Stable dosage form for local application containing voriconazole

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for local application in the form of cream or ointment contains as effective amount of voriconazole or its pharmaceutically acceptable salt, or a pharmaceutical carrier. Said dosage form of voriconazole contains max. 3 wt % of water. What is also described is a method for preparing the dosage form of voriconazole for treating local and non-systemic mycotic infections in an individual.

EFFECT: dosage form for local application under the invention maintains storage stability at temperature approximately 40°C and relative humidity approximately 75% for at least three months and has total storage impurity content is no more than 9 wt % as related to total weight of the dosage form.

12 cl, 1 dwg, 30 ex

Priority of invention

[0001] This application claims priority under provisional patent application India 1204/MUM/2008, filed June 6, 2008, the application 1967/MUM/2008, filed on September 16, 2008, and 1587/MUM/2008, filed on July 24, 2008, and under 35 U.S.C. §119(e) according to provisional patent application U.S. 61/103315, filed October 7, 2008, the contents of each of which is incorporated into the present application by reference.

The technical field

[0002] the Present invention relates to a stable dosage form for topical application, containing voriconazole or its pharmaceutically acceptable salt; and the way of its reception. In particular, the present invention relates to a stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salt, optional corticosteroid and a pharmaceutical carrier; and the use of such dosage forms for the treatment of local or non-systemic fungal infections in a subject.

The level of technology

[0003] Voriconazole (Formula I) has the chemical name (2R,3S)-2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol, empirical formula C₁₆H₁₄F₃N₅O and molecular weight 349,3.

[0004] Voriconazole commercially available in the form of liofilizirovannoe what about the powder for preparation of solution for intravenous injection, in the form of a coated film-coated tablets for oral administration and also in powder form for the preparation of suspensions for oral administration (VFEND^®supplied by Pfizer). Voriconazole is intended for the treatment of various fungal infections caused by Aspergillus fumigatus and other Aspergillus species, non-A. fumigatus, systemic esophageal candidiasis and expressed fungal infections caused by Scedosporium apiospermum.

[0005] Voriconazole described in the patent EP 0440372. Voriconazole and its dosage forms are described in U.S. patent No. 5116844; 5364938; 5567817; 5773443 and 6632803.

[0006] the Publication of the patent application U.S. No. 2005/0043251 relates to compositions containing various antifungal agents for the topical treatment of otitis external ear. Publication of international patent application PCT WO 2005/051353 refers to water the dosage form for parenteral administration based micelles poloxamer containing voriconazole.

Brief description of the invention

[0007] the Present invention relates to a stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salts and a pharmaceutical carrier, and the specified dosage form for local application essentially does not contain water.

[0008] In the context of the present invention a stable medicament is i.i.d. form for local use may be for example, presented in the form of a gel, cream, ointment, emulsion, suspension, solution, eye drops, lotion, nail lacquer, uterine rings, solution for douching, suppositories, lozenges, spray, swab, film or foam. Dosage form for local application is intended for local application on the affected part of the body of the subject. Preferably, the stable dosage form for topical application are presented in the form of a cream or ointment.

[0009] According to a variant implementation of the stable dosage form for topical application contains an effective amount of voriconazole or its pharmaceutically acceptable salt, which comprises from about 0.01 to about 5 wt.% or preferably from about 0.05 to about 2 wt.% (w/w, relative to the total weight of the dosage form).

[0010] According to another implementation variant of the stable dosage form for local application essentially does not contain water. Preferably, the stable dosage form for topical application according to the present invention contains not more than about 3 or not more than about 2 wt.% water (w/w, relative to the total weight of the dosage form). Alternatively, the stable dosage form for topical application according to the present invention can be anhydrous (not contain water).

[0011] According to another options is the ant implementation of the present invention dosage form for local use is stable when stored under conditions of accelerated degradation, that is, the total content of impurities in pharmaceutical form, formed during storage at a temperature of about 40°C and a relative humidity of approximately 75% within 3 months, is not more than 9 wt.% of the total weight of the dosage form). Preferably the dosage form contains not more than 5.5 wt.% of the total weight of the dosage form 2,4-debtor-2-(1H)-1,2,4-triazole-1-elicitation (impurities formed during the hydrolysis of voriconazole in the future in the present application is called an admixture of (A)formed under the same storage conditions for 3 months.

[0012] According to a particular implementation variant of the present invention a stable dosage form for topical application, containing voriconazole or its pharmaceutically acceptable salt is a dosage form in the form of cream, which essentially does not contain water, and the total content of impurities in the dosage form in the form of cream formed during storage at a temperature of about 40°C and a relative humidity of about 75% for at least 3 months, is not more than 9 wt.% (of the total weight of the dosage form). Preferably the dosage form in the form of cream contains not more than 5.5 wt.% (of the total weight of the dosage form) impurity And formed under the same storage conditions for 3 months.

[0013] According to another particular implementation variant of the present invention proposed a stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salt as the active ingredient), corticosteroid (as a second active ingredient and a pharmaceutical carrier, and the specified dosage form for local application does not actually contain water. Preferably, the corticosteroid is clobetasol, halobetasol, fluocinonide, betamethasone, dexamethasone, beclomethasone, alcomate, diflorasone, fluticasone, hydrocortisone, mometazon, fluotsinolon, desonide and triamcinolone.

[0014] In the context of the present invention an effective amount of corticosteroid for topical use is roughly 0.005 to about 5 wt.% or preferably from about 0.01 to about 3 wt.% of the total weight of the dosage form. The preferred ranges of the mass fraction in percent (by weight of the total dosage form) for various corticosteroids, are considered in this application include: mometazon (ranging from 0.01 to 1%), betamethasone (ranging from 0.01 to 1%), fluotsinolon (ranging from 0.01 to 1%), beclomethasone (ranging from 0.01 to 1%), desonide (ranging from 0.01 to 1%), fluticasone (ranging from 0.01 to 1%) hydrocortisone (in the range from 0.01 to 5%), dexamethasone (ranging from 0.01 to 1%), alcomate (ranging from 0.01 to 1%) and diflorasone (ranging from 0.01 to 1%).

[0015] Preferably, the stable dosage form for topical application according to the present invention contains:

a) voriconazole in the range from about 0.05 to about 2 wt.%;

b) mometasone furoate in the range from about 0.01 to about 1 wt.%; and

c) a pharmaceutical carrier,

moreover, the specified dosage form essentially does not contain water.

[0016] According to another implementation variant, a method for preparing a stable pharmaceutical forms for topical application, containing voriconazole or its pharmaceutically acceptable salt and a pharmaceutical carrier, including (a) joint fusion of one or more fillers by heating them to a temperature of about 75°C with the formation of the molten mass; (b) obtaining a dispersion of voriconazole or its salt in a solvent; (C) mixing the dispersion obtained in step (b), with the molten mass under stirring; and (d) homogenization of the mixture for 15-30 min and gradually cooled to ambient temperature environment.

[0017] Another embodiment of the present invention relates to a method of treatment of local or non-systemic fungal infection in a subject in need of such treatment, and this act is about comprises applying to the affected area of the body of the subject of the stable dosage form for local use, containing an effective amount of voriconazole or its pharmaceutically acceptable salt. Preferably the subject is a mammal such as man.

A brief description of graphic materials

[0018] Figure 1: Diagram showing the impurity content and the total content of impurities in the dosage forms in the form of a cream containing 0.5 wt.% voriconazole, with different amounts of water during storage at a temperature of about 40°C and a relative humidity of approximately 75%within 3 months.

Detailed description of the invention

[0019] following are the definitions of terms used in this application. However, if the definition in this application, does not coincide with that definition in an earlier preliminary application (according to which priority is claimed), the meaning of the term (term) is determined in accordance with this application.

[0020] Voriconazole is unstable in water (subject to hydrolysis, resulting in the recombination products retroaldol decay produces inactive enantiomer). This instability in the water over time leads to an increase in impurity content. The high content of impurities, in turn, leads to the formation of dosage forms with reduced or impaired activity. Thus, the retention time of the dosage forms for topical what about the application on the basis of voriconazole, containing water, significantly less compared to other dosage forms for topical use. The problem of production in industrial scale stable dosage forms for topical use on the basis of voriconazole still remained unresolved. However, according to the present invention proposed an unexpected problem with a stable dosage forms for topical application, containing voriconazole or its pharmaceutically acceptable salt, and specified dosage form for local use is stable when stored under conditions of accelerated degradation (i.e. at a temperature of about 40°C and a relative humidity of about 75%) for at least 3 months.

[0021] Not limited to any particular theory, collected and presented in this application the data indicate that the preparation of the compositions according to the methods of the present invention with the corresponding water content relative to voriconazole or its pharmaceutically acceptable salt leads to a stable dosage forms for local use. Such a stable dosage form for local application on the basis of voriconazole or its pharmaceutically acceptable salt, prepared as described in the present application methods may use is taken for treatment of local or non-systemic fungal infections and seborrheic dermatitis of the subjects, those in need of such treatment.

[0022] in Addition, suitable combination therapy for the treatment of present simultaneously fungal infections and seborrheic dermatitis, in particular, if two or more active ingredients have different mechanisms of action. For example, the authors of the present invention have found that a composition comprising voriconazole as a first active ingredient and a corticosteroid as the second active ingredient may be effective in the treatment of local or non-systemic fungal infections and seborrheic dermatitis of the subject.

[0023] the Present invention relates to a stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salts and a pharmaceutical carrier.

[0024] the Term "dosage form for local use" (synonym: "composition for local application"), used in this application refers to a pharmaceutical agent intended for topical or local application on the affected area of the body in need thereof of a subject, and includes such dosage forms as a gel, cream, ointment, emulsion, suspension, solution, drops, lotion, nail Polish, Royal ring, a solution for douche, suppository, toffee, spray, swab, film or foam. Predpochtitel is but dosage form for local use is a cream or ointment. According to the present invention described specific types of dosage forms for local use, including comps shampoos; compositions for nails (type varnishes, waxes, coatings, reinforcing layers, basics lacquer, means to strengthen nails and inserts); dosage forms for vaginal and rectal administration (e.g., tablet, pad, suppository, soft gelatin capsule and fallopian ring); and ointments for the mouth.

[0025] as Used in this application, the terms "effective amount" or "effective amount for local use" voriconazole or its pharmaceutically acceptable salts include non-toxic to the amount of active ingredient sufficient to achieve the desired effect when applied topically. "Effective amount" varies depending on the disease and its severity and the age, weight and physical condition susceptible to treatment of the subject and its susceptibility to the active ingredient.

[0026] According to a variant implementation of the stable dosage form for topical application include an effective amount of voriconazole or its pharmaceutically acceptable salt, which comprises from about 0.01 to about 5 wt.% or preferably from about 0.05 to about 2 wt.% (of the total weight of the dosage form). Preferably the stable dosage form for topical application according to the present invention includes from about 0.1 to about 2 wt.% voriconazole or its pharmaceutically acceptable salt (by weight of the total dosage form).

[0027] According to another implementation variant of the stable dosage form for local application essentially does not contain water. The term "essentially no water-containing" (or "essentially anhydrous") in relation to dosage forms for topical use according to the present invention means a dosage form for topical use containing not more than about 5 wt.% water (by weight of the total dosage form). Preferably, the stable dosage form for topical application according to the present invention contains not more than about 3 or not more than about 2 wt.% water (by weight of the total dosage form). Alternatively, the stable dosage form for topical application according to the present invention can be anhydrous (not contain water). The water content in the dosage form for topical application according to the present invention can be generally determined using a moisture analyzer using the method of Karl Fischer (Karl-Fischer (KF).

[0028] According to another implementation variant dosage form for local application in accordance with the present invention is stable when stored under conditions of accelerated degradation for at least 3 months.

[0029] the Dosage form for local use, called "the camera is at school in the context of the present invention, has a total content of impurities formed during storage under accelerated degradation (i.e. at a temperature of about 40°C and a relative humidity of about 75%) for at least 3 months, not more than 9 wt.% (of the total weight of the dosage form). As described in this application, the total content of impurities in the dosage form for local use until its premises in terms of the accelerated degradation is less than about 0.5, or 0.2 wt.% (with respect to voriconazole). The content of impurities is higher than 9 wt.% is unacceptable due to a number of reasons, including reduced activity and/or retention of the dosage form.

[0030] According to a variant implementation of the dosage form for local application in accordance with the present invention contains not more than 5.5 wt.% impurities (chemical name 2,4-debtor-2-(1H)-1,2,4-triazole-1-ilization), formed under the same storage conditions for 3 months.

[0031] According to a particular implementation variant of the present invention a stable dosage form for topical application, containing voriconazole or its pharmaceutically acceptable salt is a dosage form in the form of cream, which essentially does not contain water, and dosage form in the form of a cream has a total content of impurities, forming the SJ when stored at a temperature of about 40°C and a relative humidity of about 75% for at least 3 months, no more than 9 wt.% (of the total weight of the dosage form). Preferably the dosage form in the form of cream contains not more than 5.5 wt.% (of the total weight of the dosage form) impurity And formed under the same storage conditions for 3 months.

[0032] According to another particular implementation variant of the present invention proposed a stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salt as the active ingredient), corticosteroid (as a second active ingredient and a pharmaceutical carrier, and the specified dosage form for local application essentially does not contain water. Preferably, the corticosteroid is clobetasol, halobetasol, fluocinonide, betamethasone, dexamethasone, beclomethasone, alcomate, diflorasone, fluticasone, hydrocortisone, mometazon, fluotsinolon, desonide and triamcinolone.

[0033] In the context of the present invention an effective amount of corticosteroid for topical use is roughly 0.005 to about 5 wt.% or preferably from about 0.01 to about 3 wt.% (of the total weight of the dosage form). The preferred ranges of the mass fraction (of the total weight of the dosage form) for various corticosteroids, which rassm travaudia in this application, include mometazon (ranging from 0.01 to 1%), betamethasone (ranging from 0.01 to 1%), fluotsinolon (ranging from 0.01 to 1%), beclomethasone (ranging from 0.01 to 1%), desonide (ranging from 0.01 to 1%), fluticasone (ranging from 0.01 to 1%), hydrocortisone (in the range from 0.01 to 5%), dexamethasone (ranging from 0.01 to 1%), alcomate (ranging from 0.01 to 1%) and diflorasone (ranging from 0.01 to 1%).

[0034] More preferably, the stable dosage form for topical application according to the present invention contains:

a) voriconazole in the range from about 0.05 to about 2 wt.%;

b) mometasone furoate in the range from about 0.01 to about 1 wt.%; and

c) a pharmaceutical carrier,

moreover, the specified dosage form essentially does not contain water.

[0035] Another embodiment of the present invention relates to a method of treatment of local or non-systemic fungal infection in a subject in need of such treatment, and this method comprises applying to the affected area of the body of the subject of the stable dosage form for topical application containing an effective amount of voriconazole or its pharmaceutically acceptable salt. Preferably the subject is a mammal such as man.

[0036] the Term "local or non-systemic fungal infection in the context of this izobreteny which includes dermatophyte infection of the outer integument (skin, nails, hair and scalp and mucous membranes of the mouth/nose/vagina/rectum, caused by species of Tinea, Epidermophyton, Trichophyton and Microsporum. Fungal infections that can be treated with voriconazole, described in detail in the literature, in particular in the European patent EP 440372, and include infection of the outer integument, caused, for example, Candida spp., Tinea spp., Trichophyton spp., Microsporum spp. or Epidermophyton floccosum; infections of the mucous membranes caused by Candida spp.; systemic infection caused including Candida spp., Cryptococcus neoformans, Aspergillus spp., Fusarium spp., Scedosporium spp., Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma spp. or Blastomyces dermatiditis.

[0037] as Used in this application, the terms "treat" or "treatment" in relation to the pathological condition, disorder or disease means: (1) suppression of the pathological condition, disorder or disease, i.e. stopping or slowing the development of the disease or at least one clinical or subclinical symptom, or (2) the relief of the disease, i.e. remission pathological conditions, disorders or diseases or at least one clinical or subclinical symptom. The terms "treat" or "treatment"as used in this application, also include prevention, mitigation, prevention, reduction or inhibition of a fungal infection in a subject.

[0038] Used in the present the first application, the term "subject" includes humans and other animals, such as domestic animals (e.g. Pets, including cats and dogs) and non-domestic animals (such as wild animals). Preferably the subject is a person.

[0039] the Term "active ingredient"is used interchangeably with the terms "active ingredient" or "active compound" in the present application, includes voriconazole or its pharmaceutically acceptable salt.

[0040] the Term "salt" or "pharmaceutically acceptable salt" includes salts and esters, which, according to reasonable medical conclusion, are suitable for use in contact with the tissues of humans and lower animals do not exhibit nonspecific toxicity, do not cause irritation and allergic reactions have a favorable ratio of benefits/risk and effective for their intended use. Typical salt accession acids include hydrochloride, hydrobromide, sulfate and bisulfate. Typical salts of alkaline and alkaline-earth metals include salts of sodium, calcium, potassium and magnesium.

[0041] the Term "pharmaceutically acceptable"as used in relation to ingredients, refers to the ingredients, approved by the governmental authorities or listed in the U.S. Pharmacopoeia or other generally recognized Pharmacopoeia among legal for use in mammals, such as man.

[0043] As is known in the art, the creams are viscous liquid or semisolid emulsions of the type oil-in-water" or "water in oil". The basis for this cream-type oil-in-water" are vodosnabzhenie and contain an oil phase, an emulsifier and the aqueous phase. The oil phase, also called the "internal" phase, in General, consists of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume, and generally represents the humidifier. The emulsifying agent in the dosage form in the form of cream in General is a non-ionic, anionic, cationic or amphoteric surface-active substance.

[0044] Ointments are semisolid compositions, typically based on petrolatum or other petroleum products. Specialists in the art it is obvious, cosoba ointment base, which can be used is a framework that provides the optimal delivery of medicines and preferably also has other desired action, such as mitigation. Like other carriers or fillers, the basis for ointments should be inert, stable, does not cause irritation and sensitization. As described in the publication Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), str-1404, ointment bases can be divided into four classes: oily base; mulgirigala bases; emulsion bases and water-soluble bases. Oily ointment bases include, for example, vegetable oils, animal fats and semi-solid hydrocarbons obtained from crude oil refining. Mulgirigala ointment bases, also known as absorbent ointment bases, do not contain or contain a small amount of water and include, for example, the sulfate, hydroxystyrene, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are emulsion-type water in oil (W/M) or emulsion of the type oil-in-water (M/C) and include, for example, cetyl alcohol, glycerylmonostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are derived from glycols with different molecular weight; to obtain additional the Noi information see also Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995).

[0045] the Dosage form for topical application according to the present invention includes pharmaceutical carrier (alternatively, a "pharmaceutically acceptable excipient"). Suitable pharmaceutical carriers are carriers for local use, including but not limited to) polymers, geleobrazovanie, thickeners, diluents, disintegrating agents, binding agents, lubricants, preservatives, surfactants, solvents, emulsifiers, emollients, humectants, substances with buffer capacity, chelating agents, and mixtures thereof. Examples of these additives are described, for example, in publications Howard C. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy (20th Ed. 2000); and A.Kibbe, Handbook of Pharmaceutical Excipients (3rd Ed. 2000), the contents of each of which is incorporated into the present application by reference.

[0046] Suitable geleobrazovanie and thickeners include, for example, but are not limited to these: carbomer (CARBOPOL), modified cellulose derivatives, natural, synthetic or semi-synthetic gums, such as xanthan gum, Arabia gum and tragant, sodium alginate, gelatin, modified starches, polymers based on cellulose, such to the to hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methyl cellulose; copolymers, such as copolymers of maleic anhydride and methylvinylether ether, colloidal silicon dioxide and methacrylate derivatives, polyethylene oxides, copolymers of polyoxyethylene and polyoxypropylene, polyvinyl alcohol and the like, and mixtures thereof.

[0047] Examples of solvents include, but are not limited to these: water, tetrahydrofuran, isopropyl alcohol, propylene glycol, liquid petrolatum, ether, petroleum ether, alcohols (e.g. methanol, ethanol and higher alcohols), aromatic hydrocarbons (for example, Bensen and toluene), alkanes (e.g. pentane, hexane and heptane), ketones (e.g. acetone and methyl ethyl ketone), chlorinated hydrocarbons (e.g. chloroform, carbon tetrachloride, dichloromethane and dichloroethane), acetates (e.g. ethyl acetate), oils (for example, isopropylmyristate, diisopropylamide and mineral oil) and mixtures thereof.

[0048] Examples of emulsifiers include, but are not limited to the list) sesquistearate methylglucose, PEG-20 methylglucose sesquistearate, steareth-21, peg 20 sorbitan the monostearate, polyethylene glycol 60 sorbitan the monostearate, polyethylene glycol 80 sorbitan the monostearate, steareth-20, ceteth-20, PEG-100 stearate, stearoyl of sarcosinate sodium, hydrogenated lecithin, it is coil glycerolipid sodium, stearyl sodium sulphate, sterilair lactylate sodium, PEG-20 glycerylmonostearate, sucrose monostearate, politerati sucrose, polyglyceryl 10 stearate, polyglyceryl 10 myristate, stearate 10, deja-IG-3-phosphate, deja-IG-10-phosphate, BCP-5 ceteth 10 sodium phosphate, BCP-5 ceteth 10 potassium phosphate, steareth-2, PEG-5 soy Sterol oil, PEG-10 soy Sterol oil, diethanolamine cetilistat, servicemonitor, dietilenglikoluretan, glycerylmonostearate and mixtures thereof.

[0049] Examples of softening agents include, but are not limited to these: triglycerides of Caprylic/capric acids, castor oil, ceteareth-20, ceteareth-30, Cetearyl alcohol, ceteth 20, cetosteatil alcohol, cetyl alcohol, cetyl-stearyl alcohol, cocoa butter, diisopropylamide, glycerin, glycerylmonostearate, glycerylmonostearate, literallayout, isopropylmyristate, isopropylpalmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffin, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethyleneglycol ethers of fatty alcohols, polyoxypropylene-15-stearyl ether, propylene glycol stearate, squalene, steareth-2 or steareth-100, stearic acid, stearyl alcohol, urea and mixtures thereof.

[0050] Examples of film-forming polymers that can be used in the compositions of varnishes is La nail according to the present invention, include, for example, polyvinyl acetate, mixtures of polymers (or copolymers) of vinyl acetate and acrylic or methacrylic acid, copolymers of (meth)acrylic acid and esters of (meth)acrylic acid, copolymers of esters of (meth)acrylic acid and comonomers containing the amino group and/or group Quaternary amine, etc. These polymers can be used individually or in mixtures with each other or with other film-forming polymers that meet the requirements of the present invention.

[0051] Examples of plasticizers include, but are not limited to the list) 1,2,3-preventiontreatment (triacetin), dibutyl phthalate, dioctylphthalate, dialogselect, dietilftalat, isobutyrate acetate sucrose, butylacetoacetate, butilstearat, triethylcitrate, dibutylated, polyethylene glycol, dipropyleneglycol, polypropyleneglycol, propylene glycol esters of fatty acids, such as dipelargonate propylene glycol, and mixtures thereof.

[0052] Examples of enhancers penetration of the drug into the nail plate include (but are not limited to these) 2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2-n-undecyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxane, 2-n-undecyl-1,3-dioxane, 2-n-reptilelike acetal, 2-n-octillery acetals, such as 2-n-octillery-dimethylacetal; 2-n-nonrendered-tetali, 2-n-DecimalDigit-acetals, 3,7-dimethyl-2,6-octadienal (citral) acetals, citronel-acetals, 2-n-nonyl-1,3-dioxolane (2-NND), decanal-dimethylacetal or decanal-diethylacetal, and mixtures thereof, and also include surfactants.

[0053] Examples of humectants include, but are not limited to the list) propylene glycol, glycerin, butyleneglycol, sorbitol, triacetin, and mixtures thereof.

[0054] Examples of diluents include, but are not limited to these: lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose, calcium sulphate, xylitol, lactic, etc. and mixtures thereof.

[0055] Examples of disintegrating agents include, but are not limited to the list) croscarmellose sodium, crosspovidone, polyvinylpyrrolidone, starch glycolate, sodium, corn starch, microcrystalline cellulose, hypromellose, hydroxypropylcellulose, etc. and mixtures thereof.

[0056] Examples of binding agents include (but are not limited to these) polyvinylpyrrolidone/povidone, lactose, starch, modified starch, sugar, Arabian gum, tragant, guar gum, pectin, binding agents based on wax, microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose hypromellose, hydroxypropylcellulose, copolyvidone, gelatin, sodium alginate, etc. and mixtures thereof.

[0057] Examples of lubricants include, but are not limited to the list) magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, colloidal silicon dioxide, Carnauba wax, hydrogenated vegetable oils, mineral oils, polyethylene glycols, sodium fumarate and the like and mixtures thereof.

[0058] Suitable compounds having buffer properties include (but are not limited to these), for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof.

[0059] Suitable chelating agents include mild chelating agents such as ethylenediaminetetraacetic acid (EDTA), disodium salt of EDTA and EDTA derivatives and mixtures thereof.

[0060] Suitable preservatives include, but are not limited to the list), for example, Phenoxyethanol, parabens (such as methylparaben and propylparaben), propylene glycols, sorbates, urea derivatives (such as diazolidinyl urea and mixtures thereof.

[0061] According to the present invention is also a method for preparing a stable pharmaceutical forms for topical application, containing voriconazole or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, and specified drug fo the mA essentially does not contain water. As described in this application, the preparation of the dosage form in the form of creams in General includes the following steps:

(a) joint fusion of one or more fillers by heating them to a temperature of about 75°C with the formation of the molten mass;

(b) obtaining a dispersion of voriconazole or its salt in a solvent;

(c) mixing the dispersion obtained in step (b), and the fused mass with stirring; and

(d) homogenization of the mixture for 15-30 min and gradually cooled to ambient temperature.

[0062] the Stable dosage form in the form of a cream according to the present invention can also be prepared by dispersion of voriconazole or its salts in the molten base for creams and homogenization of the mixture for 30 min with subsequent cooling.

[0063] it is Necessary to understand what possible other embodiments of the invention in addition to considered in this application. Thus, the above description does not limit the present invention, and only offers the preferred options for its implementation. Other schemes and methods can be implemented by experts in the field of technology within the essence and scope of the present invention.

[0064] the Following examples are given for the possibility of practical application of the invention, the special the sheets in the art and are illustrative only. The examples do not limit the scope of the invention.

Examples

[0065] Examples 1-3: Dosage form for topical application in the form of a cream containing voriconazole

The cooking process

Voriconazole was dispersible in hexyleneglycol under stirring. Mixed all the other ingredients and add to this mixture a colloidal solution of voriconazole at a temperature of about 70°C under stirring, followed by gomogenizirovannom for about 15 minutes Then the composition was gradually cooled to about 36°C to obtain a cream from white to not-quite white.

The water content of these formulations was between 0.5 and 0.8 wt.% of the total weight of the dosage form, which was determined using the KF method.

[0066] the Data on stability evaluation

[0067] the Dosage form according to examples 1-3 was kept at a temperature of about 40°C and a relative humidity of about 75% after packaging in aluminum tubes with lids. Within six months at monthly intervals dosage forms were analyzed for the content of impurities and conducted a quantitative assessment of voriconazole. The results of this study on stability evaluation are presented in the table below.

[0068]

[0069] the Method of determining the stability of dosage forms for topical use on the basis of voriconazole

Related substances (HPLC method)

Reagents: acetonitrile, methanol, triethylamine, phosphoric acid and purified water (Milli-Q or equivalent).

[0070] the Mobile phase

Preparation of mobile phase A: 0.2% triethylamine in water. Brought the pH to 3.0 with orthophosphoric acid.

Preparation of mobile phase B: acetonitrile:methanol (50:50, vol/vol.).

Preparation of diluent: acetonitrile:methanol (50:50, vol/vol.).

[0071] the Preparation of the investigated solution

Carefully weighed about 75,0 mg sample voriconazole and carried it in a volumetric flask with a capacity of 50 ml was Added about 20 ml of diluent and were treated by ultrasound for dissolution. Drove up to the mark with diluent and mixed. Filtered through a nylon membrane filter (0.45 µm).

[0072] the Preparation of the diluted standard solution

Carefully weighed about 75 mg internal working standard voriconazole and carried it in a volumetric flask with a capacity of 50 ml was Added about 20 ml of diluent and were treated by ultrasound for dissolution. D. who drove up to the mark with diluent and mixed.

5.0 ml of this solution was diluted to 100 ml with diluent and mixed.

Next, 1.0 ml of this solution was diluted to 100 ml with diluent and mixed.

[0073] preparation of the solution placebo

Weighed the equivalent of 75 mg of sample voriconazole number of placebo and was transferred into a volumetric flask of 50 ml was Added about 20 ml of diluent and were treated by ultrasound for dissolution. Drove up to the mark with diluent and mixed.

Filtered through a nylon membrane filter (0.45 µm).

[0074] the Chromatographic conditions

Gradient

[0075] the Evaluation of the suitability of the system

The relative standard deviation (CCA) for the six repeated injections was not more than 5.0%.

The following parameters represent the limit of detection (limit of detection, LOD) and limit of quantitation (limit of quantification, LOQ) for impurity A, formed by the hydrolysis of voriconazole.

The order of execution

Was injected into the chromatograph equal volume of diluent solution placebo and diluted control solution, and then injected with a solution of the sample and recorded chromatogram.

[0076] Examples 4, 5 and comparative example A: Dosage form in the form of a cream containing 1% (wt.) voriconazole, with different water content

Cooking method corresponds to the method described for examples 1-3.

[0077] Data stability

Dosage forms according to the examples 4, 5 and comparative example And kept at a temperature of about 40°C and a relative humidity of about 75% after packaging in aluminum tubes with lids. The results of studies evaluating stability after 1 month is presented in the table below.

[0078] Examples 6, 7 and comparative example B: Dosage form in the form of a cream containing 2% (wt.) voriconazole, with different water content

The way in which otopleniya corresponds to the way described for examples 1-3.

[0079] Data stability

The dosage form according to examples 6, 7 and comparative example were stored at a temperature of about 40°C and a relative humidity of about 75% after packaging in aluminum tubes with cap. The results of stability studies after 1 month is presented in the table below.

[0080] Examples 8, 9 and comparative example C: Dosage form in the form of a cream containing 0.5% (wt.) voriconazole, with different water content

Cooking method corresponds to the method described for examples 1-3.

[0081] Example 10: stability testing of dosage forms in the form of a cream containing various concentrations of voriconazole

Series of samples dosage forms in the form of a cream containing various concentrations of voriconazole and different amounts of water, was prepared according to the above description.

Dosage forms in the form of a cream was kept at a temperature of about 40°C and a relative humidity of about 75% after packing them in lacquered aluminum soft tubes with lids. The results of the study on stability evaluation after 1, 2 and 3 months are presented in the table below.

[0082] Examples 11-12: Dosage form in VI is e cream containing 0.1% and 0.25%) (wt.) voriconazole

Cooking method corresponds to the method described for examples 1-3.

[0083] Examples 13-15: Composition in the form of a shampoo containing 0.1%, 0.5% and 1% (wt.) voriconazole

Method of cooking

1. Voriconazole was dissolved in a mixture of surfacea (Surfadone) and polyethylene glycol so as to obtain a colorless solution under conditions of high temperature (about 80°C).

2. All other ingredients, except hydroxypropylcellulose, was dissolved in the solution obtained in step 1 under stirring. Insoluble particles were filtered off to obtain a homogeneous mixture.

3. Hydroxypropylcellulose were added when the temperature of the mixture of step 2 to about 50°C under stirring in such a way as to obtain a dense composition in the form of a shampoo.

[0084] Examples 16-18: the Composition in the form of nail Polish containing 0.1%, 0.5% and 1% (wt.) voriconazole

Method of cooking

1. Dissolved copolymer ammonium methacrylate in a mixture of ethanol, butyl acetate and ethyl acetate under stirring to obtain a solution. Then add the glycerine triacetate (triacetin) under stirring for uniform distribution.

2. Added voriconazole in the mixture obtained in step 1 was dissolved under stirring to form a solution.

3. Drove volume of ethanol.

[0085] Examples 19-22: Composition in the form of ointments for oral cavity containing 0.5% and 1% (wt./about., the ratio of mass to volume) voriconazole

Method of cooking

1. Voriconazole was dissolved in propylene glycol under stirring to obtain a solution.

2. If applicable, add the glycerin to the mixture obtained in step 1 under stirring.

3. Drove volume propylene glycol and filtered by the final dosage form through a sieve No. 200.

[0086] Examples 23-26: Dosage form in tablet form for vaginal administration, containing voriconazole (100, 200, 300 or 400 mg)

Method of cooking

1. Voriconazole, lactose, pregelatinized starch and croscarmellose sodium sieved through a stainless steel sieve No. 40.

2. All sifted on the stage 1 ingredients was stirred for 10 minutes.

3. Povidone K-30 was dissolved in water and added to the binder solution in the dry mixture of step 2 to obtain granules.

4. Croscarmellose sodium and magnesium stearate were sifted through sieve No. 40, was mixed with the granules obtained in step 3, and then extruded into pellets thus, to obtain tablets containing 100, 200, 300 or 400 mg voriconazole.

[0087] Example 27: Dosage form in the form of tablets containing 50 mg of voriconazole/p>

Method of cooking

1. Voriconazole, dextrose and lactose were sieved through a stainless steel sieve No. 40.

2. All sifted on the stage 1 ingredients was stirred for 10 minutes.

3. Povidone K-30 was dissolved in isopropyl alcohol and this binder solution was added to the dry mass obtained in step 2, to obtain pellets.

4. Magnesium stearate and pregelatinized starch were sieved is via the sieve # 40 and mixed with the granules, received on the phase III, and then extruded into lozenges.

[0088] Examples 28-29: Composition in the form of a cream for topical application, containing voriconazole and mometazon

Method of cooking

1. The ingredients in step 1 was heated at a temperature of about 70°C.

2. Both drug substances were dispersible in hexyleneglycol and was added to the mixture obtained in step 1, at a temperature of 70°C under stirring.

3. Homogenized for 15 minutes and cooled to room temperature to obtain the ointment.

[0089] Example 30: Ointment containing voriconazole and mometazon

Method of cooking

1. The ingredients in step 1 was heated at a temperature of about 70°C.

2. Both drugs were dispersively in the above phase at 70°C under stirring.

3. Homogenized for 15 minutes and cooled to room temperature to obtain the ointment.

1. Dosage form for topical application in the form of a cream or ointment containing from 0.01 wt.% up to 5 wt.% voriconazole or its pharmaceutically acceptable salts and a pharmaceutical carrier, and the specified dosage form contains not more than 3 wt.% water.

2. Dosage form for topical application according to claim 1, characterized in that it contains from 0.05% to 2 wt.% voriconazole or its pharmaceutically acceptable salt.

3. Dosage form for topical application according to claim 1, characterized in that it contains not more than 5.5 wt.% 2,4-debtor-2-(1H)-1,2,4-triazole-1-elicitation.

4. Dosage form for topical application according to claim 1, characterized in that it contains not more than 2 wt.% water.

5. Dosage form for topical application according to claim 1, characterized in that it contains not more than 1 wt.% water.

6. Dosage form for topical application according to claim 1, characterized in that the dosage form is anhydrous.

7. Dosage form for topical application according to claim 1, Otley is audacia fact, that said dosage form further comprises a corticosteroid in an amount of 0.005 wt.% up to 5 wt.%.

8. Dosage form for topical application according to claim 7, characterized in that the content of the corticosteroid is from 0.01 wt.% up to 3 wt.%.

9. Dosage form for topical application according to claim 7, wherein the corticosteroid is selected from the group consisting of clobetasol, halobetasol, fluocinonide, betamethasone, dexamethasone, beclomethasone, alometasone, diflorasone, fluticasone, hydrocortisone, mometasone, fluoqinolona, desonide and triamcinolone.

10. Dosage form for topical application in the form of a cream or ointment containing from 0.01 wt.% up to 5 wt.% voriconazole or its pharmaceutically acceptable salt, from 0.01 wt.% up to 1 wt.% mometasone pharmaceutical carrier, and the specified dosage form contains not more than 3 wt.% water.

11. Method of preparation of dosage forms for topical application according to claim 1, comprising (a) joint fusion of one or more fillers by heating them to a temperature of about 75°C with the formation of the molten mass; (b) obtaining a dispersion of voriconazole or its pharmaceutically acceptable salt in a solvent; (c) mixing the dispersion obtained in step (b), with the molten mass under stirring; and (d) homogenization of the mixture in accordance with the s approximately 15-30 minutes

12. Method of preparation of dosage forms for topical application according to claim 10, characterized in that the method comprises (a) joint fusion of one or more fillers by heating them to a temperature of about 75°C with the formation of the molten mass; (b) obtaining a dispersion of voriconazole or its pharmaceutically acceptable salt and mometasone in a solvent; (C) mixing the dispersion obtained in step (b), with the molten mass under stirring; and (d) homogenization of the mixture for about 15-30 minutes