WO2005087270A1 - Compositions anti-vaginite comprenant un triazole - Google Patents
Compositions anti-vaginite comprenant un triazole Download PDFInfo
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- WO2005087270A1 WO2005087270A1 PCT/GB2004/003972 GB2004003972W WO2005087270A1 WO 2005087270 A1 WO2005087270 A1 WO 2005087270A1 GB 2004003972 W GB2004003972 W GB 2004003972W WO 2005087270 A1 WO2005087270 A1 WO 2005087270A1
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- vaginitis
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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
- A61K31/33—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
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- 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
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
Definitions
- ANTI-VAGINITIS COMPOSITIONS This invention concerns novel pharmaceutical compositions for combating primary and/or secondary vaginal infections.
- the invention is concerned with the treatment of mixed vaginal infections, e.g. the treatment of acute and recurrent vulvovaginal candidiasis, bacterial vaginosis, trichomonal vaginitis and/or their causative agents.
- Vaginitis is most often caused by infection with Candida albicans, Trichomonas vaginalis or Gardnerella sp, either singly or mixed.
- Certain derivatives of imidazole and nitroimidazole are known to have anti- fungal, anti-bacterial and/or anti-protozoal activity and are often used to treat such conditions.
- compositions for topical administration are widely known and used for treating vaginal infections. Such compositions may contain only a single active ingredient, e.g. metronidazole, however those containing two or more active ingredients are generally considered more suitable for the treatment of mixed infections.
- Topical formulations which contain a combination of actives are, for example, described in WO 97/44032 and include combinations such as metronidazole and miconazole nitrate .
- combinations such as metronidazole and miconazole nitrate .
- the invention thus provides a pharmaceutical composition for topical administration comprising at least one triazole compound active against Candida albicans, preferably at least one such compound which is additionally active against one or more non-albicans Candida species, in combination with at least one additional anti-vaginitis medicament.
- the composition should include at least one triazole compound active against Candida albicans .
- non-albicans Candida species are now thought to make up as much as 20% of fungal infections, it is preferred that such compounds should also be effective against at least one non-albicans Candida species.
- the advantage of formulations containing such compounds is that these are effective in treating a wider range of infections regardless of their causative agents .
- Other Candida species commonly associated with vaginal infections include Candida Galbra ta , Candida parapsilosis, Candida tropicalis , Candida lusi taniae, Candida krusei , Candida dubliniensis and Candida neoformans and it is desired that the triazole agent should be active against one or more of these species, in addition to exhibiting activity against Candida albi cans .
- the triazole compound may be used in the form of the free base or as a pharmaceutically acceptable salt, for example the nitrate .
- suitable triazole compounds for use in the invention include terconazole, itraconazole, fluconazole, voriconazole and ravuconazole . Of these, terconazole is preferred. It has a particularly broad spectrum of activity and has been shown to be effective against Candida albicans, Candida glabrata, Candida parapsilosia , Candida tropical is , Candida pseudotropicalis , Candida stellatoidea and Candida lusi taniae .
- Terconazole has the further advantage that this does not kill useful lactobacillus microorganisms which form part of a healthy vaginal flora.
- the use of a second anti-vaginitis medicament according to the invention also provides for a broader spectrum of activity against vaginal infections.
- This medicament may be any agent suitable for topical application in the treatment of vaginitis. Typically, this will exhibit anti-fungal, anti-bacterial or anti- protozoal properties (or any combination of these) .
- the presence of a second medicament or combination of medicaments active against Candida albicans and/or Trichomonas vaginalis and/or Gardnerella sp . is particularly preferred.
- Preferred formulations in accordance with the invention are those comprising at least one triazole compound as herein described, together with at least one anti-vaginitis medicament selected from the group consisting of the following agents: (a) an anti-fungal compound, in particular an anti-fungal imidazole; (b) an anti-protozoal compound, preferably a compound having both anti-protozoal and antibacterial activity, e.g. a nitroimidazole; and (c) an anti-bacterial agent.
- Anti-fungal compounds suitable for use in the invention include griseofulvin, nystatin, polymixin B, terbinafin and atovaquone (Meprone) .
- Preferred anti- fungals are the imidazoles and pharmaceutically acceptable salts thereof.
- Suitable fungicidally active imidazole compounds include those active against Candida albicans such as tioconazole, butoconazole, miconazole (e.g. miconazole nitrate), ketoconazole, clotrimazole, isoconazole, seperconazole, econazole, oxiconazole and sulconazole.
- Particularly preferred for use in the invention are tioconazole or butoconazole . These agents may also be used in the form of their pharmaceutically acceptable salts.
- Anti-protozoal agents for use in the invention include Paromomycin, Diclazuril (Clinacox) and Letrazuril .
- Preferred anti-protozoals are those which are known to be active against Trichomonas vaginalis .
- Particularly preferred anti-trichomonal drugs are those which also have anti-bacterial activity, in particular against Gardnerella sp and other pathogens capable of causing vaginitis, e.g. anaerobic bacteria, group B and D streptococcus and/or pathogens causing other primary or secondary vaginal/genital infections.
- anti-protozoal agents examples include tinidazole, metronidazole, ornidazole, secnidazole and nimorazole. Tinidazole is particularly preferred. These agents may also be used in the form of their pharmaceutically acceptable salts.
- the anti-bacterial agent for use in the invention is preferably one which is active against Gardnerella sp and other pathogens capable of causing vaginitis, e.g. anaerobic bacteria, group B and D streptococcus and/or pathogens causing other primary or secondary vaginal/genital infections. Broad spectrum antibiotics such as pivampicillin or clindamycin may usefully be included.
- Suitable anti-bacterial agents include chlorquinaldol, diiodohydroxyquinoline, chloramphenicole and spiramycin (rovamycin) .
- Especially preferred formulations according to the invention are those comprising two active medicaments, i.e. a single triazole compound in combination with one additional anti-vaginitis medicament (preferably an anti-fungal or anti-protozoal compound) .
- these may comprise terconazole (triazole) in combination with tioconazole, butoconazole, tinidazole, metronidazole or ornidazole .
- the invention is particularly concerned with the use of a combination of terconazole (anti-fungal) and tinidazole (anti-protozoal and antibacterial) .
- Combinations of two or more (e.g. three or four, preferably three) active agents may also be used in the formulations herein described. These may include, for example, a single triazole compound together with an anti-fungal (e.g. an anti-fungal imidazole) and an anti- protozoal (e.g. an anti-protozoal nitroimidazole) .
- an anti-fungal e.g. an anti-fungal imidazole
- an anti- protozoal e.g. an anti-protozoal nitroimidazole
- One example of such a combination is that comprising terconazole, tioconazole and tinidazole.
- the quantity of active medicaments may be readily determined by those skilled in the art and will depend " on several factors, including the nature of the medicaments and of any other non-active components, the method of application, etc.
- the triazole derivative (s) e.g. terconazole
- Terconazole may be used in amounts of from 0.1 to 5.0% by weight, preferably from 0.4 to 1.6% by weight, e.g. about 0.8 wt . % .
- Terconazole is conveniently used in amounts of from 50 to 250 mg, preferably 50 to 200 mg, per pessary (in an overall pessary weight of 2500 mg) , more preferably from 50 to 150 mg and suitably about 80 mg.
- the second anti-vaginitis medicament (s) may be present in a total amount of from 0.5 to 10% by weight, preferably from 1 to 6% by weight, e.g. about 3 wt . % .
- Tinidazole is conveniently used in amounts of from 50 to 500 mg per pessary (in an overall pessary weight of 2500 mg) , more preferably from 100 to 200 mg and suitably about 150 mg.
- Tioconazole may be used in similar amounts, e.g. about 100 mg (in an overall pessary weight of 2500 mg) .
- Particularly preferred combinations of agents for use in the invention are those which demonstrate enhanced (e.g.
- Synergism is considered to include any one of the following: an unexpectedly faster cure rate, cure time or symptom improvement (i.e. improvement in at least one sign or key symptom of vaginitis) ; a reduction in the relapse rate of any given type of vaginitis (i.e. the rate of reappearance of the infection after cessation of the medicament) ; a broader spectrum of activity; fewer and/or reduced local or systemic side effects; and reduced toxicity associated with the use of the combined formulation compared to the expected additive effect of each individual active ingredient.
- the invention thus provides formulations as herein described in which the active agents are present in synergistically effective amounts .
- the weight ratio of triazole compound (s) to the second anti-vaginitis medicament (s) will generally be in the range of from 1:10 to 1:0.2, preferably from 1:10 to 1:0.5, e.g. about 1:2.
- a further advantage associated with the use of the combination of actives herein described is that these are believed to slow down the development of resistance against at least one of the active agents present in the formulations .
- a lowering of the dose of one or more of the actives may advantageously be achieved using the combinations herein described.
- anaesthetics include aptocaine, bupivacaine, butanilicaine, carticaine, cinchocaine, clibucaine, ethyl parapiperidinoacetyl- aminobenzoate, etidocaine, lidocaine (lignocaine) , mepivacaine, oxethazaine, prilocaine, pyrrocaine, ropivacaine, tolycaine, vadocaine, benzocaine, pramoxine and mixtures' thereof .
- the anaesthetic may also be used in the form of a salt.
- the local anaesthetic may be used in an amount of 0.1-10.0% by weight, preferably 1.0-7.0%.
- the local anaesthetic is preferably lidocaine and may be used in the form of its free base (for example in an amount of 1.0-3.0%, by weight, preferably about 1.5%) or a salt such as its hydrochloride, for example 1.5-4.0% by weight, preferably about 2%.
- the use of the anaesthetic at these low concentrations results in the compositions being well tolerated.
- the compositions may be in the form of a pessary, gel, cream, tampon or foam containing the active medicaments.
- the compositions take the form of a pessary or cream.
- a conventional cream base may be used, e.g. containing oily or waxy materials such as liquid paraffin, white petroleum or cetyl alcohol, water and one or more surfactants to produce a water-in-oil emulsion.
- a bactericide such as benzalkonium chloride is conveniently present.
- pessaries these comprise a pessary base containing the active medicaments and any local anaesthetics.
- the pessary base may be of any conventional material for vaginal administration such as glycerol/gelatin glyco-gelatin, macrogols (polyethylene glycols), natural, synthetic or semisynthetic hard fats, and fractionated palm kernel oil .
- Preferred materials are hard fats which consist mainly of mixtures of the triglyceride esters of the higher saturated fatty acids along with varying proportions of mono- and diglycerides . Special grades may contain additives such as beeswax, lecithin, polysorbates, ethoxylated fatty alcohols and ethoxylated partial fatty glycerides .
- suitable hard fats include the range of products sold under the trade name Witepsol (e.g.
- compositions further include a surfactant to promote dispersal of the active components and to provide for continuous penetration of the active components into the mucosal folds.
- the surfactant may be a cationic, non-ionic, anionic or amphoteric surfactant although non-ionic surfactants are preferred.
- Anionic surfactants include salts of long chain alkyl sulphonate esters such as sodium lauryl sulphate, sodium cetostearyl sulphate and sodium tetradecyl sulphate; salts of long chain carboxylic acids such as stearates .
- Cationic surfactants include quaternary ammonium or pyridinium compounds such as benzalkonium chloride (a mixture of benzyl alkyl dimethyl chlorides, the alkyl chain ranging from C 8 to C 18 ) , tetradecyltrimethyl ammonium bromide and cetylpyridinium chloride.
- Amphoteric surfactants include lauryl 1-carboxy glycine and lecithins such as soya lecithin.
- Non-ionic surfactants include glycol and glycerol esters such as glyceryl monostearate; macrogol esters and ethers such as cetomacrogol; sorbitan and mannitan esters such as sorbitan tristearate; and polyoxyethylene derivatives of such sorbitan esters, for instance polyoxyethylene (20) sorbitan mono-oleate.
- the level of surfactant required in the pessary formulation will be readily determined by those skilled in the art and will depend on the specific surfactant and the nature of the pessary base; conveniently it is in the range 0.1 to 10 percent by weight, preferably 1 to 5 percent .
- One or more wound healing or skin protectant agents may also be present in the compositions. These may be selected from demulcents, absorbents and emollients and include dimethicone (demulcent) , allantoin (absorbent) , sucralfate and glycerin (absorbent, demulcent and emollient) . Examples of other suitable emollients include cocoa butter, white petrolatum and shark liver oil.
- Dimethicone has been found to be particularly advantageous in facilitating healing of the vaginal mucosa and is therefore particularly preferred for use in the formulations herein described. Since a film of dimethicone permits the passage of oxygen molecules, this effectively allows the skin to breathe whilst acting to repel water. Through this mechanism, dimethicone can exert its skin protective properties, thereby reducing maceration and damage to the vaginal mucosa. Due to its surface active properties, dimethicone is also believed to facilitate the spread of the active components around and into the folds of the vaginal mucosa where causative organisms of vaginitis tend to bury themselves (this is thought to be a significant factor in the high recurrence rates for vaginal infections) .
- the formulations might provide for delayed (sustained) release of one or more of the active agents. This may, for example, be achieved using any of the methods described in WO 97/44032, the entire contents of which are incorporated herein by reference.
- a preferred system may comprise a delayed (sustained) release agent which provides for continuous delivery of the active medicament (s) over time.
- the delayed (sustained) release of one or more of the active agents can be expected to affect, preferably reduce, the degree of systemic absorption of at least one active agent thereby providing reduction of any systemic side effect/toxicity profile. Dimethicone is particularly suitable for use in this regard.
- an anti-inflammatory and/or anti-pruritic agent such as hydrocortisone, hydrocortisone acetate, methylprednisolone acepronate, betamethasone valerate . , or the like, a weak topical steroid and/or chamomille.
- Boric acid and/or lactic acid may also advantageously be included as a further active ingredient and may be used to adjust the pH of the final formulation close to that found in the vaginal mucosa under normal physiological conditions, e.g. in the range 3.8 to 4.2.
- the compositions may also include chlorophyll as a deodorant.
- estrogens such as estriol, conjugated estrogens and promestrien.
- Anti-viral agents such as acyclovir, penciclovir, trifluridine, afovirsen, arildone, brivudine, 1-docosanol, edoxudine, ganciclovir, idoxuridine, moroxydine, tromantadine and valacyclovir may also be present.
- Conventional microbicides capable of preventing HIV and/or other sexually transmitted infections may also be included in the formulations herein described. Examples of such agents include those which disrupt or otherwise disable HIV, such as surfactants, e.g.
- menfegol menfegol, benzalkonium chloride, docosanol, C31G (Savvy, nonoxynol-9, sodium cholate) , polybiguanides, sodium dodecyl sulphate; antibiotics, e.g. gramicidin, magainins, defensins, protegrins; acidifying agents, e.g. Buffer Gel, Acidform, Lactobacillus crispatus; oxidising agents, e.g. chlorhexidine, povidone iodine, hydrogen peroxide/peroxidase gel; antibodies, e.g. anti-
- HIV antibodies e.g. cellulose acetate phthalate
- reverse transcriptase inhibitors e.g. UC-781, loviride, tenofovir
- agents which block HIV attachment/fusion such as long-chain anionic polymers, e.g. dextrin-2-sulphate, naphtalene sulphonate polymer (Pro 2000) , carrageenan, polystyrene sulphonate, cellulose sulphate, cellulose acetate phthalate, polymeric dimandelic acid ether (SAMMA)
- dendrimers e.g. SPL7013, HIV-binding peptides/proteins, e.g.
- compositions herein described may be formulated for rapid or delayed (sustained) release, or preferably both, of the local anaesthetic (s) .
- any suitable method such as those described in WO 97/44032, may be used to provide rapid and/or delayed release of this substance (s) .
- rapid and delayed (sustained) release may be achieved using a local anaesthetic in two or more different forms having different solubilities, for example in hydrophobic and hydrophilic forms.
- An anaesthetic such as lidocaine may, for example, be provided in both salt and free base forms which result in differing rates of release of the anaesthetic, thus providing both immediate and sustained action.
- Such compositions can for example contain 0.1- 3.5% (preferably about 2.0%) by weight of lidocaine HC1 and 0.1-3.0% (preferably about 1.5%) by weight of lidocaine.
- the total amount of lidocaine and its hydrochloride is preferably not more than 5% by weight.
- the relative amounts of the free base and the salt used can be varied depending on the nature of the pessary or cream base, in particular according to the lipophilic and hydrophilic properties of the base. However, in general the composition can contain 20-80% of the free base form of the anaesthetic and 80-20% of the salt form, on the basis of the total weight of the two forms.
- a lidocaine salt such as the hydrochloride can be included in a pessary base (e.g. a cocoa butter-based - Im ⁇
- the free base can be dissolved directly in the pessary base.
- Similar techniques can be used to include the anaesthetics in a cream formulation.
- the salt form can be mixed with the aqueous phase ingredients of the cream and the free base form with the oily phase ingredients .
- the two phases can then be mixed together to form a cream emulsion containing the two forms of the anaesthetic in the different phases.
- the release rate of the lidocaine from this phase can therefore be adjusted to enable a slow but continuous release of lidocaine from the oil phase.
- the hydrophilicity and the pH of the aqueous phase can be changed to vary the release of lidocaine from the aqueous phase. In this manner it is possible to tailor the release rate profiles of lidocaine from the two phases so that they complement each other, resulting in prolonged release of lidocaine from the cream base containing the emulsion of the two phases.
- the pharmaceutical compositions herein described may contain a bioadhesive agent, in particular a mucoadhesive agent, to promote adhesion and thus prolonged contact of the composition to the mucosa membranes, e.g. the vaginal epithelium.
- a bioadhesive agent in particular a mucoadhesive agent
- the formulations may remain attached to the epithelial surfaces for a period of at least about 24 hours.
- the use of a bioadhesive may also provide for controlled, e.g. delayed or sustained, release of the active agents from the formulation which can reduce the need for frequent administration.
- compositions containing a bioadhesive agent are novel and form a further aspect of the invention.
- the invention thus provides a pharmaceutical composition comprising at least one triazole compound active against Candida albicans , in combination with at least one additional anti-vaginitis medicament, wherein said composition further comprises at least one physiologically tolerable bioadhesive (e.g. a mucoadhesive) .
- Bioadhesive (i.e. mucoadhesive) agents which may be used in compositions of the invention may be natural or synthetic, polyanionic, polycationic or neutral, water- soluble or water-insoluble, but are preferably large (e.g.
- bioadhesives having a molecular weight of 500 to 3000 kDa, e.g. 1000 to 2000 kDa), water-insoluble cross-linked (e.g. containing 0.05 to 2%, e.g. 0.75 to 1.5% cross-linker by weight of the total polymer, prior to any hydration) , water-swellable polymers capable of forming hydrogen bonds.
- the bioadhesives have a mucoadhesive force greater than 100, especially preferably greater than 120, particularly greater than 150, as assessed according to the method of Smart et al . , 1984, J. Pharm. Pharmacol., 36, p295-299, expressed as a percent relative to a standard in vi tro .
- bioadhesives include, but are not limited to, poly (carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic, methoxyethyl methacrylic, methoxyethoxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters.
- poly (carboxylic acid-containing) based polymers such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic, methoxyethyl methacrylic, methoxyethoxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters.
- polymers examples include the EUDRAGIT ® polymers available from R ⁇ hm GmbH, Germany, in particular the EUDRAGIT ® grades for sustained release which are based on copolymers of acrylate and methacrylates with quaternary ammonium groups as functional groups as well as ethylacrylate methylmethacrylate copolymers with a neutral ester group. These polymers are insoluble and permeable and their release profiles can be altered by varying mixing ratios and/or film thickness.
- Suitable EUDRAGIT ® polymers include the EUDRAGIT ® RL-types which are highly permeable, the EUDRAGIT ® RS-types which are poorly permeable and the EUDRAGIT ® NE-types which are swellable and permeable. EUDRAGIT ® RL-types, e.g. EUDRAGIT ® RL-100, are preferred.
- cellulose derivatives may be used such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof, e.g. hydroxypropyl methyl cellulose-E15 (HPMC E-15) or Sodium carboxymethyl cellulose-H (Sodium CMC-H) .
- these may be used together with a plasticizer.
- Combinations of two or more cellulose derivatives may also be employed, for example HPMC E-15 and Sodium CMC-H.
- Other naturally occurring or synthetic polymers may also be used such as gums, e.g. acacia gums, xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psillium seed gum and gum arabic; clays such as manomorillonite clays, e.g.
- Veegum attapulgite clay
- polysaccharides such as dextran, pectin, amylopectin, agar,- carrageenan, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch
- lipophilic formulations containing polysaccharides e.g. Orabase (Bristol Myers
- carbohydrates such as polysubstituted with groups such as sulphate, phosphate, sulphonate or phosphonate, e.g. sucrose octasulphate; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan (chloride salt, lactate or glutamate) or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminium oxide; atherocollagen; polyvinyl polymers such as polyvinyl alcohols, polyvinylmethyl ethers, polyvinylpyrrolidone, polycarboxylated vinyl polymers (such as polyacrylic acid as mentioned above) ; polysiloxanes; polyethers; polyalkylene oxides and glycols, e.g.
- polyethylene oxides and glycols polyalkoxys and polyacrylamides and derivatives and salts thereof; polyglycolic and polylactic acid homopolymers and copolymers; glycolide and lactide copolymers, e.g. poly-L- (lactide co- glycolide) .
- the above described polymeric bioadhesives may also be cross-linked and may be in the form of copolymers. Where present, any cross-linking agent should be provided in an amount to provide sufficient bioadhesion, i.e. to allow the system to remain attached to the target epithelial surfaces for a sufficient time to allow the desired dosing to , take place.
- poly (acrylic acid) polymers or copolymers, e.g. with di- or poly functional allyl ethers or acrylates to make the polymer insoluble
- polyalkenyl polyether e.g., polyalkenyl polyether
- Appropriate bioadhesives having this form are available commercially (e.g. from Goodrich) as Polycarbophil, e.g. Noveon AA-1, Carbomer (Carbopol) , e.g.
- Chitosans are a class of preferred mucoadhesives for use in the invention. In addition to their bioadhesive properties, these also exhibit antifungal and antimicrobial effects. Their bioadhesive properties, due essentially to their molecular weight and salt type, can be varied by the use of cross-linking agents, e.g. tripolyphosphate (TPP) , dialdehydes, epichloridrine, etc. Hydrophilic pressure sensitive materials can provide high adhesive strength towards both dry and moistened substrates and are also suitable for use in the invention. The Corplex adhesive hydrogels are one example of such materials (see Controlled Release
- hydrogels make up the Corplex-100 series.
- Corplex- 200 series which are obtained by additional cross- linking of a film-forming polymer in the Corplex-100 hydrogels by a hydrophilic polymer that contains the complementary reactive groups in the repeating units of the backbone and forms an H-bonded interpolymeric complex.
- the polymeric bioadhesives herein described may be used in combination with additional excipients .
- plasticizers such as glycerol , propylene glycol, diethyl phthalate, dibutyl phthalate, etc., may be added.
- Preferred bioadhesives for use in the compositions of the invention are those which are able to release the active substances into the vaginal epithelium without affecting the normal vaginal flora and which cause minimal irritation. These include polyacrylic hydrogels, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, xanthan gum and chitosan. In situ-gelling mucoadhesive polymer vehicles may also be used in delivery of the pharmaceutical compositions herein described.
- One example of such a system is based on the use of Polycarbophil as a mucoadhesive polymer in combination with poloxamers which are used to confer in situ-gelling thermosensitivity to the system (see Controlled Release Society 30th Annual Meeting PROCEEDINGS, 2003: #902) .
- Such systems offer high vaginal retention and are described, for example, in US 2003/0091642 the contents of which are incorporated herein by reference .
- a preferred example of such a vehicle is that comprising Lutrol F127 in combination with Carbopol 5984.
- Glyceryl Monooleate behaves in a manner similar to certain polymers in that, in excess water it swells and forms a physically stable viscous gel that is capable of releasing a dissolved or dispersed active (drug) by slow diffusion. GMO has been classified as having moderate to excellent bioadhesive properties. Unswollen GMO has the greatest mucoadhesion, followed by the partly swollen lamellar phase and the fully swollen cubic phase. Glyceryl Monooleate-based systems are thus capable of undergoing an in-si tu transformation to a semi-solid system on contact with the vaginal mucosa and may therefore find use as a suitable bioadhesive in the compositions herein described.
- the drug release profile of GMO systems can be controlled by varying the surface-to-volume ratio, the drug loading, and the water content and by the addition of salt, glycerin, propylene glycol or any similar amphiphilic substance of low molecular weight.
- One drawback of using a GMO system based in the cubic phase can be its stiffness. In order to overcome this problem a solvent can be utilized.
- Another approach is the addition of a vegetable or animal oil . Both approaches can be used successfully for sustained release of biologically active materials such as those described herein.
- the GMO system provides good adhesion to mucosa and enables controlled release of the active medicaments from the formulation.
- GMO/water liquid crystalline gels may also be suitable for vaginal delivery of the drugs herein described.
- Thermoreversible gels which have a very low viscosity at ambient temperature (allowing them to be considered a liquid) and which are viscous at body temperature may also be used to deliver the compositions in accordance with the invention.
- the liquid form of such materials prior to application facilitates an even distribution on the vaginal mucosa whilst the more viscous form permits better adherence to the mucosa by limiting its flow.
- Poloxamers such as Lutrol F127 and Lutrol F68 are block copolymers that form thermoreversible gels and these are particularly suitable for use in the invention. These materials form gels which exhibit maximum viscosity in the range from 30 to 60 °C.
- the sol-gel transition temperatures and the viscosity of aqueous solutions vary with the concentration.
- gel viscosities ranging from 1200 to 2600 mPa at 37°C may be achieved.
- Gels formed from mixtures of Lutrol F127 and/or Lutrol F68 have the additional advantage that these exhibit no reduction in viscosity with increasing temperature over a wide range.
- Thermoreversible gels derived from starch may also be used in the formulations of the invention. Such materials may be derived from starch by enzymatic treatment, e.g. using glucosyltransferases such as phosphorylases or ⁇ -1, 4- ⁇ -l, 4 glucosyltransferases such as amylomaltase (AMase) .
- Controlled release includes rapid release as well as prolonged or sustained release.
- One way in which controlled release may be achieved is by appropriate selection of a bioadhesive, for example by selecting a bioadhesive which is capable of providing delayed (sustained) release of one or more components of the formulation.
- Bioadhesive systems suitable for use in this regard are generally known and described in the art and include, in particular, the polymeric bioadhesives herein described. Such systems can be adjusted to control the release rate of active by varying the amount of cross-linking agent in the polymer.
- a particularly preferred polymer for use in this regard is Polycarbophil which is commercially available from B. F. Goodrich under the tradename N0VE0N ® -AA1.
- Polycarbophil is a polyacrylic acid cross- linked with divinyl glycol .
- Solid Lipid Nanoparticles may also be used to provide controlled release of one or more the active agents herein described.
- the lipid phase of an emulsion (or a portion thereof) is exchanged with a solid lipid (i.e. a lipid which is solid at room temperature and also at body temperature) .
- the solid lipids can be obtained by high-pressure homogenization or by microemulsion techniques.
- One or more of the active agents described herein can be solubilized or molecularly dispersed into the solid lipid particles (the particles obtained are normally in the range of 200 nm to 2 ⁇ m and are thus termed nanoparticles) .
- the structure obtained is typically a function of (1) the formulation composition; lipids, active ingredients, surfactants etc.; (2) the production conditions; hot or cold homogenization; and (3) the interaction between the various ingredients.
- One example of such a system is a matrix composed of Compritol and Poloxamer 188.
- ion exchange systems based on the interaction between soluble polymers and oppositely charged drugs may provide for controlled release. Examples of such systems include Carbopol in combination with chondroitin 6-sulphate or lambda carrageenan (see Controlled Release Society 30th Annual Meeting PROCEEDINGS, 2003: #392).
- bioadhesives which may be used to give controlled and prolonged release of one or more actives to the vaginal mucosa are described in US-A- 6,306,914, the contents of which are incorporated herein by reference.
- a yet further example of such a system is an agent which comprises a graft copolymer of a poly- ⁇ - glycoside and at least a graft copolymerizable , ⁇ - ethylenically unsaturated monocarboxylic acid or acid derivative as described in WO 00/47644, the entire contents of which are also incorporated herein by reference .
- Other systems which are able to release an active agent in a controlled manner for an extended period in the vaginal cavity are described in US-A-4 , 551, 148 , the contents of which are incorporated herein by reference.
- Such systems comprise liquid or semi-solid adjacent unit cells having common lipoidal external phases, non- lipoidal internal phases and emulsifiers .
- the external and internal phases of these systems comprise an emulsion, emulsion/dispersion, double emulsion, suspension within an emulsion or mixture.
- the active agent or agents will be contained within the non-lipoidal phases.
- VagiSite ® KV Pharmaceutical Company, Mo, USA
- the VagiSite ® system is a high internal phase ratio water-in-oil emulsion system that exhibits bioadhesive properties to mucosal tissues.
- the biphasic system is composed of a drug laden internal phase and a water-insoluble external phase.
- Combinations of two or more of the bioadhesive technologies herein desribed may be used in the formulations of the invention.
- One example of such a combination is that based on GMO, block copolymers and solid lipid nanoparticles.
- the mucoadhesive properties of GMO may, for example, be enhanced with any of the block copolymers herein described, e.g.
- GMO may be combined with a Lutrol block copolymer to provide a programmed release of active (s) over a period of time.
- a dilution-thickening effect can further be achieved by mixing in specific amounts block copolymers and a mesomorphic GMO phase.
- GMO in the cubic phase may also be used as the solid lipid phase of a solid lipid nanoparticle (SLN) .
- SPSN solid lipid nanoparticle
- Programmd drug release can further be achieved by incorporating a block copolymer into a molten GMO of the lipid phase of a solid lipid nanoparticle matrix.
- the bioadhesives described herein may be prepared using standard processes and procedures well-known in the art, although many are available commercially, e.g.
- bioadhesive agent may itself comprise the carrier or excipient in any pharmaceutical formulation and thus in those cases, a further carrier or excipient need not necessarily be present .
- compositions herein described are suitable for the treatment and/or prevention of primary and/or secondary vaginal infections, e.g. mixed vaginal infections such as those associated with acute and recurrent vulvovaginal candidiasis, bacterial vaginosis and trichomonal vaginitis. These are also considered to be effective in treating any secondary candidial, bacterial and/or trichomonal infections which might result from treatment of such causative agents.
- vaginal infections due to group B and D streptococcus and the like, infections due to microorganisms causing vulvitis and vulvovaginitis, and other vaginal infections e.g.
- compositions in accordance with the invention may also find more general use in treating primary and/or secondary genital infections in both men and women, including sexually transmitted infections, e.g. infections due to chlamydia; balanitis; penile dermatitis; herpes genitalis; gonorrhea; etc.
- the pessaries may be manufactured by conventional methods, for instance by admixture of the active ingredients in the molten pessary base and pouring the resulting mixture into chilled moulds.
- the pessaries may be presented in a pack to provide a complete course of treatment, for example with some of the pessaries containing a combination of actives in accordance with the invention for initial use (e.g. over the first three days) and some containing only a single anti-vaginitis medicament for use when the symptoms have begun to subside.
- a 7-day regimen of treatment using pessaries containing the actives terconazole and tioconazole might comprise a combination of these two actives for the first three days and tioconazole alone for the remaining four days .
- a "Combi-pack" may comprise one or more pessaries together with a cream for external use to provide a particular course of treatment in which at least one pessary and/or the cream comprises a combination of actives as herein described.
- a pack of pessaries may be provided in which one or more pessaries contains a combination of actives in accordance with the invention, the pack further comprising a cream containing either a single anti- vaginitis medicament or a combination of active agents in accordance with the invention intended for a full course of treatment (e.g. 3, 5 or 7 days) .
- a cream containing either a single anti- vaginitis medicament or a combination of active agents in accordance with the invention intended for a full course of treatment (e.g. 3, 5 or 7 days) are also provided.
- "Combi-packs" containing at least one pessary which contains either a single anti-vaginitis medicament or a combination of medicaments in accordance with the invention for the first day (single dose treatment) or for a course of 3 , 5 or 7 days, together with a cream for external use containing a combination of actives as herein described.
- Packs of pessaries which include at least one pessary containing a combination of actives as herein described are considered to form part of the invention.
- a pack comprising one or more pessaries and/or a cream in which at least one pessary or said cream comprises a combination of active agents as herein described also forms part of this invention. It is common practice in vaginitis therapy that oral treatment is combined with topical treatment, particularly in resistant cases, in non-responders or in the treatment of recurrent conditions, e.g. vulvovaginal candidiasis or trichomoniasis .
- topical formulations herein described may be used in conjuction with oral therapy, for example in combination with oral administration of conventional agents having any combination of anti- fungal, anti- protozoal and antibacterial properties.
- conventional agents having any combination of anti- fungal, anti- protozoal and antibacterial properties.
- the two active ingredients are mixed into the molten Suppocire and the resulting mixture is poured into pre- cooled moulds.
- the moulds are passed through a cooling tunnel at -10°C, the pessaries are removed from the moulds and packaged.
- the oily phase components are mixed at 60°C.
- the aqueous phase comprising the remaining components is also blended at 60°C and the two phases combined and blended.
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Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA200601647A EA011952B1 (ru) | 2004-03-10 | 2004-09-17 | Противовагинитные композиции, содержащие триазол |
BRPI0418623-0A BRPI0418623A (pt) | 2004-03-10 | 2004-09-17 | composição farmacêutica, e, embalagem |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0405406.0A GB0405406D0 (en) | 2004-03-10 | 2004-03-10 | Anti-vaginitis compositions |
GB0405406.0 | 2004-03-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005087270A1 true WO2005087270A1 (fr) | 2005-09-22 |
Family
ID=32117416
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2004/003972 WO2005087270A1 (fr) | 2004-03-10 | 2004-09-17 | Compositions anti-vaginite comprenant un triazole |
Country Status (7)
Country | Link |
---|---|
CN (1) | CN1960763A (fr) |
BR (1) | BRPI0418623A (fr) |
EA (1) | EA011952B1 (fr) |
GB (1) | GB0405406D0 (fr) |
PL (1) | PL380815A1 (fr) |
TR (1) | TR200606411T1 (fr) |
WO (1) | WO2005087270A1 (fr) |
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WO2007079389A2 (fr) * | 2006-01-05 | 2007-07-12 | Drugtech Corporation | Composition et méthode d'utilisation de celle-ci |
WO2007079390A2 (fr) | 2006-01-05 | 2007-07-12 | Drugtech Corporation | Medicament utilise par voie topique |
WO2007079391A2 (fr) * | 2006-01-05 | 2007-07-12 | Drugtech Corporation | Systeme d'administration de medicament |
WO2014026707A1 (fr) | 2012-08-13 | 2014-02-20 | Edko Pazarlama Tanitim Ticaret Limited Sirketi | Compositions anti-vaginite à libération et adhérence améliorées |
WO2014027006A1 (fr) | 2012-08-13 | 2014-02-20 | Edko Pazarlama Tanitim Ticaret Limited Sirketi | Formulations bioadhésives destinées à être utilisées dans l'administration de médicaments |
WO2014210156A1 (fr) * | 2013-06-25 | 2014-12-31 | Mission Pharmacal Company | Nouvelles formulations pour le traitement de troubles vaginaux |
US9211286B2 (en) * | 2006-09-12 | 2015-12-15 | Curatek Pharmaceuticals Holding, Inc. | Terconazole composition and method |
US9789057B2 (en) | 2003-09-19 | 2017-10-17 | Perrigo Pharma International Designated Activity Company | Pharmaceutical delivery system |
US10758630B2 (en) | 2010-08-13 | 2020-09-01 | The Johns Hopkins University | Topical compositions and methods of detection and treatment |
CN112190541A (zh) * | 2020-09-27 | 2021-01-08 | 安婕妤化妆品科技股份有限公司 | 一种私密护理凝胶产品 |
WO2021154188A1 (fr) * | 2020-01-31 | 2021-08-05 | Exeltis Ilac Sanayii Ve Ticaret Anonim Sirketi | Composition pharmaceutique appropriée pour une administration vaginale |
US11166968B2 (en) | 2015-09-29 | 2021-11-09 | Kimberly-Clark Worldwide, Inc. | Synergistic composition for maintenance of healthy balance of microflora |
WO2021257179A1 (fr) * | 2020-06-18 | 2021-12-23 | National Medical Supply, LLC | Gel vaginal |
US12029748B2 (en) | 2017-02-28 | 2024-07-09 | Kimberly-Clark Worldwide, Inc. | Synergistic composition for maintenance of healthy balance of microflora |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995017175A1 (fr) * | 1993-12-23 | 1995-06-29 | The Procter & Gamble Company | Compositions antimicrobiennes pour mouchoirs jetables |
WO1996003149A1 (fr) * | 1994-07-22 | 1996-02-08 | Warner-Lambert Company | Compositions fongicides et cicatrisantes et procedes de preparation et d'utilisation |
WO1999055333A1 (fr) * | 1998-04-24 | 1999-11-04 | Laboratoire Innothera (Societe Anonyme) | Association pharmaceutique d'imidazoles pour le traitement local des vulvo-vaginites infectieuses et des vaginoses |
WO2002003896A1 (fr) * | 2000-07-11 | 2002-01-17 | Umd, Inc. | Dispositif et methode de traitement intravaginal ou transvaginal d'infections fongiques, bacteriennes, virales ou parasitaires |
US20030073646A1 (en) * | 1997-01-22 | 2003-04-17 | Marton Milankovits | Pharmaceutical compositions primarily for the treatment of genitourinary infections |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9610359D0 (en) * | 1996-05-17 | 1996-07-24 | Edko Trading Representation | Pharmaceutical compositions |
-
2004
- 2004-03-10 GB GBGB0405406.0A patent/GB0405406D0/en not_active Ceased
- 2004-09-17 EA EA200601647A patent/EA011952B1/ru not_active IP Right Cessation
- 2004-09-17 CN CNA2004800430095A patent/CN1960763A/zh active Pending
- 2004-09-17 BR BRPI0418623-0A patent/BRPI0418623A/pt not_active IP Right Cessation
- 2004-09-17 WO PCT/GB2004/003972 patent/WO2005087270A1/fr active Application Filing
- 2004-09-17 PL PL380815A patent/PL380815A1/pl not_active Application Discontinuation
- 2004-09-17 TR TR2006/06411T patent/TR200606411T1/xx unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995017175A1 (fr) * | 1993-12-23 | 1995-06-29 | The Procter & Gamble Company | Compositions antimicrobiennes pour mouchoirs jetables |
WO1996003149A1 (fr) * | 1994-07-22 | 1996-02-08 | Warner-Lambert Company | Compositions fongicides et cicatrisantes et procedes de preparation et d'utilisation |
US20030073646A1 (en) * | 1997-01-22 | 2003-04-17 | Marton Milankovits | Pharmaceutical compositions primarily for the treatment of genitourinary infections |
WO1999055333A1 (fr) * | 1998-04-24 | 1999-11-04 | Laboratoire Innothera (Societe Anonyme) | Association pharmaceutique d'imidazoles pour le traitement local des vulvo-vaginites infectieuses et des vaginoses |
WO2002003896A1 (fr) * | 2000-07-11 | 2002-01-17 | Umd, Inc. | Dispositif et methode de traitement intravaginal ou transvaginal d'infections fongiques, bacteriennes, virales ou parasitaires |
Non-Patent Citations (1)
Title |
---|
FARAH C A ET AL: "TINIDAZOLE-TIOCONAZOLE COMBINATION IN THE TREATMENT OF VAGINAL INFECTION DUE TO TRICHOMONAS GARDNERELLA-VAGINALIS OR CANDIDA-ALBICANS", BIOLOGICAL ABSTRACTS. - MICROFILMS, BIOSIS. PHILADELPHIA, PA, US, vol. 84, 1987, pages COMPLETE01, XP002091996, ISSN: 0192-6985 * |
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WO2007079389A3 (fr) * | 2006-01-05 | 2007-12-27 | Drugtech Corp | Composition et méthode d'utilisation de celle-ci |
WO2007079391A3 (fr) * | 2006-01-05 | 2008-03-13 | Drugtech Corp | Systeme d'administration de medicament |
JP2009522362A (ja) * | 2006-01-05 | 2009-06-11 | ドラッグテック コーポレイション | 薬物送達システム |
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US11529346B2 (en) | 2020-06-18 | 2022-12-20 | National Medical Supply, LLC | Vaginal gel |
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Also Published As
Publication number | Publication date |
---|---|
GB0405406D0 (en) | 2004-04-21 |
BRPI0418623A (pt) | 2007-05-29 |
PL380815A1 (pl) | 2007-03-19 |
TR200606411T1 (tr) | 2007-01-22 |
EA011952B1 (ru) | 2009-06-30 |
CN1960763A (zh) | 2007-05-09 |
EA200601647A1 (ru) | 2007-02-27 |
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