyrrolidone-VA, ethylene glycol 6000-caprolactam-vinyl acetate copolymer, polyvinyl alcohol, poly(ethylene oxide), poly-(lactic-co-glycolic acid), polyamide, alginate, carrageenin (carrageenan), chitosan and cellulose gum) bioadhesion attribute by the bioadhesion of enhanced activity composition (medicine) and mucomembranous surface, increase thus the holdup time of improving treatment via local action or systemic Absorption.
In certain embodiments, wherein pharmaceutical composition can further comprise surfactant and/or by the bioadhesion of enhanced activity composition and mucomembranous surface or enhancing/the maintain lipid of systemic Absorption, via local action or systemic Absorption, provide and improve therapy thus, and reduce side effect; More specifically when medicine has poor water solublity.
In some other embodiment, the present invention is directed to the pharmaceutical composition that is fast dissolving tablet agent form, its rapid disintegrate when inserting patient's vagina, form viscous suspension, and spread rapidly and widely, and be used for treating via local action or systemic Absorption with drug suspension/solution coating vaginal mucosa.
Still in some other embodiment, the present invention relates to the fast dissolving tablet agent that comprises rapid dispersion microgranule, these rapid dispersion microgranules comprise at least one sugar alcohol and at least one disintegrating agent.This tablet can quick disintegrate when inserting patient's vagina, forms viscous medicaments suspension, and spreads fast and widely with by medicine suspension/solution coating vaginal mucosa.
Brief Description Of Drawings
Fig. 1 illustrates the schematic diagram of ' solution tablet rapidly ' as imagined in certain embodiments of the present invention.
Fig. 2 is illustrated in the average tenofovir plasma concentration-time graph after single tenofovir fast dissolving tablet agent (RDT) vagina administration of doe.
Fig. 3 is illustrated in the average tenofovir plasma concentration-time graph after female tenofovir fast dissolving tablet agent (RDT) multiple dose (totally 7 administrations once a day) administration of exempting from vagina.
After Fig. 4 demonstrates single tenofovir fast dissolving tablet agent (RDT) vagina administration that is shown in doe, after administration 2 and average free and total tenofovir content of the abdominal part of 24hr and vagina tissue.
After Fig. 5 is illustrated in female tenofovir fast dissolving tablet agent (RDT) multiple dose (totally 7 administrations once a day) administration of exempting from vagina, after administration 2 and average free and total tenofovir content of the abdominal part of 24hr and vagina tissue.
After Fig. 6 is illustrated in single tenofovir fast dissolving tablet agent (RDT) vagina administration of doe, after administration 2 and 24hr
Figure BDA0000425444130000071
in average administration before and administration after tenofovir concentration.
After Fig. 7 is illustrated in tenofovir fast dissolving tablet agent (RDT) multiple dose (totally 7 administrations once a day) administration of doe vagina, after administration 2 and 24hr
Figure BDA0000425444130000072
in average administration before and administration after tenofovir concentration.
Detailed description of the invention
Below describe and be included in that to understand in the present invention can be Useful Information.This not admits that any information providing at this is prior art or admits that definite or implicit any publication of mentioning is prior art.
For all objects, the All Files of quoting at this is combined in this in full with it by reference, and this reaches, and as each independent document, indicate definitely or individually will be by reference and the same degree of combination.Except as otherwise noted, otherwise as used above, and the following term that runs through description of the present invention be interpreted as having following implication:
As used herein, term " medicine ", " active matter ", " bioactive materials ", " activating agent " or " active pharmaceutical ingredient " comprise pharmaceutically acceptable and treatment compounds effective, pharmaceutically acceptable salt, stereoisomer and stereoisomer mixture, solvate (comprising hydrate), polymorph or its prodrug.Except as otherwise noted, otherwise while mentioning medicine in the description of different embodiments of the invention, mentioned thing is contained basic medicine, pharmaceutically acceptable salt, stereoisomer and stereoisomer mixture, solvate (comprising hydrate), polymorph or its prodrug.
Term " salt " refers to the product that reacts formation with the medicine of " free alkali " form by applicable inorganic or organic acid.Applicable acid comprises having enough acidity to form those of sta-salt, for example, have hypotoxic acid, for example, through checking and approving the salt for the mankind or animal.The sour unrestricted example that can be used to form the salt of vagina active medicine (for example metronidazole or tenofovir) comprises mineral acid, for example, and HF, HCI, HBr, HI, H 2sO 4, H 3pO 4; The unrestricted example of organic acid comprises organic sulfonic acid, for example C 6-16aryl sulfonic acid, C 6-16heteroaryl sulfonic acid or C l-16alkyl sulfonic acid, for example phenyl, Alpha-Naphthyl, betanaphthyl, (S)-Camphora, methyl, ethyl, n-propyl group, iso-propyl group, n-butyl, the second month in a season-butyl, iso-butyl, tert-butyl, amyl group and hexyl sulfonic acid; The unrestricted example of organic acid comprises carboxylic acid, for example C l-16alkyl, C 6-16aryl carboxylic acid and C 4-16heteroaryl carboxylic acid, for example acetic acid, glycolic, lactic acid, acetone acid, malonic acid, 1,3-propanedicarboxylic acid, tartaric acid, citric acid, fumaric acid, succinic acid, malic acid, maleic acid, hydroxy-maleic acid, benzoic acid, hydroxy benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and 2-phenoxy benzoic acid; The unrestricted example of organic acid comprises aminoacid, such as the aminoacid of natural generation, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.Other applicable salt can be found in such as S.M.Birge(Bill heat) etc. people, J.Pharm.Sci.(pharmaceutical journal), 1977, 66, in 1-19 page.In most of embodiment, " salt " refers to biologically the salt of perhaps pharmaceutically acceptable or nontoxic (particularly for mammalian cell) mutually.The salt of useful medicine can be the mixture of mixture crystallization or amorphous phase or different crystal forms or crystallization and amorphous phase form in the present invention.
Term " prodrug " mean be applicable to patient's administration and without excessive toxicity, stimulation, anaphylaxis, etc., and for desired use compounds effective form, comprise ketal, ester and zwitterionic form.Prodrug transforms in vivo, for example, in blood, pass through hydrolysis.Thoroughly discuss the 14th volume that is provided in A.C.S. academic discussion collection of thesis, T.Higuchi(Xi Guqi) and V.Stella(Si Tela), Pro-drugs as Novel Delivery Systems(is as the prodrug of novel delivery system) in, and Edward(Edward) sieve B.Roche(cuts) compile, the biology reversible carrier of Bioreversible Carriers in Drug Design(in drug design), American Pharmaceutical Association(American Pharmaceutical Association) and Pergamon Press(Pei Geman publishing company), in 1987.
Term " fast dissolving tablet agent ", " rapid disintegration tablet " or " DT " refer to after administration/insertion vaginal canal, in patient's vaginal canal fast (for example about 8min, about 6min, about 4min or about 2min in) tablet of disintegrate.For example, when (testing as described here, USP<701> disintegration time method of testing) time, disintegration rate can change, but slower than the disintegration rate of Orally disintegrating tablet, or faster than the disintegration rate of routine or bioadhesion vaginal tablet.
Term " disintegrate in fact " refers to and reaches disintegrate at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about the disintegrate level of 90% or approximately 100% disintegrate.Term " disintegrate " is different from term " dissolving " part and is that " disintegrate " refers to composition breakage of particles or the forfeiture of structure cohesion that forms tablet, and " dissolving " refers to that solid dissolves (for example, medicine dissolves in solvent or gastric juice) in liquid.
Term " water-soluble polymer " refers to that polymer solvable (that is, significant quantity dissolves), in aqueous medium, is independent of pH value.
Art words " bioadhesive material " do not refer to there is no the adhesion of the pharmaceutical composition of bioadhesive material to be compared, the polymer of the pharmaceutical composition that improvement contains bioadhesive material and the adhesion of mucosa or similar biological surface.The unrestricted example of bioadhesive material comprises bioadhesive polymer, for example hydroxypropyl cellulose.
Term " patient's compliance " refers to that doctor's advice follows the patient of a certain dosage regimen of needed concrete medicine and do not observe dosage regimen.Compliance or to follow dosage regimen be main medical problem in the world not, expends multi-million dollar and affects millions of people's life style.
Term " about " about numerical value comprises that represented numerical value is together with the value that approaches this numerical value as used herein.For example, " approximately 60 seconds " comprise that lucky 60 seconds for example, together with the value (, 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.) that approaches 60 seconds.
Unless clearly indication only refers to what substitute or substitute were mutual repulsion, otherwise the term "or" of using in application claim is used for meaning "and/or".Special consideration, any one that any project list of use term "or" means in those listed projects also can specifically be got rid of from related embodiment.
Follow long-standing Patent Law, unless stated otherwise, otherwise word " (a and an) " represents one (kind) or a plurality of (kinds) while being combined with sealing " comprising (comprising) " with the word in claims or description.
Unless otherwise indicated, otherwise be attached to the weight percent that is shown compositions (for granular or RDT) according to the scale of the pharmaceutically acceptable active matter of difference in the different pharmaceutical compositions of some embodiment of the present invention or excipient.Therefore, 10% active matter in RDT compositions refers to existence or the content of the active matter of 10% weight in RDT.
In certain embodiments, the present invention be directed to the pharmaceutical composition that comprises the medicine that is selected from lower group, following of this group forms: antifungal; Antibacterial agent; Antimicrobial; Antiviral agent; Anti-infective; Spermicide; Hormone; Antibiotic; Antiviral agent; Analgesic; Anti-trichomonal agent; Antiprotozoan agent; Anti-mycoplasma agent; Antiretroviral agent; Nucleoside analog; Reverse transcriptase inhibitors; Protease inhibitor; Contraceptive; Apositia and appetite suppressant; Steroid; Anthelmintic; Anesthetics; Anti-arthritic; Antiasthmatics; Convulsion is scraped; Antidepressants; Antidiabetic; Diarrhea; Hydryllin; Antiinflammatory; Migraine preparation; Anti-motion sickness agent; Antinauseant; Antitumor drug; The agent of Kang Pajinsenshi disease; Pruritus; Psychosis; Antipyretic; Spasmolytic; Anticholinergic agent; Sympathomimetic; Xanthine derivative; Cardiovascular preparation; Calcium channel blocker; Beta receptor blockers; Antiarrhythmic drug; Antihypertensive drug; Diuretic; Generally, crown, around with cerebral blood vessel expander; Erection disturbance agent; Central nervous system stimulant; Cough and Sheng are emitted preparation; Decongestant; Diagnostic agent; Hormone; Hypnotic; Immunosuppressant; Muscular flaccidity agent; The parasympathetic nervous that disappears is done medication; Tranquilizer; Antioxidant; Vitamin; Mineral; With herb extracts or preparation; Parasympathomimetic agent; Analeptic; Tranquilizer; The Orally active medicine that represents remarkable first pass effect; Or its combination, albumen/peptide, reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTI), protease inhibitor (PI), integrase inhibitor, growth promoting hormones and luteinising hormone-releasing hormo (LHRH), etc., or its pharmaceutically acceptable salt, solvate or ester, be applicable to treating via local action or systemic Absorption by vagina administration.
Reverse transcriptase inhibitors RTI is a class antiretroviral drugs that is used for the treatment of HIV infection, tumor and cancer.RTI suppresses reverse transcriptase, and a kind of retrovirus needs so that the activity of the viral dna polymerase copying.The binding mode of NRTI is substantially the same: they are analog of the synthetic needed natural generation Deoxydization nucleotide of viral DNA.NNRTI is specificity Inhibit the replication of HIV-1 and targeting HIV1-RT, and except NRTI and protease inhibitor, has obtained the compound of certain status in treatment HIV-1 infects.PI is the medicine that a class is used for the treatment of or pre-anti-virus (comprising HIV and hepatitis C) infects.Integrase inhibitor (for example dust is for La Wei and MK-2048) is that a class is intended to block intergrase, a kind of by the antiretroviral drugs of the effect of the viral enzyme in viral genome Insertion Into Host Cell DNA.
Therefore, in certain embodiments, the present invention is directed to a kind of pharmaceutical composition, this pharmaceutical composition comprises one or more medicines that are selected from lower group, and this group is comprised of the following: antiretroviral agent is by forming below: NRTI(for example, A Lita shore, Entecavir, emtricitabine, tenofovir, Abacavir, adefovirdipivoxil, its salt and composition thereof), NNRTI(for example, nevirapine, Delavirdine, efavirenz, rilpivirine (rilpivirine), UC-781, MKC-442, quinoxaline HB Y097, DMP266, its salt and composition thereof), protease inhibitor (for example, indinavir, amprenavir, Prezista, Lip river is for that Wei, viracept see nelfinaivr, ritonavir, Sai Kuinawei, atazanavir, tipranavir, its salt and composition thereof), and integrase inhibitor (for example, dust is for drawing Wei, MK-2048, its salt and composition thereof), except treating the individuality of suffering from HIV/AIDS, being used for suppressing or eliminating AIDS growth or seriousness in addition can be for preventing initial HIV infection.Different commercially available vaginal cream, ointment, gel, insert/ring and tablet can be buied at present.For example, Dahl(Da Er) in EP1773296, disclose the preparation of the medicine vagina gel that comprises tenofovir.This dosage form may not be of value to be suffered from the individual of AIDS or wants to avoid HIV to propagate during sexual activity or those individualities of infection risk, because gel/applicator may be subject to for example seepage, in a jumble and the impact of the limiting factor of low hold-up time the same as other similar gels preparations.Yet, be desirable to provide very much the improved composition or the method that during sexual activity, reduce HIV propagation or infection risk.
In certain embodiments, the present invention is directed to the quick soluble particles of the medicine that comprises at least one applicable vagina administration that is selected from lower group or the pharmaceutical composition of tablet form, this group is comprised of the following: diphosphonate (for example, fosamax, clodronate, etidronate, pamldronate, Tiludronate, ibandronate, neridronic acid salt, Risedronate, zoledronic acid, incadronate, YM 529 and olpadronate), antimigraine drug, for example, antimigraine drug in the group that below choosing freely, item forms: Ergotamine, dihydroergotamine, ergotin (ergostine), butalbital, phenobarbital, acetamide phenol, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, aspirin, flurbiprofen, tolfenamic acid, butorphanol, Pethidine, methadone, sumatriptan, naratriptan, razatriptan, Zolmitriptan, Almogran, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate and divalproex sodium), anti-nausea pill, for example anti-nausea pill in the choosing group that freely following item forms: Mei Duokela amide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, Aprepitant, marezine, promethazine, sldenafil, oxytocin, oxytocin, oxibutynin, bromocriptine, rifamycin, azithromycin, for hormone, replace the steroid of therapy or contraception, calcitonin, LHRH and frequency are like thing, insulin, and human growth hormone, and combination.Can adopt the vagina can form of administration, for example comprise those of suppository, these suppositorys as penetration enhancer and one or more mucosa-adherent polymer (for example contain the poor medicine of solubility/bioavailability and foaming agent, carbomer, chitosan, hydroxyethyl-cellulose), surfactant (for example, palmitostearate), or lipid (for example, palmitostearate, phospholipid).
In certain embodiments, the present invention is directed to the pharmaceutical composition of quick soluble particles form, the medicine that comprises at least one applicable vagina administration, at least one sugar alcohol (for example mannitol) or sugar (for example lactose) and at least one polymer adhesive (for example low replacement hydroxyethyl-cellulose).For example such composition can be treated via local action or systemic Absorption for time in the vaginal canal Pharmaceutical composition insertion is had to the patient/experimenter who needs to it.
In certain embodiments of the present invention, the pharmaceutical composition of soluble particles form further comprises disintegrating agent, for example crospovidone fast.This disintegrating agent can contribute to the quick disintegrate of quick soluble particles, to form the viscous suspension that contains medicine in the vaginal canal it being had to the patient/experimenter who needs.
In some other embodiment of the present invention, the pharmaceutical composition of soluble particles form further comprises at least one bioadhesive polymer fast, for example low replacement hydroxyethyl-cellulose.This bioadhesive polymer can provide by desired concn, it applies vaginal mucosa in the time of can forming the viscous suspension that contains medicine in patient/experimenter's vaginal canal, improves its bioadhesion and therapeutic efficiency thus via the longer holdup time of local action or systemic Absorption.
The example of sugar alcohol/saccharide is including, but not limited to mannitol, Sorbitol, xylitol, arabitol, erythritol, glycerol, hydrogenated starch hydrolysate, hydroxyl isomaltulose, lactose, lactose, maltose alcohol, sucrose, maltose and combination thereof.
The example of applicable binding agent for example, including, but not limited to polyvinylpyrrolidone (PVP), poly(ethylene oxide), HYDROXY PROPYL METHYLCELLULOSE or hydroxypropyl emthylcellulose (, methylcellulose E5 or E15 or Pharmacoat tM603), hydroxypropyl cellulose (for example,
Figure BDA0000425444130000131
lF), low replacement hydroxyethyl-cellulose and polysaccharide.Binding agent can be by for example existing from the amount of the scope of approximately 0.5 % by weight-3 % by weight based on quick soluble particles.
The example of disintegrating agent for example, including, but not limited to crospovidone, Explotab, starch, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, glue (, gellan gum), and combination.Disintegrating agent can be present in the pharmaceutical composition of quick soluble particles form, for example, from approximately 1% to approximately 10%, from approximately 3% to approximately 7%, to approximately 5%, comprise four corner and subrange between it.
The unrestricted example of applicable bioadhesive polymer including, but not limited to hydroxy propyl cellulose rope, hydroxypropyl emthylcellulose, low replacement hydroxyethyl-cellulose, hydroxyethyl ethylcellulose, polycarboxylic acids, polyvinylpyrrolidone, vinylpyrrolidone-VA (for example,, from BASF's
Figure BDA0000425444130000132
vA64), polyvinyl alcohol, poly(ethylene oxide), carbomer ( 974P, 941,940,934, G70), poly-(lactic-co-glycolic acid), polyamide, carrageenin, chitosan and various cellulose gum (for example, xanthan gum).Bioadhesive polymer can be present in the pharmaceutical composition of quick soluble particles form; For example, from approximately 3% to approximately 10%, from approximately 4% to approximately 8%, to approximately 5%, comprise four corner and subrange between it.
The unrestricted example of the applicable surfactant that can adopt comprises DL-alpha tocopherol, surfactant, and (for example, CAPTEX200, polysorbas20, Tween 80, vitamin E TPGS, Capryol90, CREMOPHOR EL, CARBITOL, PEG400, lecithin, Brij92, LABRASOL, glyceryl triacetate (triacetin), sodium lauryl sulfate, ethylene glycol monostearate, polysorbate and pool Lip river are husky
Figure BDA0000425444130000145
lauryl sodium salicylate, sodium lauryl sulphate), and composition thereof.
The unrestricted example of the applicable lipid that can adopt comprises lecithin; Hydrolecithin; LYSOLECITHIN SUNLECITHIN A, hydrogenation LYSOLECITHIN SUNLECITHIN A; Lysophosphatide and derivant thereof; Phospholipid and derivant thereof; Alkyl sulfate; Soap; Docusate sodium (sodium docusate); Stearyl alcohol, palmitostearate ( aTO5); The mixture of monoglyceride, diester and three esters
Figure BDA0000425444130000144
pEG monoesters and diester, PEGylation, and composition thereof.
In certain embodiments of the present invention, the pharmaceutical composition of fast dissolving tablet agent form further comprises: comprise sugar or sugar alcohol in conjunction with the rapid dispersion microgranule of disintegrating agent, according to the U.S. Patent Application Serial Number 10/827 that common generation determines, 106(is disclosed as US 2005/0232988) description produce.Still in some other embodiment of the present invention, fast dissolving tablet agent compositions can further comprise rapid dispersion microgranule, and these rapid dispersion microgranules comprise sugar alcohol (for example mannitol), super-disintegrant (for example low-substituted hydroxypropyl cellulose) and have the polyfunctional additive (for example starch, modified starch and hydroxypropyl cellulose) of binding agent and disintegrating agent.
Applicable disintegrating agent for example, including, but not limited to crospovidone, Explotab, starch, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, glue (gellan gum) and combination thereof.Exemplary saccharide or sugar alcohol can be selected from lower group, and this group is comprised of the following: 1,2,3,4,5-pentanepentol, erythritol, glycerol, hydrogenated starch hydrolysate, hydroxyl isomaltulose, lactose, lactose, maltose alcohol, mannitol, Sorbitol, xylitol, sucrose, maltose and combination thereof.Sugar or sugar alcohol also can use artificial sweetening agent (for example Sucralose) to supplement or replace.Typically scope is from about 1:99 to about 10:90 by weight for the ratio of the disintegrating agent in rapid dispersion microgranule and sugar or sugar alcohol, or about 5:95 is to about 10:90, and comprises four corner and the subrange between it.In certain embodiments, the U.S. Patent Application Serial Number 10/827 of determining according to common generation, 106(is disclosed as US2005/0232988) in description, disintegrating agent or sugar or sugar alcohol or the two exist to have the particle form of approximately 30 μ m or less mean diameter, and when compositions has multifunction additive, sugar or sugar alcohol exist with the particle form of the right approximately 60 μ m of tool or less mean diameter.For example multifunction additive by weight 1%-2.5% be present in rapid dispersion microparticle compositions.The ratio of the granule that contains medicine and quick disintegrate granule can scope from about 5:1 to about 1:5, about 3:1 to about 1:3, or about 2:1 is to about 1:2, or about 1:1, comprises four corner and subrange between it.
It is 100rpm that American Pharmacopeia I(oar speed is used in the dissolution in vitro test of pharmaceutical composition of the present invention) or II(oar speed be 50rpm) and depend on that the suitable dissolve medium (900mL) (HPLC method) of medicine carries out.
The disintegrate of RDT of the present invention according to USP<701> slaking test test.Alternately, the disintegration time that is prepared as the pharmaceutical composition of RDT tablet can be used the Irving according to Owen() and Katz(card thatch) disclosure (Owen(Irving) and Katz(card thatch), 1999.Contraception(contraception), 59, the vaginal secretions stimulus object of 91-95) preparing is determined.Consider that in vaginal canal, available liquid volume is little, dissolving test for example can drip RDT, in (containing a small amount of buffer that pH value is about 6 ammonium acetate buffer, in test tube 3.5mL), and put with the centrifugal 2min of 4000rpm in due course, and by HPLC, test the sample filtering via 0.45 μ m PTFF filter and carry out.
In a particular embodiment, RDT of the present invention comprises separately or with 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 tenofovir or its pharmaceutically acceptable salt of the ratio of the about 1:5 treatment effective dose of being combined with emtricitabine.After inserting vagina, RDT is disintegrate in fact in patient's vaginal canal, forms viscosity, is easy to the suspension of diffusion, and diffusion/coating vaginal mucosa is to provide effect via local action or systemic Absorption.Except rapid dispersion microgranule, RDT of the present invention optionally comprises pharmaceutically acceptable bioadhesive polymer, for example be selected from a kind of in lower group, this group is comprised of the following: low substituted hydroxy cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polycarboxylic acids, polyvinylpyrrolidone, vinyl pyrrolidone-VA are (for example,, from BASF's
Figure BDA0000425444130000151
vA64), from BASF poly-(ethylene glycol 6000-caprolactam-vinyl acetate) (13:57:30) copolymer), polyvinyl alcohol, poly(ethylene oxide), poly-(lactic-co-glycolic acid), polyamide, alginate, carrageenin, chitosan and various cellulose gum (for example, xanthan gum).
In certain embodiments, RDT is heavy at least about 50mg; For example, 100mg or larger; 200mg or larger; 300mg or larger; Or 500mg or larger.In some other embodiment, RDT is heavily not more than about 2000mg; For example, 1600mg or less; 1400mg or less; 1200mg or less; 1000mg or less; 800mg or less; Or 500mg or less.In another embodiment, RDT is heavily not more than about 800mg.In another embodiment, RDT is heavily not more than about 600mg.In another embodiment, RDT is heavily not more than about 500mg.For example dosage form of the present invention can comprise two or more particle swarms that contains antibiotic medicine, for example, comprise at least one metronidazole particle swarm as described herein.For example dosage form can comprise fast dissolved particles group of tenofovir as described herein (nucleoside reverse transcriptase inhibitor), and emtricitabine particle swarm in addition, for preventing AIDS.
In one embodiment, two kinds of specific virus enzymes for the treatment of targeting as described herein: reverse transcriptase (for example, using NRTI or NNRTI) and protease (for example, using protease inhibitor).
The pharmaceutical composition of the present invention that is used for the fast dissolving tablet agent form of vagina administration can comprise Propranolol (the extensive first non-selective Beta receptor blockers of crossing (liver) metabolism of experience when oral administration) or its pharmaceutically acceptable salt or the mixture for the treatment of effective dose.
The pharmaceutical composition of the present invention that is used for the fast dissolving tablet agent form of vagina administration can comprise the antibiotic for the treatment of the metronidazole of effective dose and being optionally selected from lower group, and this group is comprised of the following: clarithromycin, sulfonamide, erythromycin, azithromycin, doxycycline, quinolones, cefoxitin, ceftriaxone cifrofloxacin, doxycycline, vancomycin, fluorine woods mycin, rifaximin and metronidazole.
The pharmaceutical composition of the present invention that is used for the fast dissolving tablet agent form of vagina administration can comprise the antifungal for the treatment of the clotrimazole of effective dose and being optionally selected from lower group, and this group is comprised of the following: nystatin, ketoconazole, itraconazole and clotrimazole.
In certain embodiments, the present invention is directed to a kind of method, first the method is prepared and is applicable to by the quick soluble particles compositions of vaginal approach administration, and said composition comprises at least one sugar alcohol, sugar or its mixture, polymer adhesive, optionally super-disintegrant or bioadhesive polymer, with treatment effective dose at least one be selected from the medicine of lower group, this group is comprised of the following: antifungal, antibacterial agent, antimicrobial, disease-resistantly go agent, spermicide, hormone preparation, anti-trichomonal agent, antiprotozoan agent, anti-mycoplasma agent, antiretroviral agent, nucleoside analog, reverse transcriptase inhibitors, protease inhibitor, contraceptive, albumen trade, peptide, steroid, growth promoter and analog thereof, or its pharmaceutically-acceptable salts, solvate or ester, secondly by the quick soluble particles that contains medicine and the U.S. Patent Application Serial Number 10/827 of determining according to common generation, 106(is disclosed as US2005/0232988) the rapid dispersion microgranule blend prepared of description, and be compressed into and contain the fast dissolving tablet agent (RDT) for the treatment of effective dose.RDT is disintegrate fast in patient/experimenter's vaginal canal, forms the viscous suspension that contains medicine, expects that it can spread fast and widely and apply vaginal mucosa for treating disease via local action or systemic Absorption.
In some other embodiment, the present invention is directed to a kind of method, first the method prepares quick soluble particles compositions, and said composition comprises at least one sugar alcohol, sugar or its mixture, polymer adhesive, optionally super-disintegrant or bioadhesive polymer, with treatment effective dose at least one be selected from the medicine of the antiretroviral agent of lower group, these antiretroviral agents are comprised of the following: NRTI(for example, A Lita shore, Entecavir, emtricitabine, tenofovir, Abacavir, adefovirdipivoxil, its salt and composition thereof), NNRTI(for example, nevirapine, Delavirdine, efavirenz, UC-781, MKC-442, quinoxaline HBY097, DMP266, its salt and composition thereof), protease inhibitor (for example, indinavir, amprenavir, Prezista, Lip river is for that Wei, viracept see nelfinaivr, ritonavir, Sai Kuinawei, atazanavir, tipranavir, its salt and composition thereof), and integrase inhibitor (for example, dust is for drawing Wei, MK-2048, its salt and composition thereof), secondly by the quick soluble particles that contains medicine and the blend of rapid dispersion microgranule, and be compressed into and contain the RDT tablet for the treatment of effective dose, for suffer from the individuality of HIV/AIDS except treatment, for example be used for suppressing or eliminate beyond AIDS growth or seriousness, can prevent primary infection.Different commercially available vaginal cream, ointment, gel, insert/ring and tablet can be buied at present.For example, Dahl(Da Er) in EP1773296, disclose the preparation of the medicine vagina gel that comprises tenofovir.This dosage form may not be of value to be suffered from the individual of AIDS or wants to avoid HIV to propagate during sexual activity or those individualities of infection risk, because the impact that may be subject to the limiting factor of for example seepage, mixed and disorderly and shorter holdup time the same as other similar gels preparations of gel/applicator.Yet, be desirable to provide very much the improved composition or the method that during sexual activity, reduce HIV propagation or infection risk.
In some other embodiment, the present invention relates to a kind of method, the method is prepared fast dissolving tablet agent compositions, said composition comprises at least one sugar alcohol (for example mannitol), polymer adhesive (for example low-substituted hydroxypropyl cellulose), disintegrating agent (for example crospovidone) optionally, with independent a kind of NRTI(for example tenofovir or emtricitabine), one or more NRTI(for example with emtricitabine or reach the tenofovir that a Wei Lin is combined), and then on rotary tablet machine, compressed package contains described quick soluble particles, rapid dispersion microgranule, microcrystalline Cellulose, the preparation of super-disintegrant (for example crospovidone) and lubricant (for example sodium stearyl fumarate) forms fast dissolving tablet agent.
In another embodiment; the method of preparing quick soluble particles comprises makes compositions granulation as described herein; said composition (for example further comprises bioadhesive polymer for being attached to RDT; viscous medicaments suspension when low replacement hydroxyethyl-cellulose), it improves in RDT insertion vaginal canal and the bioadhesion on vaginal mucosa surface.
Granulating method is unrestricted; Fluid bed or the high shear granulation method of using polymer adhesive to be dissolved in the solution in pure water, ethanol, isopropyl alcohol, acetone or its mixture are embodiments of the invention.According to the present invention; for example; granulation can for example, by top spray fluidised bed granulator (Glatt GPCG3, GPCG5, GPCG120 or Fluid Air FA0300); for example, to comprising at least one sugar alcohol and optionally on the mixture of powders of disintegrating agent or bioadhesive polymer (low substituted hydroxy cellulose), and in same fluidized bed dryer, particle drying is carried out the solution spraying that comprises polymer adhesive and dissolving or be evenly suspended in medicine wherein.Granulation also can be used high shear granulator, for example, from the GMX25(batch size of Vector company: and 4-7kg), GMX65, or GMX600(batch size: 140-160kg), and in Glatt, be dried to carry out.Consequent dried particles can sieve by passing suitable sieve, and then again sieves to collect the quick soluble particles that contains medicine with required particle size distribution by abandoning fines and optionally oversized particles being ground.
The median particle diameter that can have in order to the microgranule that contains medicine of the bioadhesive polymer granulation of improvement and vaginal mucosa bioadhesion feature with one or more is within the scope of about 100-400 μ m.In certain embodiments, be no less than 90% microgranule and be less than 600 μ m so that it is attached in fast dissolving tablet agent.
Still in another embodiment, the present invention can for the quick soluble particles by making to contain medicine with as the rapid dispersion microgranule blend of said preparation and be compressed into the method that fast dissolving tablet agent is prepared in fast dissolving tablet agent on rotary tablet machine, these fast dissolving tablet agent are for the vaginal canal administration to the patient of this type of medicine of needs, for acting on via table or systemic Absorption obtains therapeutic efficiency.
For example fast dissolving tablet agent of the present invention can produce by internal lubrication method, wherein compressed mixture compression before further with lubricant blend.Alternately, fast dissolving tablet agent can produce by external lubrication method, and wherein lubricant is not contained in tablet formulation product, but external coated on the contact drift of rotary tablet machine and the material of die surface.Lubricant, such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, Tridocosanoin, etc. can be for lubricated granules, or can be external coated to the mould of rotary tablet machine and the material of punch head surface of contact for compressed tablets.
The method for treatment patient or experimenter according to another embodiment of the present invention, comprise and will by inserting, it be had in patient's the vaginal canal of needs and carry out administration for the present composition of fast dissolving tablet agent, said composition contain treatment effective dose one or more be selected from the medicine of lower group, this group is comprised of the following: antifungal, antibacterial agent, antimicrobial, antiviral agent, spermicide, hormone, anti-trichomonal agent, antiprotozoan agent, anti-mycoplasma agent, antiretroviral agent, nucleoside analog, reverse transcriptase inhibitors, protease inhibitor, contraceptive, steroid, the Orally active medicine that represents remarkable first pass effect, albumen/peptide, comprise growth promoting hormones and luteinising hormone-releasing hormo (LHRH).
example
The present invention is described in more detail in following part.Hereinafter provide to illustrate that many examples of the present invention relate to separately or the tenofovir of being combined with emtricitabine.Should be understood that example described herein and embodiment only for illustration purposes, and difference is Given this revised or is changed and will be proposed and be contained in the application's spirit and scope by one of ordinary skilled in the art.
example 1
a: the RD microgranule that comprises tenofovir, crospovidone and Klucel:
Sodium bicarbonate (54g) is added in the pure water (2800g) in rustless steel container lentamente, is constantly stirred to dissolving simultaneously.If needed, by adding hydrochloric acid, the pH value of bicarbonate solution is adjusted to approximately 6.0, when stirring, add lentamente hydroxypropyl ground level dimension element (Klucel LF; 125g) to dissolving; Then add tenofovir (180g) to dissolving.Will be all by remove the mean diameter of caking through Comil, be less than 30 μ m(781g) mannitol and crospovidone (60g) be filled to and be equipped with the pre-warmed Glatt GPCG30 that top spray inserts, granulation air-distribution base plate, 200 sieve mesh products retain sieve and 1.0mm nozzle.Make to feed continuously fluidisation and procedure parameter is held under following condition in by quick soluble particles compositions granulation: product temperature-34 ℃ ± 1 ℃; Fluidisation air-flow-10CFM; Spray speed-10-16mL/min.When spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.
b: the RD microgranule that comprises tenofovir, crospovidone and L-HEC:
Sodium bicarbonate (54g) is added in the pure water (2500g) in rustless steel container lentamente, is constantly stirred to dissolving simultaneously.If needed, by adding hydrochloric acid, the pH value of bicarbonate solution is adjusted to approximately 6.0.When stirring, add lentamente low replacement hydroxyethyl-cellulose (L-HEC:20g) to dissolving; Then add tenofovir (180g) to dissolving.The mannitol (781g) and the crospovidone (60g) that remove caking are filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is to prepare by the spray solution disclosed in above step e x.l A.
c: the RD microgranule that comprises tenofovir, crospovidone and HPMC:
Sodium bicarbonate (39.1g) is added in the pure water (2500g) in rustless steel container lentamente, is constantly stirred to dissolving simultaneously.If needed, by adding hydrochloric acid, the pH value of bicarbonate solution is adjusted to approximately 6, when stirring, add lentamente hypromellose (HPMC; 18.1g) to dissolving; Then add tenofovir (183.2g) to dissolving.The mannitol (637.4g) and the crospovidone (43.1g) that remove caking are filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is to prepare by the spray solution disclosed in above step e x.lA.
d: rapid dispersion microgranule:
Rapid dispersion microgranule is followed the program disclosing in the U.S. Patent Application Publication No. U.S.2003/0215500 that common generation determines and is prepared.Definitely; the D-mannital (152kg) (from the Pearlitol25 of French Roquette company) with approximately 20 μ m or less mean diameter in high shear granulator (from the GMX600 of Vector) with 8kg polyvinylpolypyrrolidone (from the crospovidone XL-10 of ISP) blend; by pure water (about 32kg) granulation; use is from the Comil wet grinding of Quadro company, and to provide, has the LOD(loss on drying that is less than approximately 0.8% finally by tray drying) microgranule.Dried particles is sieved, and excessive material regrinding is to produce the rapid dispersion microgranule of the mean diameter within the scope of about 175-300 μ m.
e: tenofovir RDT(crospovidone):
Compression (referring to table 1 compositions) on the Hata tablet machine of the part instrument that is equipped with that is 15RPM in turntable speed by the RDT tablet formulation product of the tenofovir that contains Ex.1A, Ex.1B and Ex.1C (TFV) RD microgranule.Half of rapid dispersion microgranule is filled in 0.25cu-ft V blender, then fills crospovidone, microcrystalline Cellulose (Avicel PH101), TFV RD granule and remaining half rapid dispersion microgranule, and blend 10min.Sodium stearyl fumarate (Pruv) through 35 mesh screens is added in compressed mixture and blend 2min.Hata tablet machine is arranged under manual pattern for reaching the hardness of filling weight and the 10-50N of 150mg.Once arranged, tablet machine under ' automatically ' pattern with 3,4 and the compression stress operation of 5kN.For each compression stress, collect tablet under stable state with test weight, thickness, hardness and fragility.The meansigma methods of testing for each tablet batch is presented in table 1.For formula Ex.1AD(TFV RDG:Ex.1A), formula Ex.1BD(TFV RDG:Ex.1B) and formula Ex.1CD(TFV RDG:Ex.1C) tenofovir RDT tablet batch, according to the disintegration time of the USP method <701> test for DT, be respectively 60-90 second, 30-60 second and 30-60 second.When by USP method <701> when test, the RDT observing at these preparations of 4kN lower compression is in 30-60 disintegrate in second, and when test dissolving in test tube, at least 80% dissolves in 30min.
Table 1: tenofovir RDT compositions
Figure BDA0000425444130000211
example 2
a: the RD microgranule that comprises tenofovir:
Sodium bicarbonate (67.5g) is added in the pure water (2010g) in rustless steel container lentamente, is constantly stirred to dissolving simultaneously.The pH value of bicarbonate solution is through being measured as approximately 6.8.When stirring, add lentamente hypromellose (methylcellulose; 62.5g) to dissolving; Then add tenofovir (190g) to dissolving.The mannitol (890g) that removes caking is filled to pre-warmed Glatt GPCG3 and fluidisation.In spray charging and when procedure parameter being held under following condition, prepare quick soluble particles: product temperature-34 ℃ ± 1 ℃; Fluidisation air-flow-5 are to 15CFM; Spray speed-4-16mL/min.After spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.
b: the RD microgranule that comprises tenofovir:
Sodium bicarbonate (57g) is added into lentamente in the mixture of ethanol (540g) in rustless steel container and pure water (1260g), is constantly stirred to dissolving simultaneously.The pH value of bicarbonate solution is through being measured as approximately 6.2.Subsequently, add tenofovir (200g) to dissolving, then when stirring, add low replacement hydroxyethyl-cellulose (L-HEC; 20g) to dissolving.The mannitol (1023g) that removes caking is filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is prepared by spray solution under the following conditions: product temperature-34 ℃ ± 1 ℃; Fluidisation air-flow-4CFM; Spray speed-8-12mL/min.After spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.
c: the RD microgranule that comprises tenofovir:
Sodium bicarbonate (54g) is added into lentamente in the mixture of ethanol (540g) in rustless steel container and pure water (1260g), is constantly stirred to dissolving simultaneously.The pH value of bicarbonate solution is through being measured as approximately 6.15.Subsequently, add tenofovir (200g) to dissolving, then when stirring, add low replacement hydroxyethyl-cellulose (L-HEC; 30g) to dissolving.The mannitol (1023g) that removes caking is filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is to prepare by the spray solution disclosed in above step example 2B.After spray finishes, by the dry weightlessness of RD microgranule by weight approximately 1.5%.
d: tenofovir RDT:
By the RDT tablet formulation product of the tenofovir that contains Ex.2B and Ex.2C (TFV) RD microgranule (formula Ex.2BD and formula Ex.2CD), in compression stress, be compression (referring to the compositions in table 2) on the Hata tablet machine of 4kN and the turntable speed part instrument that is equipped with that is 15RPM.When operation beginning, centre and end, collect sample for the tablet character of test process.Result is presented in table 2.The in the situation that of formula Ex.2AD, with Carver forcing press, carry out compressed tablets.
Table 2: tenofovir RDT compositions
*-use Carver forcing press compressed tablets.
e: in the single and multiple dose PK of the tenofovir RDT of rabbit medial vagina administration research:
The object of this research is to evaluate the single dose of administration fast dissolving tablet agent form in the doe of the minimum body weight of 2.5KG or the pharmacokinetics (n=6 in each group: in the 1st group and the 3rd group of the tenofovir after seven every daily doses, after the 1st day or administration in the 7th day 0,0.5,1,2,4,8 and 24hr blood sampling, in the 2nd group and the 4th group, after the 1st day or administration in the 7th day 0,0.5,1.0,1.5 and 2hr blood sampling).Before administration test article, via subcutaneous administration, come administration acepromazine maleate (0.3-0.5mg/kg or until onset) moderately to make animal calm.Once calm, with 18 conduits, single tablet is inserted in the abdominal part vagina of each animal (about 8cm).Do not use lubricatedly, because this can affect tablet, absorb.During studying, carry out the detailed clinical examination of each animal every day.Observed result is including, but not limited to assessment skin, fur, eyes, ear, nose, oral cavity, thoracic cavity, abdominal part, outside genitals, extremity and foot, breathing and cyclical effect, for example, from main effect (sialorrhea), nervous system effect, comprise tremble, twitch, for reaction and the atypical behavior of touch.For the 1st group and the 3rd group 2hr or for the 2nd group and the 4th group of 24hr after administration after the 1st day or administration in the 7th day, the program of using veterinary pathologist to check and approve under yellow light, gives euthanasia or in each predetermined all animal complete that give euthanasia while cuing open inspection, cuts open inspection according to current SOP for found dead, when dying.Under yellow light, collect ilium lymph node for determining total tenofovir concentration.By by each
Figure BDA0000425444130000242
sponge is positioned in vagina prepares from the secretions of vagina to absorb
Figure BDA0000425444130000243
sponge sample, for determining total tenofovir concentration.
Gu by single tenofovir RDT(2 illustrate, the RDT of Ex.2CD) insert average tenofovir plasma concentration-time graph afterwards in doe vaginal canal, and Fig. 3 illustrates multiple dose (totally 7 administrations once a day) administration corresponding tenofovir concentration afterwards.。Fig. 4 illustrates single tenofovir RDT is inserted after doe vaginal canal after administration to 2 and the abdominal part of 24hr and average free and total tenofovir content of vagina tissue, and Fig. 5 illustrates the corresponding tenofovir concentration after multiple dose (totally 7 administrations once a day) administration.After Fig. 6 illustrates single tenofovir RDT is inserted to doe vaginal canal, after administration 2 and 24hr
Figure BDA0000425444130000251
in average administration before and tenofovir concentration after administration, and Fig. 7 illustrates after multiple dose (7 administrations once a day) administration in corresponding administration before and administration after tenofovir concentration.
For the further clinical front relatively PK research that gives the rabbit that 40mg fast dissolving tablet agent (four 10mg tablets) contrast gives 40mg l% tenofovir gel (4mL), point out, compare with 1%TFV gel, fast dissolving tablet agent form provides tissue concentration of equal value.Be different from the gel dosage form that need to use vagina applicator and follow packing, fast dissolving tablet agent technology is having a great attraction it aspect increase portability and potential reduction manufacturing cost.Extraly, this technology provides privacy and the convenience of drug administration.
example 3
a: the RD microgranule that comprises tenofovir:
By tenofovir (TFV; 829.2g), mannitol (has the Pearlitol25 that is less than 30 μ m mean diameters; 7829.2g), hydroxyethyl-cellulose (NITROSOL-HEC250L:91.6g) and crospovidone (200g) are filled in high shear granulator GMX-25.The content of product feed basin is fully mixed 2 minutes with the impeller speed being set under 150RPM.By the spray speed spray pure water with about 100g/min under following procedure parameter, make mixture of powders granulation: nozzle bore-0.085 "; Impeller arranges: speed-325RPM, time-5.5min; Chipper arranges speed-height, time-5.5min.After 5 minutes, stop spray, allow to make granule to continue again to mix 30 seconds, then stop granulator, and shovel is scraped feed basin, chopper blade and impeller blade.Continue spray to spray about 630g water and again by the contents mixed of product feed basin 2 minutes, then to discharge the content of product feed basin.In the product feed basin of pre-warmed Glatt GPCG5, fill moist granule, it is dry at 85 ℃, and loss on drying is less than 2%, as used Computrac moisture analyzer to determine.Drying condition in Glatt is as follows: product support screen-200 sieve mesh; Enter air themperature-42 ℃; Enter volume of air-40cfm; Desiccant wheel-startup.
b: the RD microgranule that comprises emtricitabine:
Emtricitabine (FTC, 682.9g) is added into lentamente in the mixture of ethanol (3974g) in rustless steel container and pure water (995g), is constantly stirred to dissolving simultaneously.Subsequently, when stirring, add low replacement hydroxyethyl-cellulose (Natrosol HEC-250L; 80.1g) to dispersed/dissolved.The mannitol (2737g) that removes caking is filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is prepared by spray solution under the following conditions: product support screen-200 sieve mesh; Jet size-1.2mm; Atomizing pressure-2 bar; Enter air themperature-72 ℃; Product temperature-38 ℃ ± 1 ℃; Fluidisation air-flow-40cfm; Spray speed-40mL/min; Desiccant wheel-startup.When spray finishes, by FTC RD microgranule to be set in 42 ℃ enter under air themperature dry, loss on drying by weight approximately 1%.
C. RDT（40-mg?TFV/40-mg?FCT）
By contain separately or the TFV RD microgranule of Ex.3A of its mixture and the RDT tablet formulation product of the FCT RD microgranule of Ex.3B first with the other drug excipient blend that comprises lubricant sodium stearyl fumarate, and in compression stress, be compression (referring to table 3 compositions) on the β tablet machine of 4-6kN and the turntable speed part instrument that is equipped with that is 15RPM.At each run, start, middle and collect sample with the tablet character in test process while finishing.
For 40mg TFV/40mg FCT RDT, by being equipped with eight (8) the individual 12mm that there is no embossing Manesty β forcing press circular, sugar-tablet instrument, be arranged to following parameter:
Tablet weight: total (10)-5.00g; Nominal: 500mg; Scope: 460-540mg
Filling weight arranges: 8mm(or for TFV, be 6mm); Precommpression arranges: 6mm
Main compression: 3.3mm(or for TFV, be 2.85mm) forced feeder setting: 3.
Setting pressure machine, to move under 25rpm and after mould table/turntable rotation several times, collect 10 tablets, then stops forcing press.Collect ten tablets for determining the weight of 10 tablets, and check tablet appearance (threshing, to lid, etc.).Regulate tablet machine if desired to produce to meet the tablet of the above listed standard about weight, thickness and hardness, and by outcome record in production batch record.If needed, readjust if desired parameter to produce the tablet that meets fragility standard listed above.
At process operation, start, middle and while finishing, 35 (35) tablets samplings are used for to the process of carrying out and test.Weight, hardness and the thickness of ten tablets of test, and the fragility of test 6.5g tablet.By outcome record on production batch record.All the other samples combine the part as composite sample in the container of suitable labelling.In each process, the independent container of test point utilization is for analytical test.
Use similar setting, the rapid disintegration tablet of 40-mg TFV/20-mg FCT, 20-mg TFV/40-mg FCT, 40-mgTFV or 40-mg FCT is compressed from its corresponding compressed mixture.
Table 3:RDT compositions (40mg TFV; 40mg FCT; 40mg TFV/40mg FCT; 40mg TFV/20mg FCT; 20mg TFV/40mg FCT)
Figure BDA0000425444130000271
example 4
a: the RD microgranule that comprises metronidazole:
By vinylpyrrolidone/vinyl acetate copolymer (for example,, from BASF AG
Figure BDA0000425444130000272
vA64; 50g) be added into lentamente ethanol in rustless steel container and the mixture of pure water, be constantly stirred to dissolving simultaneously.Subsequently, when stirring, add metronidazole (180g) to dissolving.The mannitol (770g) and the crospovidone (50g) that remove caking are filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is prepared by spray solution under the following conditions: product temperature-34 ℃ ± 1 ℃; Fluidisation air-flow-4CFM; Spray speed-8-12mL/min.After spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.
b: the RD microgranule that comprises clotrimazole:
Hydroxyethyl-cellulose (50g) is added into lentamente in the mixture of ethanol in rustless steel container and pure water, is constantly stirred to dissolving simultaneously.Subsequently, when stirring, add metronidazole (180g) to dissolving.The mannitol (720g) and the crospovidone (50g) that remove caking are filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is prepared by spray solution under the following conditions: product temperature-34 ℃ ± 1 ℃; Fluidisation air-flow-4CFM; Spray speed-8-12mL/min.After spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.
c: the RD microgranule that comprises Propranolol HCl:
By vinyl pyrrolidone-VA (for example,, from BASF's vA64; 50g) be added into lentamente the pure water in rustless steel container, be constantly stirred to dissolving simultaneously.Subsequently, when stirring, add the non-specific beta blocker Propranolol HCl(240g that represents extensive liver metabolism) to dissolving.The mannitol (560g) and the low replacement hydroxyethyl-cellulose (50g) that remove caking are filled to pre-warmed Glatt GPCG3 and fluidisation.RD microgranule is prepared by spray solution under the following conditions: product temperature-38 ℃ ± 2 ℃; Fluidisation air-flow-10CFM; Spray speed-10-20mL/min.After spray finishes, RD microgranule is dry, loss on drying by weight approximately 1%.。
d. the RDT that comprises metronidazole, clotrimazole or Propranolol HCl
By the metronidazole RD microgranule of the Ex.4A that contains aequum, the clotrimazole RD microgranule of Ex.4B, or the Propranolol HCI RD microgranule of Ex.4C, the rapid dispersion microgranule from above-mentioned Ex.1D of 5%-15% by weight, microcrystalline Cellulose (the Avicel PH101 of 5%-15% by weight), the low-substituted hydroxypropyl cellulose of 2%-5% by weight, (the RDT tablet of 1% sodium stearyl fumarate is filled a prescription Ex.4AD: metronidazole RDT by weight, formula Ex.4BD: clotrimazole RDT, with formula Ex.4CD: general medicine Luo Er HCI RDT) on the Hata tablet machine that is equipped with suitable instrument under different compression stresses and different turntable speed, compress.When operation beginning, centre and end, collect sample for the tablet properties of test process, thereby confirm the robustness of the manufacture process of every kind of tablet formulation product.
Technical staff will recognize, said procedure and compositions can suitably revise to provide one or more medicines of the desirable suitable dosage of fast dissolving tablet agent preparation of vagina administration.
Although the present invention has been combined in this specific embodiment and has been described, but will understand, it can further be revised, and the application is intended to cover and of the present inventionly conventionally follows principle of the present invention and comprise any version, application or the reorganization from this type of deviation of this disclosure, these deviations oneself of technology under the present invention know or conventional practice within the scope of, and go for the basic feature as above illustrating and occur as follows within the scope of accessory claim.
For all objects, the All Files of quoting at this, patent, patent application and publication are all incorporated in full by reference with it.

Claims (23)

1. for a pharmaceutical composition for the quick soluble particles form of vagina administration, comprise:
(a) the vagina active medicine of a treatment effective dose;
(b) a kind of have serve as binding agent together with the polymeric excipient of the double attribute of bioadhesive material;
(c) a kind of sugar alcohol, sugar or its mixture; With
(d) a kind of disintegrating agent;
The quick disintegrate when inserting patient or experimenter's vaginal canal of wherein said pharmaceutical composition, forms the viscous suspension that contains medicine, fast, diffusion widely, and coating vaginal mucosa.
2. pharmaceutical composition as claimed in claim 1, wherein said treatment active drug is selected from lower group, this group is comprised of the following: antifungal, antibacterial agent, antimicrobial, antiviral agent, anti-infective, spermicide, steroid, hormone, analgesics (comprising NSAID (non-steroidal anti-inflammatory drug)), cardiovascular agents, calcium channel blocker, Beta receptor blockers, antiarrhythmic drug, antihypertensive drug, diuretic, generally, crown, around with cerebral blood vessel expander, migraine agent, erection disturbance agent, central nervous system stimulant, tranquilizer, hypnotic, immunosuppressant, muscular flaccidity agent, the Orally active medicine that represents remarkable first pass effect, beta-adrenaline excitant, tranquilizer, antioxidant, vitamin, anti-trichomonal agent, antiprotozoan agent, anti-mycoplasma agent, antiretroviral agent, nucleoside analog, reverse transcriptase inhibitors, protease inhibitor, contraceptive, sulfa drugs, sulfonamide, sulfone, peptide, albumen, growth hormone, and luteinising hormone-releasing hormo, or its mixture or combination.
3. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitor (A Lita shore (apricitabine), Entecavir, emtricitabine, tenofovir, Abacavir (abacavir), adefovirdipivoxil, nevirapine, Delavirdine, efavirenz, UC-781, MKC-442, quinoxaline HBY097, DMP266, indinavir, amprenavir, Prezista, Lip river is for that Wei (lotinavir), viracept see nelfinaivr, ritonavir, Sai Kuinawei (sequinavir), atazanavir, tipranavir (tipranavir), dust is for drawing Wei (elvitegravir), and MK-2048, or its pharmaceutically acceptable salt, prodrug, or its mixture or combination.
4. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is a kind of antifungal that is selected from lower group, and this group is comprised of the following: butoconazole enzyme rhzomorph processed (butoconazolenystatin), oxiconazole, fluconazol, posaconazole, clotrimazole and ketoconazole or its pharmaceutically acceptable salt or its mixture or combination.
5. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is a kind of antibacterial agent that is selected from lower group, and this group is comprised of the following: clindamycin, sulfonamide, erythromycin, clarithromycin, azithromycin, doxycycline, metronidazole, macrolide antibiotics, quinolones, cephalosporin, cefoxitin and ceftriaxone or its mixture or combination.
6. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is a kind of antiviral agent that is selected from lower group, this group is comprised of the following: penciclovir, acyclovir, ganciclovir (genciclovir) and valaciclovir, or its mixture or combination.
7. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is a kind of cardiovascular agents that is selected from lower group, and this group is comprised of the following: verapamil, Propranolol, metoprolol, diltiazem, isradipine, felodipine, nifedipine and nicardipine or its mixture or combination.
8. pharmaceutical composition as claimed in claim 2, wherein said treatment active drug is a kind of NSAID (non-steroidal anti-inflammatory drug) that is selected from lower group, and this group is comprised of the following: aspirin, ibuprofen, indomethacin, sulindac, naproxen and nabumetone (nebumetone) or its mixture or combination.
9. pharmaceutical composition as claimed in claim 1, further comprise that at least one is selected from the surfactant of lower group, this group is comprised of the following: DL-alpha tocopherol, CAPTEX200, polysorbas20 Tween 80, vitamin E TPGS, Capryol90, CREMOPHOR EL, CARBITOL, PEG400, lecithin, BRIJ92, LABRASOL, glyceryl triacetate, sodium lauryl sulfate, ethylene glycol monostearate, polysorbate
Figure FDA0000425444120000031
Figure FDA0000425444120000032
lauryl sodium salicylate and sodium lauryl sulphate or its mixture.
10. pharmaceutical composition as claimed in claim 1, further comprise that at least one is selected from the lipid of lower group, this group is comprised of the following: the mixture of lecithin, hydrolecithin, LYSOLECITHIN SUNLECITHIN A, hydrogenation LYSOLECITHIN SUNLECITHIN A, lysophosphatide and its derivant, phospholipid and its derivant, alkyl sulfate, soap, docusate sodium, stearyl alcohol, palmitostearate, monoglyceride, diester and three esters, PEG monoesters and diester and PEGylation or its mixture.
11. pharmaceutical compositions as described in any one in claim 1-10, further comprise a rapid dispersion Particle Swarm, these microgranules have separately and are not more than the mean diameter of approximately 400 μ m and comprise (1) a kind of disintegrating agent and (2) a kind of sugar alcohol or sugar, and wherein said sugar alcohol or sugar have the mean diameter that is not more than approximately 30 μ m separately.
12. pharmaceutical compositions as claimed in claim 11, wherein contain the scope of the quick soluble particles of medicine and the ratio of rapid dispersion microgranule from about 50:1 to about 1:2.
13. pharmaceutical compositions as claimed in claim 11, wherein these rapid dispersion microgranules comprise a kind of disintegrating agent that is selected from lower group, and this group is comprised of the following: crospolyvinylpyrrolidone, Explotab, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose or its mixture.
14. pharmaceutical compositions as claimed in claim 11, wherein these rapid dispersion microgranules comprise a kind of sugar alcohol that is selected from lower group, and this group is comprised of the following: 1,2,3,4,5-pentanepentol, erythritol, glycerol, hydroxyl isomaltulose, lactose, maltose alcohol, mannitol, Sorbitol and xylitol or its combination.
15. pharmaceutical compositions as described in any one in claim 1 to 10, be further defined as a kind of fast dissolving tablet agent, when testing by USP method <701> disintegration time, this fast dissolving tablet agent disintegrate in approximately 60 seconds.
16. pharmaceutical compositions as claimed in claim 15, be further defined as a kind of fast dissolving tablet agent, this fast dissolving tablet agent comprises the described rapid dispersion microgranule with the mean diameter that is not more than approximately 400 μ m, this fast dissolving tablet agent further comprises disintegrating agent and sugar alcohol or sugar or its combination, have separately the mean diameter that is not more than approximately 30 μ m, wherein said fast dissolving tablet agent shows following characteristic:
I) be not more than by weight 1% fragility; With
Ii) be applicable to being packaged in vesicle or bottle for storing, transportation, commercial distribution and final enough tablet hardnesses of using.
17. 1 kinds of methods for the preparation of pharmaceutical composition claimed in claim 1, comprising:
A) prepare quick soluble particles, these quick soluble particles comprise:
I. at least one is selected from the treatment active drug of lower group, this group is comprised of the following: antifungal, antibacterial agent, antimicrobial, antiviral agent, anti-infective, spermicide, steroid, hormone, analgesic comprises NSAID (non-steroidal anti-inflammatory drug), cardiovascular agents, calcium channel blocker, Beta receptor blockers, antiarrhythmic drug, antihypertensive drug, diuretic, generally, crown, around with cerebral blood vessel expander, migraine agent, erection disturbance agent, central nervous system stimulant, tranquilizer, hypnotic, immunosuppressant, muscular flaccidity agent, the Orally active medicine that represents remarkable first pass effect, beta-adrenaline excitant, tranquilizer, antioxidant, vitamin, anti-trichomonal agent, antiprotozoan agent, anti-mycoplasma agent, antiretroviral agent, nucleoside analog, reverse transcriptase inhibitors, protease inhibitor, contraceptive, sulfa drugs, sulfonamide, sulfone, peptide, albumen, growth hormone, and luteinising hormone-releasing hormo, or its mixture or combination,
Ii. at least one selects sugar alcohol, sugar or its mixture of the group of free mannitol composition; With
Iii. be selected from the polymeric excipient of lower group, this group is comprised of the following: low replacement ethoxy seals dimension element, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polycarboxylic acids, polyvinylpyrrolidone, vinyl pyrrolidone-VA, ethylene glycol 6000-caprolactam-vinyl acetate copolymer, polyvinyl alcohol, poly(ethylene oxide), poly-(lactic-co-glycolic acid), polyamide, alginate, carrageenin, chitosan and cellulose gum.
18. methods as claimed in claim 17, the method further comprises:
B) prepare rapid dispersion microgranule, these rapid dispersion microgranules comprise:
I. at least one is selected from sugar alcohol, sugar or its mixture of lower group, and this group is comprised of the following: 1,2,3,4,5-pentanepentol, erythritol, glycerol, hydroxyl isomaltulose, lactose, maltose alcohol, mannitol, Sorbitol and xylitol or its combination; With
Ii. at least one is selected from lower group of disintegrating agent, and this group is comprised of the following: crospolyvinylpyrrolidone, Explotab, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose or its mixture; Ratio with 90:10 to 99:1;
C) by the quick soluble particles from step a), carry out blend from the rapid dispersion microgranule of step b) and the pharmaceutically acceptable excipient that at least one is selected from lower group, this group is comprised of the following: filler, disintegrating agent and lubricant, these filleies, disintegrating agent and lubricant are selected from lower group, and this group is comprised of the following: microcrystalline Cellulose, crospovidone, low-substituted hydroxypropyl cellulose, magnesium stearate and sodium stearyl fumarate; With
D) via on rotary tablet machine compression by c) product be compressed into fast dissolving tablet agent; Quick disintegrate when wherein this fast dissolving tablet agent is in inserting the vagina it is had to the patient that needs or experimenter, forms the viscous suspension that contains medicine, fast, diffusion widely, and coating vaginal mucosa.
19. methods as described in claim 17 or 18, the method further comprises:
A) preparation comprises following quick soluble particles: tenofovir, mannitol, low replacement hydroxyethyl-cellulose and optionally crospovidone and bioadhesion chitosan;
B) will there is separately the mannitol of the mean diameter that is not more than approximately 30 μ m and crospovidone granulation to produce rapid dispersion microgranule;
C) by the quick soluble particles from step a), carry out blend to form blend from the rapid dispersion microgranule of step b) and microcrystalline Cellulose, crospovidone and sodium stearyl fumarate; With
D) use rotary tablet machine that the blend of step c) is compressed into fast dissolving tablet agent; Wherein, when testing by USP method <701> disintegration time, every kind of fast dissolving tablet agent disintegrate in approximately 60 seconds.
20. methods as described in claim 18 or 19, wherein step d) further comprises and uses rotary tablet machine that the blend of step c) is compressed into fast dissolving tablet agent, this rotary tablet machine be equipped with external lubrication system so as before compressing, to make mould together with magnesium stearate and drift lubricated.
21. methods as claimed in claim 19, wherein step a) further comprises that preparation comprises emtricitabine, mannitol, low replacement hydroxyethyl-cellulose and the quick soluble particles of crospovidone and bioadhesion carbomer optionally, so that preparation contain tenofovir and the emtricitabine of treat effective dose fast dissolving tablet agent, for to it is had needs patient or experimenter's vagina administration.
22. 1 kinds of methods, the method comprises the pharmaceutical composition as described in claim 1,9,15 or 16 that contains treatment effective dose medicine is administered into it is had in the patient of needs or experimenter's vagina.
23. methods as claimed in claim 22, further comprise and by containing, treat the tenofovir of effective dose and the Pharmaceutical composition as described in claim 1,11,15,16 or 17 of emtricitabine is administered in patient or experimenter's vagina, be used for the treatment of HIV and infect.
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