UA107968C2 - Pharmaceutical compositions for local application - Google Patents

Abstract

The invention relates to pharmaceutical compositions, to pharmaceutical compositions for local application, containing mometasone furoate. Pharmaceutical compositions for local application containing the total weight of the composition: a) 0.01-0.2% by weight. dispersed mometasone furoate, b) 5-18% by weight. hexylene glycol, c) 20-40% by weight. water and e) 25-70% by weight. oil phase. These compositions are stable and can be safely and easily applied to large areas of the skin surface through appropriate for the patient population in general for the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema), and other disorders or skin disease.

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION BELONGS

The present invention relates to pharmaceutical compositions for topical application containing mometasone furoate. These compositions are stable and can be safely and easily applied to large areas of the skin surface in a manner acceptable to the general patient population.

The present invention additionally relates to the method of obtaining the indicated compositions and methods of treatment by means of the administration of the compositions.

TECHNICAL LEVEL

Topical corticosteroids, as a class, exhibit anti-inflammatory, antipruritic, and vasoconstrictive effects. They are usually used to relieve redness, swelling of the skin (swelling), itching, weathering, scaling, blistering, cracking, exudate through the skin and discomfort in psoriasis, atopic dermatitis (atopic eczema) and other skin conditions similar to contact dermatitis, seborrheic dermatitis, keratic eczema, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis or autoeczematization.

Commercially, topical corticosteroid products are available as ointments, creams, solutions, foams, and lotions. osa apa Ogyd Aatipizigayop (EBA), Sepieg og Ogyd Emaichayop apa

Vezeagtp (SOEV) YuOaia 5iapdati5 Mapiai), Yuozade ouz (mexiop 08) defines an ointment as "a semi-solid dosage form, usually containing less than 20 95 of water and volatile products and more than 50 95 of hydrocarbons, waxes or polyols as a carrier, which, as as a rule, intended for external application to the skin or mucous membranes"; cream as "an emulsion, semi-solid dosage form, usually containing more than 20 95 water and volatile products and/or less than 50 95 hydrocarbons, waxes or polyols as a carrier, which is generally intended for external application to the skin or mucous membranes "; and lotion as "an emulsion, liquid dosage form that is typically intended for external application to the skin."

Due to their physico-chemical properties, lotions are more pleasant to use (cosmetically acceptable) to the end user than ointments or creams, i.e. lotions are easier to apply than ointments or creams and are generally used to treat large areas of the body, for the skin covered with hair and on the hairy part of the head.

Although the mechanisms of the anti-inflammatory effect are unclear, there is probably some correlation

Between the therapeutic effects of corticosteroids and their vasoconstrictor activity. Analyzes of vasoconstrictor properties are usually used to compare and predict the relative therapeutic activity of corticosteroids that are applied locally (MeKep7lie

ALM., ZBiotsdNop VA.V.: Meipoi og sotragipud regsshapeoiv arzogriiop oi 5iegoidv. Agsp Oeptaioi 1962; 86: 608-610).

Mometasone furoate is a corticosteroid commonly used in the treatment of inflammatory skin disorders, allergic rhinitis (such as hay fever), and asthma.

Mometasone furoate is a fine white or whitish powder that is insoluble in water, slightly soluble in octanol, and sparingly soluble in ethyl alcohol.

The extremely poor solubility of mometasone furoate is a limitation for the development of pharmaceutical compositions for topical application.

Various solvents are used for the development of pharmaceutical compositions for topical application containing mometasone furoate, or containing said mometasone furoate partially dissolved and partially suspended, or containing a drug completely dissolved due to the presence of solubilizing agents.

Thus, the US patent Mo 05 4775529 describes pharmaceutical compositions for local use containing corticosteroids (including mometasone furoate), on a water-alcohol basis, containing a) 15-50 95 wt. propylene glycol, B) 20-40 95 wt. of isopropyl alcohol, c) 20-60 95 wt. water, 4) 0.1-3.0 95 wt. thickening agent and f) buffer to set the pH in the range between 3.0-6.0. Other pharmaceutical compositions for topical use based on mometasone furoate/propylene glycol are described in UMO 9108733, UMO2004105686 and UMO2008126076.

On the other hand, the US patent Mo 05 4808610 describes pharmaceutical compositions for local use containing a) 0.01-0.25 96 of mometasone furoate, B) 5-20 95 of hexylene glycol, c) 1.0-5.0 95 of water , a) 2.0-10.0 95 white wax, g) 40-70 95 white vaseline and other ingredients. US patent

Mo 5 4808610 shows that when mometasone furoate is partially dissolved and partially suspended in cream preparations based on propylene glycol, the resulting preparations do not have the required effectiveness; and when mometasone furoate is completely dissolved in oleyl alcohol/propylene glycol based cream preparations, the resulting preparations not only lack the required activity, but are also irritants in rabbit skin studies. In addition, according to the US patent Me 05 4808610, drugs containing agents that solubilize the drug can lead to a deterioration of activity.

Finally, European patent EP 1886686 describes pharmaceutical compositions for local use containing a) 0.01-0.2 96 wt. mometasone furoate, B) 10-90 95 wt. water and c) a combination of at least one aromatic alcohol and at least one solvent selected from two different groups, and e) other optional additives. According to the European patent EP 1886686, the combination of an aromatic alcohol and a solvent increases the solubility of mometasone furoate, eliminating its precipitation, even in the case of an increase in water content.

It has unexpectedly been found that topical pharmaceutical compositions containing mometasone furoate suspended in hexylene glycol-based preparations (i.e., topical pharmaceutical compositions containing solid particles of mometasone furoate dispersed in hexylene glycol-based preparations) are stable, demonstrate efficacy, comparable to mometasone furosate formulations available on the market, and thanks to its physicochemical properties, are easily applied to the skin (easily distributed on the skin), in particular on the skin covered with hair, are quickly absorbed without being irritating to the skin, and as a result, they are more palatable when used in the general patient population.

ESSENCE OF THE INVENTION

Now it was unexpectedly discovered that pharmaceutical compositions for local use containing, relative to the total weight of the composition: a) 0.01-0.2 90 wt. mometasone furoate, p) 5-18 95 wt. of hexylene glycol, c) 20-40 95 wt. of water and a) 25-70 90 wt. oil phase, are stable and exhibit efficacy comparable to commercially available mometasone furoate formulations, although they have a higher water content and contain mometasone furoate suspended (dispersed) in the composition rather than dissolved in it. In addition, due to their physico-chemical properties, these pharmaceutical compositions for topical application are easily applied to the skin (easily distributed on the skin), in particular on the skin covered with hair, are quickly absorbed without being irritating to the skin, and as a result, are more pleasant to use. use for the general patient population.

In addition, patients treated with pharmaceutical compositions for

From the topical application according to the present invention, skin hydration and skin absorption time are shown to be better than patients treated with mometasone furoate compositions available on the market.

In addition, the present invention relates to a composition as defined above for use in the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases.

In addition, the present invention relates to the use of a composition as defined above for the preparation of a medicament for the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases.

In addition, the present invention relates to a method of treating a subject suffering from psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases, which comprises applying to the affected area of the skin of said subject an effective amount of a topical pharmaceutical composition as defined above.

DETAILED DESCRIPTION OF THE INVENTION

Mometasone furoate

Mometasone furoate (yes, 21-dichloro-11p, 17-dihydroxy-1ba-methylpregna-1,4-diene-3,20-dione-17-(2-furoate))| is a corticosteroid with the empirical formula C27HzoSiI»Ov and a molecular weight of 521.4 g/mol.

According to this invention, mometasone furoate anhydrous is preferably used.

Anhydrous mometasone furoate is mometasone furoate in which there are no associated water molecules. Anhydrous mometasone furoate may differ from mometasone furoate monohydrate, which is the hydrated form of mometasone furoate, which has the molecular formula С27НзоСи»Ов»Н2О.

Hexylene glycol

Hexylene glycol (2-methyl-2,4-pentanediol) is a clear, colorless, viscous liquid that absorbs moisture when exposed to moist air. It is miscible with water, alcohol, ether, chloroform, acetone and many other organic solvents. Hexylene glycol has the empirical formula СеН;4О» and a molecular weight of 118.2 g/mol.

Aqueous liquid pharmaceutical compositions

This invention provides pharmaceutical compositions for local use, containing 60, relative to the total weight of the composition:

a) 0.01-0.2 95 wt. mometasone furoate, p) 5-18 95 wt. of hexylene glycol, c) 20-40 95 wt. water and a) 25-70 95 wt. oil phase.

In pharmaceutical compositions for local use according to this invention, the amount of a) mometasone furoate is preferably in the range from 0.05 to 0.15 95 wt., more preferably from 0.08 to 0.12 95 wt., relative to the total masses of composition.

The amount of compound B) of hexylene glycol is preferably in the range from 7 to 15 95 wt., more preferably from 8 to 13 95 wt., relative to the total weight of the composition.

The amount of compound c) water is preferably in the range from 25 to 40 95 wt., more preferably, from 25 to 35 95 wt., even more preferably, from 26 to 34 95 wt., relative to the total weight of the composition.

Preferably, pharmaceutical compositions for local use according to this invention additionally contain, relative to the total weight of the composition, 4) 25-70 95 wt., preferably, 30-65 95 wt., more preferably, 35-45 95 wt., oil phase.

According to the present invention, an oil is a substance that is in a viscous liquid state ("oily") at or slightly above room temperature, and is both hydrophobic (immiscible with water) and lipophilic ( which is mixed with other oils). Oil phases suitable for use according to this invention are hydrocarbon oils (mineral oils, paraffins and waxes), animal and vegetable fats and oils, fatty acids, fatty alcohols, natural waxes, silicones and polyols, other than hexylene glycol, or mixtures thereof .

Hydrocarbon oils suitable for use, that is, mineral oils, paraffins and petroleum waxes according to this invention, are: solid paraffin, liquid paraffin (liquid petroleum jelly or Ragaipit I idpidite), light liquid paraffin (light liquid petroleum jelly or Ragaipit

Repidshiidiite), white soft paraffin (white petroleum jelly), yellow soft paraffin (yellow petroleum jelly), macrocrystalline paraffin waxes (which are mixtures consisting mainly of saturated C:iv-Czo hydrocarbons and smaller amounts of isoalkanes and cycloalkanes with molecular weights between 250 and 450 g/mol, and although they are solid at room temperature, they

Zo have low melting points, which are usually between 40 "C and 60 7C), microcrystalline paraffin waxes (which consist of C.40-Ce5 compounds that contain, in addition to normal hydrocarbons, large amounts of c-alkanes and naphthenes with long alkyl side chains, c-alkanes form microcrystals, microcrystalline paraffin waxes have an average molecular weight between 500 and 800 g/mol, are solid at room temperature, and have melting points between 60 "С and 90 С) or their mixtures.

Preferred hydrocarbon oils are solid paraffin, liquid paraffin, light liquid paraffin, white soft paraffin or their mixture, particularly preferred are liquid paraffin, white soft paraffin or their mixtures.

Animal or vegetable fats and oils suitable for use according to this invention are esters of linear and/or branched, saturated and/or unsaturated alkanecarboxylic acids with a chain length of 1 to 30 carbon atoms and linear and/or branched, saturated and/or unsaturated alcohols with a chain length of 1 to 30 carbon atoms; or are esters of aromatic carboxylic acids and linear and/or branched, saturated and/or unsaturated alcohols with a chain length of 1 to 30 carbon atoms.

These oils can preferably be selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethyl hexyl laurate, 2-ethyl hexyl palmitate, 2-ethyl hexyl cocoate, 2-hexyldecylstearate, 2-ethylhexylisostearate, 2- oxytyldodecyl palmitate, cetyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate, as well as synthetic, semi-synthetic and natural mixtures of complex esters, such as jojoba oil (a natural mixture of complex esters of monounsaturated monocarboxylic acids with a Si-Cg4 chain , as well as with monounsaturated monoatomic alcohols and with a long St-

With a chain).

Other suitable oils of the ester type of saturated alkanecarboxylic acids and alcohols are methyl esters of fatty acids, preferably, methyl esters of Ce-Co4 fatty acids from animal and vegetable fats and oils, such as cottonseed, safflower, coconut, rapeseed, linseed . as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid (cetyl acid), palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, elaidic acid, petroselinic acid, linoleic acid acid, linolenic acid, arachidic acid, gadolinic acid, behenic acid and erucic acid, or their mixture

Other usable animal or vegetable fats and oils according to the present invention are triglycerides of fatty acids, especially complex triglyceride esters of linear and/or branched, saturated and/or unsaturated alkanecarboxylic acids with a chain length of 6 to 24 carbon atoms, preferably from 10 to 18 carbon atoms. Fatty acids esterifying different positions of glycerol can be different, forming a large number of possible combinations, including positional combinations. The position of various fatty acids in natural triglycerides is not random, but rather depends on the origin of the fat.

Simpler triglycerides are compounds consisting of a single fatty acid.

Triglycerides of fatty acids can preferably be selected, for example, from the group consisting of synthetic, semi-synthetic and natural oils, such as, for example, animal fats and oils, such as beef tallow, pork fat, bone oil, marine animal fats and oils (fish , such as herring, cod or sardines; cetaceans; and the like); and from vegetable fats and oils such as avocado oil, almond oil, hazelnut oil, babassu oil, beet oil, peanut oil, canola oil, hemp oil, thistle oil, safflower oil, chufa oil, coconut oil, canola oil, sorghum, wheat germ oil, sunflower oil, linseed oil, macadamia nut oil, corn oil, walnut oil, olive oil and its by-products such as olive pomace oil, palm oil and its fractions such as palm olein and palm stearin , evening primrose oil, rosehip oil, castor oil, rice bran oil, apricot kernel oil, cottonseed oil, pumpkin seed oil, palm kernel oil and its fractions such as palm kernel olein and palm kernel stearin, grape seed oil, sesame oil , soybean oil, cocoa oil, shea seed oil, and the like.

Especially preferred are vegetable fats and oils, as described above.

Fatty acids suitable for use according to this invention are Sv-

C fatty acids from vegetable and animal fats and oils, such as those previously described, such as cottonseed, safflower, coconut, canola, linseed, palm, palm kernel, sunflower, oleic, olive, olive cake oil, castor oil, animal fat, soybean, tallow oil, and the like, possibly fully or partially hydrogenated, as well as refined or synthetic fatty acids such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic (cetyl) acid, palmitoleic acid acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, arachidic acid, gadolinic acid, behenic acid and erucic acid, or mixtures of their technical grades. Fatty acids such as lauric, myristic, palmitic, palmitoleic, stearic, isostearic, 2-ethylhexane, oleic, ricinoleic, behenic or their mixtures, in particular, vegetable oils, are preferred.

Fatty alcohols suitable for use according to this invention are St-

Si fatty alcohols from vegetable and animal fats and oils, such as those previously described, such as cotton, safflower, coconut, rapeseed, linseed, palm, palm kernel, sunflower, oleic, olive, olive cake oil, castor oil, animal fat, soybean, tallow oil, and the like, possibly fully or partially hydrogenated, and refined or synthetic fatty alcohols such as caproyl alcohol, caprylic alcohol, capric alcohol, lauryl alcohol, myristyl alcohol, palmityl (cetyl) alcohol, palmitoyl alcohol, stearyl alcohol, isostearyl alcohol, 2-octyldodecanol, 2-ethylhexanoyl alcohol, oleyl alcohol, ricinoleyl alcohol, elaidyl alcohol, petroseline alcohol, linoleyl alcohol, linolenic alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol and erucyl alcohol, or mixtures their technical grades, such as cetostearyl alcohol. Fatty alcohols such as lauryl, myristyl, palmityl, palmitoleyl, stearyl, isostearyl 2-ethylhexanoyl, oleyl, ricinoleyl and behenyl alcohol or mixtures of their technical grades, such as cetostearyl alcohol, are preferred, especially compounds of plant origin.

Natural waxes suitable for use in accordance with the present invention are candelilla wax, carnauba wax, Japanese wax, esparto wax, cork tree wax, bo guaruma wax, rice wax, sugar cane wax, oigisu wax, mountain wax, beeswax,

shellac wax, spermaceti wax, lanolin wool (wax), lard wax, ceresine waxes, peat waxes, ozokerite, as well as chemically modified waxes (hard waxes), such as mineral wax esters, Fischer-Tropsch waxes , hydrogenated jojoba waxes and synthetic waxes.

Silicones suitable for use in accordance with the present invention are cyclic or linear silicones, which can be found as monomers, in general, characterized by structural elements such as

Kk

Ko-0O-51-0O-Kz where the silicon atoms can be replaced by alkyl or aryl radicals, the same or different, represented here, in general, by groups K.-Va.

Linear silicones with siloxane units suitable for use in accordance with the present invention are generally characterized by structural elements such as: ke KB

О- 5и- О-5и- in Kk t where silicon atoms can be replaced by alkyl or aryl radicals, the same or different, represented here in general by the groups K.-HB,.; (bearing in mind that the number of different radicals is not necessarily limited to 4), t can take values from 2 to 200,000.

Cyclic silicones suitable for use in accordance with the present invention are generally characterized by structural elements such as:

Kk Ev

Y 1 -0- 5I- O-81-

Ez Kk, p where the silicon atoms can be replaced by alkyl or aryl radicals, the same or different, represented here, in general, by groups K.-P,. (bearing in mind that the number of different radicals is not necessarily limited to 4), n can take values from 3/2 to 20. Fractional values of n indicate that there may be odd numbers of siloxane groups present in the ring.

3 Specific examples include cyclic methyl siloxanes of the formula (CH3)"ziOi" in which x is 3-6, or short-chain linear methylsiloxanes of the formula (CH3)"ZiO OH)" 5iOuZ OH)" in which y is 0-5. what

Some useful cyclic methylsiloxanes are hexamethylcyclotrisiloxanes (03), solids with a boiling point of 134 °C and the formula |((Me2)5iO|z; octamethylcyclotetrasiloxane (04) with a boiling point of 176 °C, a viscosity of 2.3 mm' /sec and the formula ((Me»)5iO|; decamethylcyclopentasiloxane (05) (cyclomethicone) with a boiling point of 210 "С, viscosity 3.87 mm"/sec and the formula ((Me»)5iO|» and dodecamethylcyclohexasiloxane (06 ) with a boiling point of 245 "C, a viscosity of 6.62 mm'/sec and the formula |((Me")5iO|v.

Some useful short-chain linear methylsiloxanes are hexamethyldisiloxane (MM) with a boiling point of 100 °C, a viscosity of 0-65 mm'/sec and the formula

Mezb5iOMez; octamethyltrisiloxane (MOM) with a boiling point of 152 "C, a viscosity of 1.04 mm/sec and the formula Mezb5BiOMe5iO5BiMez; decamethyltetrasiloxane (MO2M) with a boiling point of 194 C, a viscosity of 1.53 mm'/sec and the formula MezbziO(Mev5iO) 25iMez; dodecamethylpentasiloxane (MOZM) with a boiling point of 229"C, a viscosity of 2.06 mm'/sec and the formula

Mez5iO(Me»251O)z5iMez; tetradecamethylhexasiloxane (MO4M) with a boiling point of 245 °C, a viscosity of 2.63 mm'/sec and the formula MezviO(Me»2510),5iMez and hexadecamethylheptasiloxane (MO5M) with a boiling point of 270 °C, a viscosity of 3.24 mm'/sec sec and the formula

MezbiO(Me»5iO)55iMez.

In addition, long-chain linear siloxanes such as phenyltrimethicone, bis(phenylropyludimethicone, dimethicone, dimethiconol, cyclomethicone (octamethylcyclotetrasiloxane), hexamethylcyclotrisiloxane, poly(dimethylsiloxane), cetyldimethicone, and behenoxydimethicone may also be included.

In addition, mixtures of cyclomethicone and isotridecylisononanoate and cyclomethicone and 2-ethylhexylisostearate are also suitable silicones for use in accordance with this invention.

Suitable polyols other than hexylene glycol according to this invention are preferably water-soluble polyols, such as polyhydric alcohols with two or more hydroxyl groups in their molecule. Specific examples may include ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, polyethylene glycol with an average molecular weight between 100 and 1000, glucose, fructose, galactose, mannose, ribose, erythrose, maltose. , maltitose, maltotriose, sucrose, xylitol, sorbitol, treit, erythritol, glycerol, polyglycerol and starch alcohols. Preferred polyols other than hexylene glycol are ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, dipropylene glycol, polyethylene glycol having an average molecular weight between 100 and 1000, glycerol, polyglycerol, and mixtures thereof. .

Preferred pharmaceutical compositions for local use according to the present invention contain, relative to the total weight of the composition: a) 0.01-0.2 95 wt., preferably, 0.05-0.15 95 wt., more preferably, 0.08-0 ,12 95 wt. of mometasone furoate, p) 5-18 95 wt., preferably, 7-15 95 wt., more preferably, 8-13 95 wt. of hexylene glycol, c) 20-40 95 wt., preferably, 25-35 95 wt., more preferably, 26-34 95 wt. of water, and a) 25-70 95 wt., preferably, 30-65 95 wt., more preferably, 35-45 95 wt. oil phase.

In a preferred embodiment, pharmaceutical compositions for local use according to the present invention contain, relative to the total weight of the composition: a) 0.05-0.15 95 wt., preferably, 0.08-0.12 to wt. mometasone furoate,

B) 7-15 95 wt., preferably, 8-13 95 wt. of hexylene glycol, c) 25-35 90 wt., preferably, 26-34 90 wt. water, a1) 32-50 95 wt., mainly, 35-48 90 wt. oil hydrocarbons, ag) 5-12 95 wt., mainly, 7-10 95 wt. Ce-Co4 of fatty alcohols and az) 0.1-5 9o wt., preferably, 0.5-3 Fo wt. polyols other than hexylene glycol.

In another preferred embodiment, pharmaceutical compositions for local use according to the present invention contain, relative to the total weight of the composition: a) 0.08-0.12 95 wt. mometasone furoate, p) 8-13 95 wt. of hexylene glycol, c) 26-34 9o wt. water, at) 35-48 95 wt. petroleum hydrocarbons selected from liquid paraffins, white soft paraffins or their mixtures, ag2) 7-1095 wt. Se-Co4 fatty alcohols selected from lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, oleyl alcohol or their mixtures, and az) 0.5-3 9o wt. glycerin

The pH value of the pharmaceutical compositions for topical application according to this invention is generally in the range acceptable for topical administration, and is preferably in the range of 3.0 to 6.0, more preferably in the range of 3.5 to 5, 0.

The viscosity of pharmaceutical compositions for local application according to this invention is usually in the range from 2000 to 15000 mPa:sec, preferably in the range from 2500 to 10000 mPa:sec, more preferably in the range from 3000 to 7000 mPa: sec as measured at

20 "C with the use of OIM-Noiayop5 Apeoteieg (Raag RNuzisa); Meazigipd buziet 2 Z IM; 0-57 1/sec.

Pharmaceutical compositions for topical use according to this invention may optionally additionally contain other well-known pharmaceutically and/or cosmetically acceptable additives, such as, for example, anti-inflammatory agents, antioxidants, buffering agents (agents for pH regulation), chelating agents, thickeners, permeation agents, preservatives, solubilizing agents, thickening agents, wetting agents, and the like, or mixtures thereof.

Examples of useful anti-inflammatory agents are aloe vera, chamomile, alpha-bisabolol, soybean extract, green tea extract, tea tree oil, licorice extract, batyl alcohol (simple α-octadecyl glyceryl ether), selacyl alcohol (simple α-9- octadecenylglyceryl ether), hemyl alcohol (simple /α-hexadecylglyceryl ether), panthenol, allantoin, caffeine or other xanthines, glycyrrhizic acid and its derivatives, and their mixtures.

Antioxidants used can be any antioxidants that are suitable for use or common in cosmetic and/or dermatological applications. Suitable antioxidants are preferably selected from the group consisting of amino acids (eg, glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (eg, urocaninic acid) and their derivatives, peptides, such as O, I-carnosine, O - carnosine, I-carnosine, and their derivatives (for example, anserine), carotenoids, carotenes (for example, α-carotene, p-carotene, lycopene) and their derivatives, lipoic acid and its derivatives (for example, dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (for example, thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, M-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, y-linoleyl, their complex cholesteryl and glyceryl esters) and their salts, dilaurylthiodipropionate, distearylthiodipropionate, thiodipropionic acid and its derivatives (esters, simple esters, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (for example, buthionine sulfoximine iv, homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, heptathionine sulfoximine) in very small tolerable doses (for example, from pmol to

Zo μmol/kg), as well as chelating agents (metals) (for example, α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (for example, citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EOTA, ESTA and their derivatives, unsaturated fatty acids and their derivatives (for example, γ-linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol, and their derivatives, vitamin C and its derivatives (for example, ascorbyl palmitate, Mo ascorbyl phosphate, ascorbyl acetate), tocopherols and their derivatives (for example, vitamin E acetate) and coniferyl benzoate of benzoin, rutinic acid and its derivatives, ferulic acid and its derivatives, butylated hydroxytoluene, butylated hydroxyanisole , nordihydroguaiac acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, zinc and its derivatives (for example, 2pO, 2p50;), selenium and its derivatives (for example, selenomethionine), stilbenes and their derivatives (for example, stilbenoxide, trano-stilbenoxide) and derivatives (salts, esters, simple esters, sugars, nucleotides, nucleosides, peptides and lipids) of the specified active ingredients that are suitable for use according to this invention.

Any pharmaceutically acceptable buffering agent may be used to adjust the pH of the aqueous liquid pharmaceutical compositions of the present invention to a range acceptable for topical administration, preferably in the range of 3.0 to 6.0, more preferably in the range of 3.5 to 5. For example, the composition includes a pharmaceutically acceptable acid, such as acetic, citric, fumaric, phosphoric,

BO hydrochloric, lactic or nitric acids, or something similar, or their mixtures. It will also be understood that certain compositions of the present invention may have a pH in the desired range without including a pH adjusting agent specifically for this purpose. As a rule, however, a system of acid buffers is present in the composition to obtain the desired pH. The system of acid buffers contains an acidifying substance and a buffering agent. Suitable acidifying agents will be known to those skilled in the art, and illustratively include acetic, citric, fumaric, hydrochloric, phosphoric, lactic and nitric acids, and the like, and mixtures thereof. Suitable buffering agents will similarly be known to those skilled in the art and illustratively include potassium metaphosphate, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, and the like, and mixtures thereof.

Suitable emollients that can be used in the compositions of the present invention include, for example, dodecane, squalane, cholesterol, isohexadecane, isononylisononanoate, simple PPO esters, petrolatum, lanolin, safflower oils, castor oil, coconut oil, cottonseed oil , palm kernel oil, palm oil, peanut oil, soybean oil, esters of polyols of carboxylic acids, their derivatives, and the like, and their combinations.

Examples of useful permeation agents may include, for example, dimethylsulfoxide (OM50), M-methylpyrrolidine, dimethylformamide (OME), allantoin, urazole, M,M-dimethylacetamide (OMA), decylmethylsulfoxide, polyethylene glycol monolaurate, propylene glycol, propylene glycol monolaurate, glycerol monolaurate, lecithin, 1-substituted azacycloheptan-2-ones, in particular, 1-n-dodecylcyclazacycloheptan-2-one, alcohols, glycerol, hyaluronic acid, transcutol, and the like, and their combinations. Certain oil components (such as certain vegetable oils such as safflower oil, cottonseed oil, and corn oil) may also exhibit permeability-enhancing properties.

Examples of usable preservatives to prevent microbial contamination are alkylparabens, in particular, methylparaben, propylparaben and butylparaben; sodium benzoate; butylated hydroxytoluene; butylated hydroxyanisole; ethylenediaminetetraacetic acid; chlorobutanol; benzyl alcohol; phenylethyl alcohol; dehydroacetic acid; sorbic acid; potassium sorbate; benzalkonium chloride; benzethonium chloride and their mixtures. The amount of preservative used will generally vary depending on the preservative selected.

Examples of solubilizing agents are, for example, nonionic surface-active substances from at least one of the following groups: addition products of 1-30 mol of ethylene oxide or 0-5 mol of propylene oxide on linear C-C" fatty alcohols, C.i2-C2" fatty alcohols acids and alkylphenols containing 8-15 carbon atoms in the alkyl group; alkyl and/or alkenyl oligoglycosides containing 8-22 carbon atoms in the alkyl group and their ethoxylated analogues; products of addition of 1-15 mol of ethylene oxide with castor oil and/or hydrogenated castor oil; products of addition of 15-60 mol of ethylene oxide with castor oil and/or hydrogenated castor oil; partial esters of glycerol

From mAbo sorbitan with unsaturated or saturated, linear or branched fatty acids containing 12-22 carbon atoms, and/or with hydroxycarboxylic acids containing 3-18 carbon atoms and their addition products with 1-30 mol of ethylene oxide; mixtures of alkylated glycerides and alkylated glycerol, partial esters of polyglycerol (average degree of self-condensation 2-8), polyethylene glycol (weighted average molecular weight 4000-5000), trimethylolpropane, pentaerythritol, sugar alcohols (for example, sorbitol), alkyl glucosides (for example, methylglucoside, butylglucoside, lauryl glucoside) and polyglucosides (for example, cellulose) with saturated and/or unsaturated, linear or branched fatty acids containing 12-22 carbon atoms and/or hydroxycarboxylic acids containing 3-18 carbon atoms and their addition products with 1- 30 mol of ethylene oxide; mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol and/or mixed esters of fatty acids containing 6-22 carbon atoms, methylglucose and polyols, preferably glycerol or polyglycerol; mono-, di- and trialkyl phosphates and mono-, di- and/or tri-RES alkyl phosphates, and their salts; block copolymers, for example, polyethylene glycol-30 dipolyhydroxystearate; polymer emulsifiers; polyalkylene glycols and simple alkylglyceryl ethers. Particularly preferred solubilizing agents are addition products of 1-30 mol of ethylene oxide and/or 0-5 mol of propylene oxide on linear C-C" fatty alcohols, such as lauryl, myristyl, cetyl (palmityl), stearyl, oleyl, and ricinoleyl alcohols, or mixtures of their technical grades, such as cetostearyl alcohol or palmitoleyl alcohol.

A thickening agent or agent for increasing viscosity may be included for general thickening of liquid pharmaceutical compositions. Although any suitable thickening agent may be included in the composition of the present invention, the preferred thickening agent, when used, includes one or more of acacia resin, alginic acid, bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose , ethyl cellulose, glycerin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, gum tragacanth and xanthan gum, and any combination thereof. More preferred thickening agents are glycerin, hydroxypropyl methylcellulose and xanthan gum, and any combination thereof.

Examples of wetting agents (chemicals that improve the distribution and penetration properties of a liquid by reducing its surface tension) include one or more cationic surfactants, such as benzalkonium chloride; nonionic surfactants, such as block copolymers of polyoxyethylene and polyoxypropylene; polyoxyethylene glycerides of fatty acids and oils (such as polyoxyethylene (6) mono- and diglycerides of caprylic/capric acid), polyoxyethylene (40) hydrogenated castor oil; complex polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate 80; esters of propylene glycols and fatty acids, such as propylene glycol laureate; complex glyceryl esters of fatty acids, such as glyceryl monostearate; sorbitan esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; complex glyceryl esters of fatty acids, for example, glyceryl monostearate; anionic surfactants, such as sodium lauryl sulfate, sodium sulfate of simple lauryl ether; or fatty acids and their salts, such as oleic acid, sodium oleate and triethanolaminooleate.

In addition, the present invention relates to a topical pharmaceutical composition as defined above for use in the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases such as contact dermatitis, seborrheic dermatitis, keratitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis or autoeczematization.

The pharmaceutical composition for local use according to the present invention is preferably prepared in the form of a cream.

In addition, the present invention relates to the use of a topical pharmaceutical composition as defined above for the preparation of a medicament for the treatment or prevention of psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases such as contact dermatitis, seborrheic dermatitis, keratitis , dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis, or autoeczematization.

In addition, the present invention relates to a method of treating a subject suffering from psoriasis, atopic dermatitis (atopic eczema) and other skin disorders or diseases such as contact dermatitis, seborrheic dermatitis, keratitis eczema, dyshidrosis, discoid eczema, venous

For eczema, dermatitis herpetiformis, neurodermatitis, or autoeczematization, which involves applying to the affected area of the skin of said subject an effective amount of a topical pharmaceutical composition as defined above.

The method of using the pharmaceutical composition for local application according to the present invention is to apply it in such a way that it completely covers the affected area, forming a protective barrier. The usual frequency of application is once daily, although adequate maintenance therapy for some patients may be achieved with less frequent application.

The following further examples are provided to provide a person skilled in the art with a fairly clear and complete explanation of the present invention, but should not be construed as limiting the main aspects of its subject matter as set forth in the earlier parts of this description.

EXAMPLES

Example 1

Prepare a cream according to this invention, having the composition indicated in Table 1 (95 wt. relative to the total weight of the composition)

Table 1

Cream based on mometasone furoate macrogol" ,

Continuation of table 1

Cream based on mometasone furoate! Emulsifying cetostearyl alcohol type A? Has 20-30 units of ethylene oxide per molecule

This cream is prepared as follows: 1) Oil phase: white soft paraffin, liquid paraffin, cetostearyl alcohol, simple cetostearyl ether of macrogol and cetyl alcohol are added to the main container equipped with an anchor stirrer and a homogenizer. The ingredients are heated to 70 "C and melted while stirring until a homogeneous mixture is obtained. 2) Xanthan gum phase: xanthan gum is pre-dispersed in hexylene glycol. 3) Aqueous phase: approximately 90-95 wt. of the total amount of water is added to a stainless steel container and heated to 70 "C. A pH adjuster is added to the water and dissolved by stirring. Add the xanthan gum phase (stage 2) during homogenization. 4) Combining: the hot water phase of stage (3) is transferred to the main container during mixing and homogenization. 5) The combined phases are cooled to 25 "C with stirring. 6) Mometasone furoate is pre-dispersed in glycerol. This dispersion is diluted with another purified water, and then transferred to an emulsion during homogenization.

Example 2

The viscosity of the cream from Example 1 is measured at 20 "C using OIM-Noiayop5 Npeoteig (Raag Rpuzis); Meazigipd Zuhet 2 Z OIM; 0-57 1/sec.

In addition, measure the viscosity of commercially available mometasone cream, such as ESOCAGO RenNstete 0.1 95, from Ev5eh Rpagt StrN (Comparative example 1) using the same measurement conditions.

According to the product information, each gram of ESOKATF GREISTETE 0.19O contains: 1 mg of mometasone furoate in a hexylene glycol cream base; phosphoric acid; propylene glycol stearate; stearyl alcohol and segeageip-20; titanium dioxide; aluminum starch octenyl succinate; white wax; white petroleum jelly and purified water. The water content of ESOCASF Reisgete is approximately 3-5 95 wt.

The results are shown in Table 2.

Table 2

Viscosity value

Coo)

From the experimental results, it can be concluded that the cream from Example 1 (according to the present invention) can be applied more easily than the cream from Comparative Example 1 (commercially available)

Example C

An analysis of the vasoconstrictor effect, which measures the pallor of the skin (the analysis is described by MeKeplie apa

Ziopdpiop, Agsy. Oeptaiyo!., 86, 608-610 (1962)), used to determine the biological equivalence of the cream from Example 1 (according to the present invention) Her ESOKAG FO Reistete 0.1 95 (Comparative example 1).

Study population: 30 subjects with healthy skin on study field sites demonstrating adequate vasoconstriction in response to corticosteroid administration, aged 18 years or older, are studied.

Conducting research: One-time local non-occlusive application to the research fields located on the volar surface of the forearms. The color of the skin of the treated and untreated fields of the study is measured using chromametry. In addition, the degree of vasoconstriction is evaluated clinically in comparison with the untreated fields of the study.

Efficacy: Under the conditions of this vasoconstriction assay, the local bioavailability of the cream of Example 1 is shown by a strong bleaching effect. A strong bleaching effect in the cream of Example 1 compared to the effect of Comparative Example 1. Eastern AOCs (areas under the curve) are noted for the cream of Example 1 (in accordance with the present invention) and for

Comparative example 1 (commercially available). Local bioavailability of active drugs is shown by means of chromametric measurement and clinical assessment.

Example 4

Biological analysis in psoriasis for the local activity of corticosteroids - the study of psoriasis plaques (the analysis described by Yuitah apa bspoi, Asia Oeptayumepeg (5iosKi), 52, 43-48 (1972)) is also used to determine the biological equivalence of the cream from Example 1 (according to this invention) and ESOKAIH. Steat 0.1 95 (Comparative example 1).

Twenty-two subjects of both sexes are evaluated. Fields of research on psoriatic skin are cleaned of plaques and treated occlusively during the research period of 12 days.

The cream from Example 1 shows a strong positive effect in the treatment of psoriasis.

The antipsoriatic effect of the cream from Example 1 compared to the effect observed for

Comparative example 1, based on sonographic measurements and general clinical assessment. For a carrier that does not contain the active ingredient, no clinical improvement is observed.

Claims (14)

FORMULA OF THE INVENTION 1. Pharmaceutical composition for local use, containing, relative to the total mass of the composition: Zo a) 0.01-0.2 by mass. mometasone furoate, suspended (dispersed) in the composition, p) 5-18 95 wt. of hexylene glycol, c) 20-40 Fo mass. of water and 4) 25-70 95 wt. oil phase. 2. The composition according to claim 1, where the total amount of a) mometasone furoate is in the range from 0.05 to 0.15 95 wt., preferably from 0.08 to 0.12 95 wt., relative to the total weight of the composition. 3. The composition according to any of claims 1 or 2, where the total amount of B) hexylene glycol is in the range from 7 to 15 95 wt., preferably from 8 to 13 95 wt., relative to the total weight of the composition. 4. The composition according to any of the previous items, where the total amount of c) water is in the range from 25 to 40 95 wt., preferably 25-35 95 wt., more preferably 26-34 95 wt., relative to the total weight of the composition. 5. The composition according to any of the previous items, where the total amount of 4) oil phase is in the range from 30 to 65 95 wt., relative to the total weight of the composition. 6. The composition according to claim 1, containing, relative to the total mass of the composition: a) 0.01-0.2 Uo wt., preferably 0.05-0.15 95 wt. mometasone furoate, p) 5-18 95 wt., preferably 7-15 Fo wt. of hexylene glycol, c) 20-40 Fo by mass., preferably 25-35 95 by mass. of water and a) 25-70 95 wt., preferably 30-65 90 wt. oil phase. 7. The composition according to claim 6, containing, relative to the total weight of the composition: a) 0.05-0.15 95 wt., preferably 0.08-0.12 95 wt. mometasone furoate, B) 7-15 95 wt., preferably 8-13 Fo wt. of hexylene glycol, c) 25-35 Uo wt., preferably 26-34 9o wt. water, a1) 32-50 95 wt., preferably 35-48 95 wt. oil hydrocarbons, ag) 5-12 95 wt., preferably 7-10 o wt. Ce-Co4 of fatty alcohols and az) 0.1-5 95 wt., preferably 0.5-3 Fo wt. polyols other than hexylene glycol. 8. The composition according to claim 7, which contains, relative to the total weight of the composition: a) 0.08-0.12 95 wt. mometasone furoate, p) 8-13 95 wt. of hexylene glycol, c) 26-34 Fo mass. water, at) 35-48 95 wt. petroleum hydrocarbons selected from liquid paraffin, white soft paraffin or their 60 mixtures, ag) 7-10 95 wt. Ce-Co4 fatty alcohols selected from lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, oleyl alcohol or their mixtures, and az) 0.5-3 95 wt. glycerin 9. The composition according to any of the preceding items, wherein the composition additionally contains anti-inflammatory agents, antioxidants, buffering agents, chelating agents, emollients, permeability-enhancing agents, preserving agents, solubilizing agents, thickening agents, wetting agents, or mixtures thereof . 10. The composition according to any of the preceding items, wherein the composition has a pH value in the range of 3.0 to 6.0. 11. The composition according to any of the previous items, where the composition is prepared in the form of a cream. 12. The composition according to any one of claims 1-11 for use in the treatment or prevention of psoriasis, atopic dermatitis and other disorders or diseases of the skin. 13. Use of the composition according to any of claims 1-11 for obtaining a medicinal product for the treatment or prevention of psoriasis, atopic dermatitis and other skin disorders or diseases. 14. A method of treating a subject suffering from psoriasis, atopic dermatitis and other skin disorder or disease, comprising applying an effective amount of the composition according to any one of claims 1-11 to the affected area of the skin of said subject.