Polyaphron topical composition with vitamin d and corticosteroid

FIELD: medicine.

SUBSTANCE: what is described is a composition for topical application which contains a continuous phase and at least one disperse phase with said composition containing at least one polyaphron dispersion, at least one vitamin D or vitamin D analogue.

EFFECT: composition is characterised by better skin penetration or better stability.

27 cl, 3 dwg, 17 ex

 

The present invention relates to compositions for topical application containing at least one vitamin D or an analogue of vitamin D and at least one corticosteroid.

It is known that compositions containing vitamin D or vitamin D analogues, used to treat some skin diseases.

For example, in European patent EP-B-474517 describes the use of compositions containing one or more compounds 1α-hydroxy-19-nonvitamin D triple bond in the side chain, in the treatment of psoriasis.

In U.S. patent No. 4871723 described a method of treatment of psoriasis by topical application of a composition containing vitamin D and wax media. In particular, in U.S. patent No. 4871723 described a composition comprising a) a pharmaceutically effective amount of vitamin D3the active type, b) a solvent selected from esters of fatty acids, higher alcohols with 10 or more carbon atoms and propylene carbonate, and (C) an oil carrier selected from white petrolatum, yellow petrolatum and liquid paraffin.

In the application for U.S. patent 2005/002546 A1 describes a pharmaceutical composition containing the combination of active vitamin D in the pre-concentrated emulsion compositions, as well as in emulsions and submicron droplet emulsions obtained from these compositions. In particular, the pharmaceutical compositions described is in application for U.S. patent 2005/002546 A1, contain

(a) a lipophilic phase;

(b) one or more surfactants and

(C) a combination of active vitamin D.

One or more surface-active substances are present in quantities of 1%-90% by weight. calculated on the total weight of the composition, preferably from about 5% to about 85 wt.%. calculated on the total weight of the composition.

Existing in the present compositions contain vitamin D or vitamin D analogues and surfactants at relatively high concentrations, which often causes skin irritation and worsening of psoriasis. For example, in 1996 the American administration food and drug administration has required that in the instructions attached to the drug Dovonex (calcipotriene) - product containing 0.005% calcipotriol, - it was stated that approximately 25% of the subjects skin irritation and approximately 10% worsening of psoriasis. In addition, in scientific publications it was reported that some subjects who Dovonex appeared hypercalcemia (see, for example, the publication Hardman KA, Heath DA, Nelson HM, Hypercalcaemia associated with calcipotriol (Dovonex) treatment. BMJ. 1993 Apr.3; 306 (6882); 896-896).

In addition, it is known that in the treatment of certain skin diseases may use a combination of two or more pharmacologically active compounds. For example, in the treatment of psoriasis can be applied combined the consistent treatment, includes analog of vitamin D, such as calcipotriol and corticosteroid, all active connections are included in the individual preparations (as described, for example, in U.S. patent US-B-6753013).

Preparation methodistic pharmaceutical compositions containing a combination of an analogue of vitamin D and mastromatteo corticosteroid, is associated with certain difficulties due to the fact that these compounds are stable at different pH values.

For example, calcipotriol is most stable at pH values above 8, while corticosteroids, such as betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,2-dione)are most stable at pH 4-6. Therefore, it is difficult to combine in one product two active components while maintaining good stability of the active compounds, if the drug is water.

In U.S. patent US-B-6753013 described pharmaceutical composition for application to the skin, which contains at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and a solvent selected with consideration of the possible coexistence of the two active components without significant decomposition, despite the different profiles of the sustainability of such components. However, these compositions are derived from waxes and include the Usc or similar fillers, such as soft white paraffin and liquid paraffin. The disadvantage of this composition is that the mixing of vitamin D or an analogue of vitamin D and corticosteroid with wax, the wax must be heated to a temperature equal to 70°C. Such high temperatures can cause decomposition of the drug in the composition. In addition, compositions on the basis of the wax is quite oily and after application leave an oily film on the skin. Such a result is undesirable and may cause termination of the application entity.

Another disadvantage of the compositions described in U.S. patent US-B-6753013, is that to achieve favorable results in the local application of these compositions should contain large amounts of vitamin D or analogue of vitamin D for penetration through the skin a sufficient amount of vitamin D or an analogue of vitamin D, since these compositions are characterized by poor penetration through the skin. This factor is unfavorable, because it is known that vitamin D and vitamin D analogues cause skin irritation.

There is a need for an improved composition suitable for topical application, which will eliminate at least some of the problems that previously existed in this area.

The authors present invention Sosnaliev composition, containing at least one vitamin D or an analogue of vitamin D and at least one corticosteroid. It was found that such compositions are characterized by better absorption through the skin and/or better stability compared to known compositions. Such compositions have a viscosity that is acceptable for local use.

Thus, the present invention relates to compositions intended for topical application, which comprises a continuous phase and at least one dispersed phase, with the specified composition contains at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D and at least one corticosteroid.

Another object of the present invention is the composition described in the present description of the invention, which is intended for use in the treatment of psoriasis.

Another object of the present invention is the composition described in the present description of the invention, which is intended for the preparation of drugs for the treatment of psoriasis.

Another object of the present invention is the composition described in the present description of the invention, which is intended for use in implementing the method of therapeutic treatment of the human or animal.

<> Another object of the present invention is a method of treatment or prevention of psoriasis in the subject, which includes local application to a subject an effective amount of the composition according to the present invention.

In the following description, the terms used have the following meanings: hydrophilic phase or solvent means a liquid phase comprising water and water together with other miscible with water, liquids or non-aqueous liquid, miscible with water. The hydrophobic phase or solvent means phase, including pharmaceutically acceptable liquid, such as oil, which do not blend or by being mixed with the hydrophilic phase. The term ”immiscible liquid” means that when mixing such liquids form two separate liquid phases, each with a well-defined surface boundary. The term ”essentially not miscible” means that the two liquids when mixed have a well-defined surface boundary between two phases, however, each phase may contain small amounts of dissolved molecules of the other phase.

Another object of the present invention is a method of obtaining a composition of the present invention, comprising the following stages:

(i) obtaining a hydrophilic solvent, optionally containing ENISA least one vitamin D or an analogue of vitamin D, at least one corticosteroid and/or surfactant;

(ii) obtaining a hydrophobic solvent, optionally containing at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and/or surfactant;

(iii) mixing the hydrophilic solvent and a hydrophobic solvent in acceptable conditions with the formation of a composition containing at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D and at least one corticosteroid.

Another object of the present invention is a method of obtaining a composition of the present invention, comprising the following stages:

receiving the first polihronova dispersion containing vitamin D or an analogue of vitamin D;

receiving the second polihronova dispersion containing corticosteroid;

and mixing the first and second poliamidowych dispersions with the formation of the composition.

The compositions of the present invention have much better penetration of the active agent through the skin compared with the known conosciamo, such as described in U.S. patent US-B-753013. Thus, in the compositions of the present invention can be used in smaller amounts of active agents to achieve favorable outcomes. Thanks to enichem vitamin D and/or analogs of vitamin D in the compositions of the present invention reduces the likelihood of skin irritation and/or other side effects, that may improve compliance, subject to the treatment regimen. In the compositions of the present invention, the vitamin D and/or analog of vitamin D and corticosteroid can coexist in aqueous compositions, containing acceptable and controlled viscosity due to the presence of poliamidowych dispersions, together with any geleobrazovanie included in the composition. Another advantage is that the compositions of the present invention are characterized by good long-term stability even at elevated temperature (40°C). In addition, the presence of water in the compositions may be useful for dissolving water-soluble additives such as water-soluble preservatives, antioxidants, water-soluble amplifiers penetration through the skin, and the like.

Another advantage is that the compositions of the present invention are usually obtained at room temperature without heating, which makes it unlikely that the destruction of the active components in the composition.

Another advantage of the compositions of the present invention is that the composition is less fatty compared to the compositions described in U.S. patent US-B-6753013, making the application process becomes more enjoyable and increases the likelihood of compliance is subject to the treatment regimen.

The composition is according to the present invention has a low anthropogeny potential (i.e., the application of this compound to the skin causes less thinning of the skin in comparison with previously known compositions).

Another advantage of the compositions of the present invention is a low content of surface-active substances. It is known that high concentrations of surface-active substances cause skin irritation. Therefore, it is desirable that when applied to the skin and, in particular, on the affected skin, such as in the case of psoriasis, the content of the surfactant was minimal. The compositions of the present invention preferably contain less than 4% wt. surfactants, more preferably less than 3% and more preferably less than 2 wt.%. of the total weight of the composition.

The term ”poliarnaia variance” in the sense used in this description of the invention, means a certain type of hydrophilic dispersion liquid in a hydrophobic liquid or a hydrophobic liquid in the hydrophilic liquid, which comprises (a) mixing the hydrophilic phase fluid, (b) a second hydrophobic phase that is not miscible or substantially miscible with the first phase, and (C) one or more surfactants, while the dispersed phase has the form of small droplets (e.g., with diameters in the micron - submicron range, but usually with a diameter equal to at least 1 micron) and has the following characteristics that distinguish Polyarnaya variance from a standard or on ycnih emulsions and dispersions of other types:

1. These dispersions can be in a stable form, in which the volume fraction of the dispersed phase (φip) exceeds 0.7 and can reach 0,97. (φipmeans the volume ratio of dispersed phase to continuous phase, expressed as a percentage).

2. Polyarnaya dispersion, in which φipexceeds 0.7, as seen under the microscope are a collection of individual drops, located in close proximity to each other in the form of polyhedra, and remind aerosol. In this form, this dispersion has gel-like properties and is defined as the gel poliarnaia variance (GPD).

3. Sustainable Polyarnaya dispersion can be obtained by using a surfactant in the amount of less than 3%, usually less than 2% wt. of the total weight of the composition.

4. Gel Polyarnaya dispersion (described above in paragraph 2) can be diluted to any extent by adding additional quantities of the continuous phase without the addition of additional quantities of surface-active substances, when the gel-like properties disappear. If you reduce the value ϕipbelow 0.7 separate drops of the dispersed phase are separated from each other, taking the form of spherical droplets, which remain stable and intact, but may nevertheless poorly associirovat the ü and flatironing up or sink down diluted dispersion (depending on the relative density of the two phases). In the specified diluted form every drop is defined as afron colloidal liquid (CLA). A simple shake of the diluted dispersion immediately causes the re-formation of a homogeneous and stable dispersion of Aronov colloidal liquid.

All of these features alone or in combination allow you to clearly differentiate Polyarnaya dispersion of the present invention from the standard emulsions and dispersions of other types that do not possess all of these characteristics. Polyarnaya dispersion are described in the following publications Sebba: "Biliquid Foams", J. Colloid and Interface Science,40(1972) 468-474 and "The Behaviour of Minute Oil Droplets Encapsulated in a Water Film", Colloid Polymer Sciences,257(1979) 392-396, Hicks "Investigating the Generation, Characterization, and Structure of Biliquid Foams", PhD Thesis, University of Bristol, 2005, Crutchley "The Encapsulation of Oils and Oil Soluble Substances Within Polymer Films", PhD Thesis, The University of Leeds, 2006 and Lye and Stuckey, Colloid and Surfaces,131(1998) 119-136. Efroni also described in U.S. patent US-A-4486333 and publications WO 97/32559.

Polyarnaya dispersion is sometimes also referred to as ”foamed binary liquids, emulsions with a high content of dispersed phase (HIPE)”, “emulsion with a high ratio of the dispersed phase (HIPRE)and gel emulsions”. In U.S. patent No. 5573757 composition containing polyamoury dispersion, described as ”viscoelastic gel. All descriptions dispersions having the above-mentioned x is a new, refer to polihronova dispersions in the value used in the present invention.

The term ”topical application” means the use by a person or animal, preferably applied to the skin, including the face, head, feet, legs or torso.

The following is a description of the present invention. In the following paragraphs will be described in more detail different objects of the present invention. Each specified object can be combined with any other object or objects except where otherwise stated. In particular, any sign, defined as preferred or advantageous may be combined with any other sign or signs, defined as preferred or advantageous.

As mentioned above, Polyarnaya dispersion include continuous phase, dispersed phase and a surfactant. The dispersed phase preferably is essentially hydrophobic dispersed phase, known as the dispersed oil phase. The dispersed phase preferably includes a pharmaceutically acceptable oil phase.

Examples of oils that can be used in the present invention, include almond oil, walnut oil palms, black currant oil, borage oil, canola oil, castor oil, coconut oil, pécs is no cod, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard oil, oat oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ, gidrirovannoe castor oil, gidrirovannoe coconut oil, gidrirovannoe cottonseed oil, gidrirovannoe palm oil, gidrirovannoe soybean oil, partially gidrirovannoe soybean oil, gidrirovannoe vegetable oil, isopropylmyristate, isopropyltoluene, isopropyl, modified triglycerides, glycerides of Caprylic/capric acids, fractionated triglycerides, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate/capret, glyceryltrinitrate/capret/laurate, glyceryltrinitrate/capret/linoleate, glyceryltrinitrate/capret/stearate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glyceryltrinitrate, glycerides of linoleic acid, saturated poliglecaprone glycerides, synthetic medium chain triglycerides, containing mainly chain With8-C12fatty acids, medium chain triglycerides, long-chain triglycerides, mo is oficerowie triglycerides, fractionated triglycerides, and mixtures thereof.

The dispersed phase comprises monoglycerides, diglycerides or triglycerides.

It is obvious that the present invention can be used other acceptable oils.

In a preferred variant of the invention, the dispersed phase comprises a triglyceride Caprylic/capric acid and/or isopropylmyristate (IPM).

The dispersed phase, for example, may have a softening, protective, moisturizing, firming, or other cosmetic or pharmaceutical effect on the skin. The dispersed phase may also increase the viscosity of the composition and may report the dissolving ability of the active substances. The dispersed phase may contain substances that have a warming or cooling effect when applied on the skin (e.g., capsaicin or menthol).

The composition may contain at least 1% wt. the dispersed phase, more preferably at least 10 wt.%, at least 25% wt., at least 50% wt., at least 80% wt. disperse phase, calculated on the total weight of the composition.

The compositions of the present invention may be non-aqueous, essentially non-aqueous or water.

The term ”non-aqueous composition” in the sense used in this description of the invention means a composition that does not contain water and not sod is RIT intentionally added water. “Non-aqueous composition” used herein is preferably contains less than 0.5% wt. water based on the total weight of the composition, more preferably less than 0.2 wt.%. water, most preferably less than 0.1% wt. water based on the total weight of the composition.

The term ”essentially non-aqueous composition” in the sense used in this description of the invention means a composition containing less than 5 wt.%, more preferably less than 4.5 wt.%. water based on the total weight of the composition.

The term ”aqueous composition” means a composition comprising at least 5 wt.%. water based on the total weight of the composition. The aqueous composition preferably contains at least 10% or at least 15 wt.%. water based on the total weight of the composition. The aqueous composition may contain at least 35% or at least 40 wt.%. water based on the total weight of the composition. The percentage of water to water the composition is preferably from 5% to 90 wt.%, more preferably from 5% to 50% wt. and most preferably from 8% to 20% wt. calculated on the total weight of the composition.

One way of implementing the present invention relates to aqueous compositions suitable for topical application, which comprises a continuous phase and at least one dispersed phase, with the specified composition of the ash is separated by at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D and at least one corticosteroid. In this embodiment of the invention, the composition preferably contains at least 5 wt.%, more preferably at least 6%, more preferably at least 8 wt.%. water based on the total weight of the composition.

The aqueous composition suitable for topical application, preferably comprises 60-95 wt.%. the dispersed phase and 5-40 wt.%. the continuous phase is calculated on the total weight of the composition, the composition preferably contains 5-40%, 5-30%, or 8% to 20% wt. water based on the total weight of the composition, dispersed phase and/or continuous phase contains at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and at least one surfactant. More preferably the aqueous composition suitable for topical use, contains 70-90% wt. the dispersed phase and 10-30 wt.%. the continuous phase is calculated on the total weight of the composition, with the specified composition preferably includes at least 5-30% wt. or 8-20% by weight. water based on the total weight of the composition, dispersed phase and/or the continuous phase includes at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and at least one surface-active substance.

The song is about the present invention is preferably dispersed in water. The composition according to the present invention preferably can be diluted with water. This property extends the application of the present invention, for example, can improve the coating composition on the head through the hair, making the hair wet, rinse the product with any local surface if the desire or need or easily remove the product accidentally gets on your clothing. These benefits increase the attractiveness of the product for users and improve adherence to the subject a treatment regimen.

The advantage of aqueous compositions, containing at least one vitamin D or an analogue of vitamin D, is the best penetration of drugs, control over the penetration of drugs through the inclusion of certain penetration enhancers or inhibitors of penetration and a more pleasant sensation when applied to the skin.

When continuous or dispersed phase of the composition comprises water, it is desirable to control the pH within acceptable limits. Such control is desirable to obtain a stable composition. It was found that the stable compositions of the present invention can be obtained when the pH value of the composition from 7.0 to 8.5, more preferably from of 7.25 to 7.75. Obviously, to regulate the pH within the specified limits can be and is used any acceptable acid or base. The pH value of the composition generally can be increased by adding a base, which may be triethanolamine. Other acceptable reasons include, but are not limited to, trihydroxystilbene (Tris) and sodium hydroxide. The pH value of the composition can preferably be stabilized by introducing into the aqueous phase is acceptable buffer. Professionals in this field must be known acceptable buffer system having a pH value within the specified range.

The continuous phase may include or basically consist of a pharmaceutically acceptable liquid, which is miscible or substantially miscible with water and preferably is a compound of formula R1-OH, where R1means1-C10alkyl, and/or the compound of the formula BUT-R2-H, where R2means -(C2H4)nor -(C3H6)nwhere n is 1-100, preferably 1-25. R1and R2may have a linear or branched chain. R1preferably means1-C4alkyl. n is preferably 1-25. The continuous phase preferably comprises propylene glycol, polyethylene glycol, glycerin, ethanol, isopropyl alcohol, or their mixture. The polyethylene glycol or polypropylenglycol constituting a continuous phase, preferably is liquid at room temperature (20°C). polietilenglikol, for example, can contain from 1 to 12 parts of ethylene oxide or propylene oxide and/or may have a molecular weight of up to 600.

In one embodiment of the present invention the composition and preferably poliarnaia dispersion includes 0-60 wt.%, preferably 0-20 wt.%, more preferably 0-15 wt.%. With1-C4alcohol, glycol, liquid polyethylene glycol, propylene glycol, liquid polypropylenglycol, diethylene glycol, simple ethyl monoether or mixtures thereof. One advantage of the compositions of the present invention compared with the known compositions is that there is no need to use large amounts of alcohol as substances that enhance penetration through the skin. It is known that alcohol causes irritation when applied to damaged skin. The advantage of the compositions of the present invention is that the best penetration can be achieved even without the use of alcohol or without the use of vast quantities of alcohol. It was found that to achieve a favorable result, the composition of the present invention may include 0-25% wt. alcohol, more preferably 0-15 wt.%. calculated on the total weight of the composition. The alcohol is preferably isopropanol and/or propylene glycol. Such compositions have improved properties on the rate of the drug.

Obviously, in the continuous phase polifrone can be used other acceptable hydrophilic solvents.

Surfactant used in the present invention, can be introduced in one or both phases of polihronova dispersion. Acceptable surfactants include simple alkilany broadcast polyglycol, complex alkilany broadcast polyglycol, ethoxylated alcohol, an ester of fatty acids of polyoxyethylenesorbitan, ester of fatty acid polyethylene oxide, ionic or nonionic surface-active substance adduct hydrogenated castor oil/polyoxyethyleneglycol containing 25-60 ethoxyline groups, the adduct of castor oil/polyoxyethyleneglycol containing 25-45 ethoxyline groups, ester of fatty acid sorbitan (e.g., span 20 or span 80), a block copolymer of ethylene oxide and propylene oxide (for example, Pluronic L121 or Pluronic F68) or their mixture.

Obviously, that can be used other acceptable surface-active substances.

The compositions of the present invention preferably contain less than 4% wt. surfactants, more preferably less than 3 wt.%, more preferably less than 2 wt.%. of the total weight of the composition.

The composition of the present invention may include at least one of vitamins is D or analog of vitamin D, mainly in the continuous phase or mainly in the dispersed phase. Most preferably, at least one vitamin D or an analogue of vitamin D is present mainly in the dispersed phase.

Analogue of vitamin D used in the compositions of the present invention, for example, can be calcipotriol, seocalcitol, calcitriol, calcipotriol monohydrate, tacalcitol, maximality, paricalcitol, falecalcitriol, becocalcidiol, 1α,24S-dihydroxy-vitamin D2, 1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)phenyl)methoxy)methyl]-9,10-scoprega-5(Z),7(E),10(19)-triene or their mixture. More preferably, an analog of vitamin D is calcipotriol, calcitriol, tacalcitol, maximality, 1α,24S-dihydroxy-vitamin D2, 1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)phenyl)methoxy)methyl]-9,10-scoprega-5(Z),7(E),10(19)-triene or their mixture. Most predpochtitelno vitamin D analogues are calcipotriol and calcipotriol monohydrate. Other examples of acceptable analogues of vitamin D are given in U.S. patent US-B-6753013.

Synthetic analogs of vitamin D are more preferred in the compositions of the present invention, than the natural vitamin D or derivatives of vitamin D, as therapeutic effect of these latter substances may be less selective in the treatment of skin diseases such as psoriasis.

Compo is ice of the present invention may contain of 0.0001 to 0.05 wt.%. vitamin D or analogue of vitamin D, preferably 0.001 to 0.01 wt.%. and more preferably 0,0025-0,005% by weight. of the total weight of the composition.

The corticosteroid may be mainly in the continuous phase or mainly in the dispersed phase. Corticosteroid is preferably mainly in the dispersed phase. More preferably as a corticosteroid and vitamin D or an analogue of vitamin D are present mainly in the dispersed phase. Mass relationship of corticosteroid to vitamin D or analogue of vitamin D are preferably in the range from 4:1 to 50:1, more preferably from 8:1 to 20:1 and most preferably from 9:1 to 11:1.

Corticosteroid is preferably selected from one or more substances comprising betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) or its esters, such as the 21-acetate, 17-adamantoyl, 17-benzoate, 17-valerate and 17,21-dipropionate; alclometasone or its esters, such as 17,21-dipropionate; clobetasol or its esters such as propionate; clobetasol or its esters, such as 17-butyrate; desoximetasone; diflucortolone or its esters diflorasone or its esters, such as 17,21-diacetate; fluocinonide; flumetazon or its esters, such as 21 pivalate; fluotsinolon or its ethers, such as acetonide; fluticasone or e is about esters, such as 17-propionate; flupredniden or its esters, such as the 21-acetate; halcinonide; hydrocortisone or its esters, such as 17-butyrate; mometazon or its esters, such as 17-(2-furoate); and triamcinolone, or its ethers or esters, such as the acetonide. Can be selected from corticosteroids, giving nitric oxide, such as TPI 1020 (NicOx). More preferably, the corticosteroid selected from one or more substances comprising betamethasone or its esters, such as 17-valerate or 17,21-dipropionate; clobetasol or its esters such as propionate; triamcinolone, or its ethers or esters, such as acetonide or acetonide-21-N-benzoyl-2-methylalanine or acetonide-21-(3,3-dimethylbutyryl); or hydrocortisone or its esters, such as 17-butyrate. Most preferably, the corticosteroid is 17,21-dipropionate betamethasone.

The composition according to the present invention preferably contains 0.001 to 1.0% by weight. corticosteroid, more preferably 0.01 to 0,075% wt. and even preferable 0,025-0,05% wt. of the total weight of the composition.

The composition of the present invention may further include gelling and/or a rheology modifier, such as a viscosity modifier.

Gelling may be selected from, for example, alginate resins or their salts, guar gum, calderini, xanthan gum, Arabic gum, gelatin, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, carboxymethylcellulose or its salts, bentonites, silicates of magnesium, ”carbonero” (salts of cross-linked polymers of acrylic acid) or glyceryltrinitrate or their dispersions in glycols. Obviously, that can be used other acceptable geleobrazovanie. In addition, it was found that some geleobrazovanie (for example, carbomer) can also act as a chemical buffer, preventing unwanted change in the pH of the composition during storage and application.

The composition according to the present invention preferably contains 0.05 to 5.0 wt.%. the gel, more preferably 0.1 to 2.0% wt. and more preferably 0.2 to 1.0 wt.%. of the total weight of the composition.

In one embodiment of the present invention, the composition has the consistency of a gel. Gel-like consistency can be obtained from one, two, three or more poliamidowych dispersions. This composition preferably is an aqueous composition.

The composition according to the present invention can be used in the implementation of the method of therapeutic treatment of the human or animal. In addition, the composition according to the present invention can be used in the treatment of p is Oriana. The composition according to the present invention can also be used to produce medicines for the treatment of psoriasis.

In one embodiment of the present invention the composition according to the present invention can be applied on the scalp or other area of the skin through the hair. In the specified embodiment of the invention the hair is preferably moistened (e.g., water with shampoo or without shampoo and then dried with a towel). Then on the scalp causing an appropriate amount of product and RUB into the scalp through the hair. The hair can be dried naturally or with a hair dryer. Dispersible in water composition allows to evenly distribute the active substance in the skin when performing this method. Alternative or additionally, the composition can be rubbed into the scalp through dry hair and leave on for a certain time (which can range from 8 to 12 hours), after which the excess or remaining portion of the composition is washed off with water and shampoo or without shampoo. The composition of the present invention is used to treat an animal, preferably in the form of a standard dosage forms.

The compositions of the present invention may also include other additives, such as preservatives (for example, to prevent microbiological spoilage), buffers (for whom regulirovaniya pH values and in order to avoid instability and damage to the acidic environment of the skin), antioxidants and penetration enhancers. These additives can be incorporated in the continuous or dispersed phase of polihronova dispersion.

Obviously, the number and type of additives must meet the criteria of effectiveness and benefit. You need to carefully approach the selection and determining the quantity of these additives in order to avoid negative impacts on other characteristics of the present invention.

In one embodiment of the present invention, the vitamin D or an analogue of vitamin D according to the present invention is dispersed and/or dissolved in the dispersed phase of the first polihronova dispersion. Corticosteroid is dispersed and/or dissolved in the dispersed phase of the second polihronova dispersion. Then the first and second Polyarnaya dispersion is mixed with the formation of the compositions of the present invention. In the composition of the present invention may be present in the third or subsequent Polyarnaya dispersion. Third or subsequent Polyarnaya dispersion may include, for example, substances such as emollient oils (the best feeling), the protective oil that prevents dehydration of the skin and improves the penetration of skin active agents, warming or cooling the skin of the substance or sunscreen agents. These substances are preferably present is comfort in the dispersed phase poliamidowych dispersions.

In one embodiment, the present invention analogue of vitamin D is calcipotriol or calcipotriol monohydrate.

In a particularly preferred composition of the dispersed phase forms a triglyceride Caprylic/capric acid continuous phase forms demineralized water, an analog of vitamin D is calcipotriol and corticosteroid is betamethasone dipropionate.

In one embodiment of the present invention, the composition includes at least one dispersed phase, which contains at least one of the substances constituting the triglycerides of capric/Caprylic acid, squalane, Dimethicone, cyclomethicone, and mixtures of two or more of the above substances, an analog of vitamin D is calcipotriol and corticosteroid is betamethasone dipropionate. Preferred surface-active substances in the specified embodiment of the invention are Laureth-4 and Poloxamer 188. The continuous phase preferably includes water. Such a variant embodiment of the invention shown in example 1. This composition remains stable over a long period of time, for example within 3 months, 6 months or 9 months. This composition is characterized by good solubility of the active substances and the best penetration through the skin, vyzyvae the pleasant sensation on the skin during and after application.

In another embodiment of the invention the composition according to the present invention includes at least one dispersed phase, which contains at least one of the substances constituting the triglycerides of capric/Caprylic acid, squalane, Dimethicone, isopropylmyristate, cyclomethicone, and mixtures of two or more of the above substances, an analog of vitamin D is calcipotriol and corticosteroid is betamethasone dipropionate, a preferred surface-active substances in the specified embodiment of the invention are Laureth-4 and Poloxamer 188. The continuous phase preferably includes water and polyacrylic acid neutralized with triethanolamine, resulting in a gel with a controlled viscosity. Such a variant embodiment of the invention shown in example 3. In this composition used water-gel phase to achieve greater cramptons viscosity and buffer capacity with excellent pH value.

In another embodiment of the invention the composition according to the present invention includes at least one dispersed phase, which contains at least one of the substances constituting the triglycerides of capric/Caprylic acid, squalane, Dimethicone, isopropylmyristate and cyclomethicone, and mixtures of two or more of the above in the substances analogue of vitamin D is calcipotriol and corticosteroid is betamethasone dipropionate, a preferred surface-active substances in the specified embodiment of the invention are Laureth-4 and Poloxamer 188. The continuous phase preferably includes water and xanthan gum, resulting in a gel with a controlled viscosity. Such a variant embodiment of the invention shown in example 5. It was found that the use of xanthan gum provides excellent stability at a lower viscosity, which is necessary in the case of use as a lotion, not a cream.

In another embodiment of the invention the composition according to the present invention includes at least one dispersed phase, which contains at least one of the substances constituting the triglycerides of capric/Caprylic acid, squalane, Dimethicone, silicone elastomer, isopropylmyristate and cyclomethicone, and mixtures of two or more of the above substances, an analog of vitamin D is calcipotriol and corticosteroid is betamethasone dipropionate, a preferred surface-active substances in the specified embodiment of the invention are Laureth-4 and Poloxamer 188. The continuous phase preferably includes water, isopropyl alcohol and polyacrylic acid, neutral is sofanou the triethanolamine, resulting in a gel with a controlled viscosity. Such a variant embodiment of the invention shown in example 13. Silicone elastomer added to the dispersed phase to improve the cosmetic properties of the product. The product obtained in accordance with this embodiment of the invention, is characterized by a pleasant feeling after application (residual sensation perceived by the skin after application of the product) and improved protective properties.

In another embodiment of the invention the composition according to the present invention includes a dispersed phase, which contains isopropylmyristate and at least one of the substances constituting squalane, Dimethicone, silicone elastomer and cyclomethicone. In the specified embodiment of the invention, the corticosteroid is betamethasone dipropionate, an analog of vitamin D is calcipotriol, and preferred surfactants are Laureth-4 and Poloxamer 188. The continuous phase preferably includes water and polyacrylic acid neutralized with triethanolamine, resulting in a gel with a controlled viscosity. The product obtained in accordance with this embodiment of the invention, is characterized by a significantly better penetration compared with other options implemented the program of the invention.

One object of the present invention is a method of obtaining a composition described in the present description of the invention, which comprises the following stages:

(i) obtaining a hydrophilic solvent, optionally containing at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and/or surfactant;

(ii) obtaining a hydrophobic solvent, optionally containing at least one vitamin D or an analogue of vitamin D, at least one corticosteroid and/or surfactant;

(iii) mixing the hydrophilic solvent and a hydrophobic solvent in conditions suitable for formation of a composition containing at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D, and at least one corticosteroid.

Acceptable methods of obtaining poliamidowych dispersions described in U.S. patent US-A-4486333. Professionals in this field should be clear that, where possible, can be used other ways to get.

Another object of the present invention is a method of obtaining a composition described in the present description of the invention, which comprises the following stages:

receiving the first polihronova dispersion containing vitamin D or similar vitamins to anti scar is on D;

receiving the second polihronova dispersion containing corticosteroid;

and mixing the first and second poliamidowych dispersions with the formation of the composition.

This method may further include:

obtaining a third or subsequent polihronova dispersion containing one or more active agents, such as sunscreen agent, cooling agent, a warming agent, antipruritic agent, substance, giving the product an aesthetic appearance, cosmetic, foaming agent, a flavoring, a colorant, an antioxidant or emollient oil, and mixtures of these substances;

and mixing a third or subsequent polihronova variance with those of the first and second poliarnoye variance with the formation of the composition. The composition described in the present description of the invention, can be applied on the skin in the form of an aerosol or sprayable solution. For example, in EP 1575542 described the introduction of foam binary liquid in the aerosol.

The composition according to the present invention can be introduced into the aerosol by adding water and a gaseous propellant (e.g., butane).

The composition according to the present invention can be obtained, for example, in the form of lotion or cream. This composition can be stored in any appropriate vessel, tube, bottle, sachet, aerosol, Raspletin is or sealed containers injection type. To maintain the composition in a stable state preferably prevent the ingress of oxygen into the container. The compositions of the present invention is preferably hermetically sealed in airtight containers to prevent decomposition of the songs to their use.

The present invention will be further described based on examples with reference to the following figures.

The figure 1 shows the HPLC chromatogram of stable sample (example 7). Shows peaks for calcipotriol (3.9 minutes) and betamethasone dipropionate (BDP) (5,3 min). There are no signs of decomposition. Conditions HPLC: column: NovaPak C18, particle size 4 microns, the size of the column of 3.9×150 mm (Waters), mobile phase: 55% acetonitrile in water. Flow rate: 1 ml/minute. The column temperature: 25°C.

The figure 2 shows the HPLC chromatogram of volatile sample. Shows the decomposition of betamethasone dipropionate (additional peak and shoulder peak corresponding to 2.5 minutes) and some signs of decomposition of calcipotriol (a very small peak corresponding to 3.3 min). Conditions HPLC: column: NovaPak C18, particle size 4 microns, the size of the column of 3.9×150 mm (Waters), mobile phase: 55% acetonitrile in water. Flow rate: 1 ml/minute. The column temperature: 25°C.

The figure 3 shows the HPLC chromatogram of decomposition kalipur the Ola, as evidenced by the presence of extraneous peaks (4.5 min and 3.6 min) on both sides of the main peak of calcipotriol (3.9 minutes). In this sample there was no betamethasone dipropionate (BDP), so the peaks cannot be attributed to the decomposition of the BDP. Conditions HPLC: column: NovaPak C18, particle size 4 microns, the size of the column of 3.9×150 mm (Waters), mobile phase: 55% acetonitrile in water. Flow rate: 1 ml/minute. The column temperature: 25°C.

Determination of resistance

In the present invention the product is stable when stored in compliance with the following criteria.

The product is stored in closed airtight glass container in which the free space is not more than 5% of the total volume used capacity.

The product and above the capacity is kept at a constant temperature equal to 40°C, in standard laboratory thermostat (for example, air thermostat 'Function Line' Heraeus model UT6, temperature control within ±0.3°C at 150°C).

The product is examined at the end of the test. The test period is equal to at least 3 months and preferably at least 6 months from the date of commencement of storage.

Below are the criteria for successful storage:

MethodThe criterion of successful store
Visual comparison of the appearance of the stored sample with a standard sample stored at 20°C for the same period.A visual comparison shows the presence of very slight differences, if such a distinction at all between the stored sample and the standard sample. In particular, the appearance of the sample is homogeneous without any signs of separation into two or more separate phases.
Microscopic examination of at least 200-fold magnification and compare the appearance of the stored sample under the microscope with the existing image of the appearance of this sample at the beginning of storage.The study shows the presence of very minor changes, if such a change takes place, the size and size distribution poliamidowych drops without any signs of phase separation.
Analysis of the pharmacologically active components of the composition by extraction and the following HPLC method.The content of each of the active substance should not decrease more than 5% wt. compared with the initial content at the beginning of the test storage after 3 months storage. Known productionline active substances, if such products are generally present, in aggregate, should not exceed 5% of the initial content of active substances on the basis of measurements of the area under the curve. Cm. figures 1-3 for further clarification.

All stored samples that satisfy the above criteria in the above test conditions are considered stable if stored in accordance with the purposes of the present invention.

The guidelines of the American administration food and drug administration ”Guidance for Industry Q1A (R2) Stability Testing of New Drug Substance and Products”, which although not mandatory, specified more stringent storage conditions, which include storage at specific temperatures (e.g. 40°C) during a specific period of time (6 months) and at a controlled relative humidity (relative humidity 75%). In the European Agency for the evaluation of medicinal products ICH Q1A (R2) Stability Testing Guidelines: Stability Testing of New Drug Substances and Products” specified identical conditions for more stringent tests for safety. The above method is tested for safety in accordance with the purposes of the present invention does not include the control of relative humidity, as the product is stored in closed glass containers, walls and tubes which are neroni Emami for the passage of water vapor.

The above definition of the stability during storage is specifically designed for the purposes of the present invention. However, data stored in some of the examples were obtained by replacing the closed glass containers (laboratory glass beaker) hermetically sealed tubes of Eppendorf. This method has been used for relatively small amounts of sample and reasonably corresponds to the method specified in the definition as Eppendorf tubes also create an impenetrable barrier to water vapor and other components of the composition. Research method for Eppendorf tubes (plastic) is identical to the method specified in the definition.

The present invention is further illustrated by the following examples.

EXAMPLE 1

Three gel Polyarnaya dispersion of the following composition were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0695%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,0
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3465%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

% wt./wt.
GEL POLIARNAIA DISPERSION 3
The oil phase
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-1920, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 17,20
GEL POLIARNAIA VARIANCE 218,60
GEL POLIARNAIA DISPERSION 374,20
* The content of calcipotriol in the final composition is 50 mcg/g
** The content of betamethasone dipropionate in the final composition is 643 µg/g (th is equivalent to 500 µg/g of betamethasone).

Method get

Three Polyarnaya dispersions were obtained separately as described below.

In a 250 ml low a beaker (inner diameter 6.5 cm) was injected aqueous (continuous) phase in an amount necessary to obtain 30 g poliarnogo gel. The aqueous phase was stirred at 200 rpm using a four-bladed stirrer with a diameter of 6.0 cm and at the same time from the Pasteur pipette was added dropwise oil (dispersed) phase. Speed add in the beginning of the process was slow (about one drop every 7 seconds), but after adding 10% oil phase speed was increased, resulting in a total time of receipt poliarnogo gel was equal to about 20 minutes.

To obtain each gel polihronova dispersion of active ingredients are dissolved in the appropriate phase, gently stirring in a closed beaker using a magnetic stirrer at room temperature overnight.

To obtain the final product was mixed three separate Polyarnaya dispersion.

Measuring sustainability - conditions 1A

Measure the resistance produced as described below. In the example data stability during storage were obtained using the Eppendorf tubes.

Calcipotriol and be Amazon were extracted from the composition, obtained in example 1 in isopropanol and analyzed by HPLC under the following conditions.

Conditions HPLC:

Column: NovaPak C18, particle size 4 microns, the size of the column of 3.9×150 mm (Waters).

Mobile phase: 47% acetonitrile in water.

Flow rate: 1 ml/minute.

The column temperature: 25°C.

Retention time for calcipotriol was equal to 6.8 minutes.

Retention time for betamethasone was equal to 9.9 minutes.

It was found that after storage for 2 months at 40°C. the levels of calcipotriol and betamethasone, respectively 102%±3% and 99%±1% of initial levels.

Measuring sustainability - conditions 1b

Measure the resistance produced as described below. The samples were stored in (airtight) laboratory glass beakers in the corresponding thermostat at 40°C in accordance with the above description.

Calcipotriol and betamethasone were extracted from the composition obtained in example 1 in isopropanol, mixing the sample in isopropanol, and then were treated with ultrasound and centrifuged. Aliquots of the supernatant were analyzed by HPLC under the following conditions.

Conditions HPLC:

Column: NovaPak C18, particle size 4 microns, the size of the column of 3.9×150 mm (Waters).

Mobile phase: 55% acetonitrile in water.

Flow rate: 1 ml/min

The column temperature: 25°C.

Retention time for calcipotriol was equal to 3.9 minutes.

Retention time for betamethasone was equal to 5.3 minutes.

It was found that after storage for 2 months at 40°C. the levels of calcipotriol and betamethasone, respectively 102%±3% and 99%±1% of initial levels.

EXAMPLE 2

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,06766%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
Oil f is for %
A solution of betamethasone dipropionate** (0,3066%) in a mixture of isopropylmyristate (Lexol IPM NF - Inolex) and triglyceride Caprylic/capric acid (Mygliol 812 - Condea) with a ratio of 3:2 wt./wt.89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)1,00
Triethanolamine (tea)to pH 7,50
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 19,19
GEL POLIARNAIA VARIANCE 223,61
GEL POLIARNAIA DISPERSION 347,27
Propylene glycolof 10.05
Water-based gel9,88
* Soda is the content of calcipotriol in the final composition is a 55.4 ág/g
** The contents of the BDP in the final composition is equal to 502 mg/g

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added propylene glycol and neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

The neutralized gel was obtained by adding triethanolamine (base) to the dispersion of polyacrylic acid with the formation of a transparent gel having a pH value equal to 7,5±0,2. Specialists in this field there is a method of neutralization of polyacrylic acid gels.

Measuring sustainability

Stability was tested by the method described in example 1b.

It was found that after storage for 3.5 months at 40°C in laboratory glass beakers levels of calcipotriol and betamethasone dipropionate, respectively 104±12% and 95±2% of initial levels.

Currently, the test of the stability of this sample.

In the publication of Simonsen and others, Drug Development and Industrial Pharmacy, 30(10) (2004) 1095-1102, indicated that the introduction of propylene glycol in the product containing calcipotriol and betamethasone, causes rapid decomposition of one of the two active substances in chief of the dependence on pH, although propylene glycol is a very good amplifier to the flow velocity. The authors of the above mentioned publications have come to the conclusion that it is impossible to enter the propylene glycol in the resulting product. The above example shows that the authors of the present invention has overcome this problem. In table 2, shown in example 2 of U.S. patent US-B-6753013, illustrates the decomposition of calcipotriol in the product containing calcipotriol, betamethasone dipropionate and propylene glycol, after storage for 2.5 months at 40°C.

EXAMPLE 3

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

Poloxamer 188 (Pluronic F68 - BASF)
GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0573%) in a mixture of isopropylmyristate (Lexol IPM NF - Inolex) and triglyceride Caprylic/capric acid (Mygliol 812 - Condea) with a ratio of 3:2 wt./wt.89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3838%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimetic is n (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)1,00
Triethanolamine (tea)to pH 7,50
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 112,95
GEL POLIARNAIA VARIANCE 220,18
GEEL IS the FIRST POLIARNAIA DISPERSION 3 57,05
WATER-based GEL9,82
* The content of calcipotriol in the final composition is 66,1 mcg/g
** The content of betamethasone dipropionate in the final composition is equal to 690 ág/g (equivalent to 537 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1b.

It was found that after storage for 9 months at 40°C in tightly closed laboratory glass beaker levels of calcipotriol and betamethasone dipropionate were, respectively, 97±7% and 105±6% of the initial levels.

EXAMPLE 4

Three gel Polyarnaya dispersion of the following composition were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0237%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Sucrose (Fisher)1,00
Demineralized water8,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3085%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Sucrose (Fisher)1,00
Demineralized water8,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)20,00
Dimethicone (Q7-9120, 20 CP - Dow Corning)35,00
Cyclomethicone (STb5NF - Dow Corning)29,10
Elastomer DC10 (Dow Corning)5,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Sucrose (Fisher)1,00
Demineralized water8,00

The FINAL PRODUCT/td> % wt./wt.
GEL POLIARNAIA VARIANCE 127,99
GEL POLIARNAIA VARIANCE 226,56
GEL POLIARNAIA DISPERSION 345,45
* The content of calcipotriol in the final composition is 59,0 mcg/g
** The content of betamethasone dipropionate in the final composition is 730 µg/g (equivalent to 568 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in example 1.

Measuring sustainability

Stability was tested by the method described in example 1b.

It was found that after storage for 4.5 months at 40°C in tightly closed laboratory glass beaker levels of calcipotriol and betamethasone dipropionate were, respectively, 100% and 119% of the initial levels.

After 6 months, the levels of calcipotriol and betamethasone dipropionate were, respectively, 42% and 65% of the initial levels.

Currently, the test of the stability of this sample at room temperature.

EXAMPLE 5

Three gel Polyarnaya dispersion and water is the first gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0452%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Monooleate polyoxyethylene(20)sorbitan (Surfacare T80)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,2889%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Monooleate polyoxyethylene(20)sorbitan (Surfacare T80)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
0,50
NaH2PO4(in the form of phosphate buffer with pH 7,50, 50 mm)0,60
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 111,66
GEL POLIARNAIA VARIANCE 227,54
GEL POLIARNAIA DISPERSION 350,87
WATER-based GELto 9.93
* The content of calcipotriol in the final composition is 47,0 mcg/g
** The content of betamethasone dipropionate in the final composition is 709 μg/g (equivalent to 551 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring is about the formation of homogeneous mixture poliamidowych dispersions.

EXAMPLE 6

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,02687%) isopropylmyristate (Lexol IPM NF - Inolex)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Propane-2-ol2,70
Demineralized waterof 5.40

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3289%) isopropylmyristate (Lexol IPM NF - Inolex) 89,00
Laureth-4 (Volpo L4 - Croda)1,00

The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Propane-2-ol (Fisher)2,70
Demineralized waterof 5.40

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F8 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10, a Noveon)2,00
Propane-2-ol (Fisher)30,00
50% triethanolamine (aqueous solution)to pH 7,29
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 125,00
GEL POLIARNAIA VARIANCE 225,00
GEL POLIARNAIA DISPERSION 340,00
WATER-based GEL10,00
* The content of calcipotriol in the final composition is equal to 67.9 mcg/g
** The content of betamethasone dipropionate in a horse is Noah composition is 783 ág/g (equivalent to 609 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A, the samples were stored in sealed Eppendorf tubes.

It was found that after storage for 3 months at 40°C. the levels of calcipotriol and betamethasone, respectively 101% and 106% of the original levels. Currently, the test of the stability of this sample.

After storage for 6 months at 40°C. the levels of calcipotriol and betamethasone, respectively 107% and 100% of the initial levels.

EXAMPLE 7

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution calcipotriol the La* (0,0258%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90

The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,325%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)20,00
Dimethicone (Q7-9120, 20 cSt Dow Corning)35,00
Elastomer DC10 (Dow Corning)5,00
Cyclomethicone (STb5NF - Dow Corning)26,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Carbomer ETD 2020, supplier)2,00
Dinitroanthraquinone acid (Na2EDTA, Fisher)0,20
Sodium bisulfite (NaHSO3, Fisher)0,50
20% aqueous NaOH solutionto pH 7,71
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 125,00
GEL POLIARNAIA VARIANCE 225,00
GEL POLIARNAIA DISPERSION 320,00
WATER-based GEL30,00
* The content of calcipotriol in the final composition is 57,4 mcg/g
** The content of betamethasone dipropionate in the final composition is 723 ág/g (equivalent to 562 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring to education homogen the th mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A, the samples were stored in sealed Eppendorf tubes.

It was found that after storage for 3 months at 40°C. the levels of calcipotriol and betamethasone were, respectively, 96% and 103% of the initial levels. Currently, the test of the stability of this sample. A further test of the stability after storage for 6 months at 40°C showed that the levels of calcipotriol and betamethasone were, respectively, 96% and 103% of the initial levels.

EXAMPLE 8

A commercial product (Dovobet (LEO Pharma), no party EA).

Dovobet is a commercial product sold under the names Daivobet and Taclonex.

ProductIngredient (in order of concentration)The feeling on the skin
Example 1 in U.S. patent No. 6753013 B11. The betamethasone dipropionate
2. Calcipotriol (hydrate)
3. Simple polyoxypropylene-15-stearyl ether
4. α-Tocopherol
5. White soft paraffin
Very sticky and oily surface
Dovobet (also known as Daivobet, Taclonex) 1. The betamethasone dipropionate
2. Calcipotriol (hydrate)
3. Simple polyoxypropylene-15-stearyl ether
4. α-Tocopherol
5. White soft paraffin
Very sticky and oily surface

Sample commercial product was stored in a tightly closed laboratory glass beaker at 40°C. similarly to the above examples.

After storage for 3 months, the sample was analyzed by the extraction method described in example 1. Analysis by HPLC (similar to above) showed that the levels of calcipotriol and BDP in medicine were, respectively, 91% and 70% compared with analyses of the received sample.

EXAMPLE 9

One gel poliarnaia dispersion of the following composition was obtained as described below.

GEL POLIARNAIA VARIANCE
The oil phase%
The solution of calcipotriol* (0,0133%) and BDP (0,1554%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)90,00
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
NaOH solution (20% wt./wt.)to a pH of 8.50
Demineralized waterto 9.00
* The content of calcipotriol in the final composition is 120 mcg/g
** The content of betamethasone dipropionate in the final composition is 1399 µg/g (equivalent 1088 mg/g betamethasone).

Method get

Poliarnaia dispersion was obtained by the method described in example 1.

Measuring sustainability

Measure the resistance was performed by the method described in example 1b.

It was found that after storage for 1 month at 40°C in tightly closed laboratory glass beaker was divided compositions with education systems containing significant oil phase on top poliarnogo gel. In the sample stored at room temperature for 18 months, the levels of calcipotriol and betamethasone were, respectively, 97%±3% and 98%±3% of initial levels.

EXAMPLE 10

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0671%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3294%) in a mixture of isopropylmyristate (Lexol IPM NF - Inolex) and triglyceride Caprylic/capric acid (Mygliol 812 - Condea) with a ratio of 3:2 wt./wt.89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)1,00
Triethanolamine (tea)to pH 7,00
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 18,89
GEL POLIARNAIA VARIANCE 223,35
GEL POLIARNAIA DISPERSION 357,81
WATER-based GEL9,95
* The content of calcipotriol in the final composition is 53,2 mcg/g
** The contents of the BDP in the final composition is 692 ág/g (equivalent to 538 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

The stability of the COI is tivali way described in example 1b.

It was found that after storage for 2 months at 40°C in tightly closed laboratory glass beaker levels of calcipotriol and betamethasone dipropionate, respectively 103±2% and 106±3% of initial levels. Next, after storage for 6 months at 40°C. the levels of calcipotriol and betamethasone dipropionate, respectively 106±2% and 105±3% of initial levels. Currently, the test of the stability of this sample.

EXAMPLE 11

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0581%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,2908%) in a mixture of isopropylmyristate (Lexol IPM NF - Inolex) and triglyceride Caprylic/capric acid (Mygliol 812 - Condea) with a ratio of 3:2 wt./wt.89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA DISPERSION 3 64/59/8
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)9,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)44,10
Cyclomethicone (STb5NF - Dow Corning)36,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

BUFFER% wt./wt.
Salt phosphate bufferto pH 7,50
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 110,15
GEL POLIARNAIA VARIANCE 225,32
GEL POLIARNAIA DISPERSION 353,54
BUFFER10,99
* The content of calcipotriol in the final composition is equal to 52.5 mcg/g
** The content of betamethasone dipropionate in the final composition is 656 µg/g (equivalent to 510 ág/g of betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the buffer and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Ustoichivosti tested by the method described in example 1b.

It was found that after storage for 6 months at 40°C in tightly closed laboratory glass beaker levels of calcipotriol and betamethasone, respectively 106±2% and 105±1% of initial levels.

EXAMPLE 12

Three gel Polyarnaya dispersion of the following composition were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0283%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
The solution of calcipotriol* (0,0400% in the aqueous phase) in 29,6% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3289%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
A solution of betamethasone dipropionate** (0,2252%) 33,8% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)20,00
Dimethicone (Q7-9120, 20 CP - Dow Corning)35,00
Cyclomethicone (STb5NF - Dow Corning)29,10
Elastomer DC10 (Dow Corning)5,00
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)2,00
Triethanolamine (tea)to pH 7,29
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 125,00
GEL POLIARNAIA VARIANCE 225,00
GEL POLIARNAIA DISPERSION 330,00
WATER-based GEL20,00
* The content of calcipotriol in the final composition is 72,0 mcg/g
** The content of betamethasone dipropionate in the final composition is 782 µg/g (equivalent to 608 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except for the introduction of the gel phase.

Measuring sustainability

Stability was tested by the method described in example 1A.

It was found that after storage for 6 months at 40°C in a sealed tube Eppendorf levels to lipitrol and betamethasone was, accordingly, 106% and 117% of the initial levels. Currently, the test of the stability of this sample.

EXAMPLE 13

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0283%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
The solution of calcipotriol* (0,0400% in the aqueous phase) in 29,6% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,3289%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
A solution of betamethasone dipropionate** (0,2252%) 33,8% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)20,00
Dimethicone (Q7-9120, 20 CP - Dow Corning)35,00
Cyclomethicone (STb5NF - Dow Corning)29,10
Elastomer DC10 (Dow Corning)5,00
Laureth-4 (Volpo L4 - Croda)0,90

The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)2,00
Triethanolamine (tea)to pH 7,29
Isopropanol (30,6% wt./wt.) in demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 125,00
GEL POLIARNAIA VARIANCE 225,00
GEL POLIARNAIA DISPERSION 320,00
WATER-based GEL30,00
* The content of calcipotriol in the final composition is 72,0 mcg/g
** The content of betamethasone dipropionate in the final composition is 782 µg/g (equivalent to 608 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A.

It was found that after storage for 6 months at 40°C in a sealed tube Eppendorf levels of calcipotriol and betamethasone, respectively 104% and 116% of the initial levels. Currently, the test of the stability during storage.

EXAMPLE 14

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
R is the target of calcipotriol* (0,0243%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
The solution of calcipotriol* (0,0400% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,203% wt./wt.) in the triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
A solution of betamethasone dipropionate** (0,192% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)19,8
Dimethicolon 20 (Dow Corning)34,60
Cyclomethicone (STb5NF - Dow Corning)increased by 28.70
Elastomer DC10 (Dow Corning)4,90
Laureth-4 (Volpo L4 - Croda)1,00
Tween 80 (Polysorbate 80 - Surfachem)1,00
The aqueous phase
Isopropanol3,00
Demineralized water6,00
Gidrirovannoe castor oil Polyoxyl 40 (Cremophor RH 40 - BASF)1,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)2,00
Triethanolamine (tea)to pH 7,29
Isopropanol (30,6% wt./wt.) in demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 115,00
GEL POLIARNAIA VARIANCE 227,00
GEL POLIARNAIA DISPERSION 340,00
WATER-based GEL18,00
* The content of calcipotriol in the final composition is of 37.8 ág/g
** The content of betamethasone dipropionate in the final composition is 534 ág/g (equivalent to 415 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispers the th 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A.

It was found that after storage for 3.5 weeks at 40°C in a sealed tube Eppendorf levels of calcipotriol and betamethasone dipropionate were, respectively, 99% and 138% of the initial levels. Currently, the test of the stability during storage.

EXAMPLE 15

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0243%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
Rast is the PR of calcipotriol* (0,0400% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,203% wt./wt.) in the triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
A solution of betamethasone dipropionate** (0,192% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Wells is an (isolated from olive - A & E Connock)19,8
Dimethicolon 20 (Dow Corning)34,60
Cyclomethicone (STb5NF - Dow Corning)increased by 28.70
Elastomer DC10 (Dow Corning)4,90
Laureth-4 (Volpo L4 - Croda)1,00
Tween 80 (Polysorbate 80 - Surfachem)1,00
The aqueous phase
Isopropanol3,00
Demineralized water6,00
Gidrirovannoe castor oil Polyoxyl 40 (Cremophor RH 40 - BASF)1,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)2,00
Triethanolamine (tea)to pH 7,29
Isopropanol (30,6% wt./wt.) in demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 115,00
GEL POLIARNAIA VARIANCE 227,00
GEL POLIARNAIA DISPERSION 330,00
WATER-based GEL28,00
* The content of calcipotriol in the final composition is of 37.8 ág/g
** The content of betamethasone dipropionate in the final composition is 534 ág/g (equivalent to 415 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A.

It was found that after storage for 3.5 weeks at 40°C in a sealed tube Append the FA levels of calcipotriol and betamethasone was, respectively, 95% and 136% of the initial levels. Currently, the test of the stability during storage.

EXAMPLE 16

Three gel Polyarnaya dispersion and water-based gel, the following compounds were obtained as described below.

GEL POLIARNAIA VARIANCE 1
The oil phase%
The solution of calcipotriol* (0,0243%) triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
The solution of calcipotriol* (0,0400% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA VARIANCE 2
The oil phase %
A solution of betamethasone dipropionate** (0,203% wt./wt.) in the triglyceride Caprylic/capric acid (Mygliol 812 - Condea)89,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
A solution of betamethasone dipropionate** (0,192% wt./wt.) 33.3% wt./wt. isopropanol in demineralized water9,00
Poloxamer 188 (Pluronic F68 - BASF)1,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)19,8
Dimethicolon 20 (Dow Corning)34,60
Cyclomethicone (STb5NF - Dow Corning)increased by 28.70
Elastomer DC10 (Dow Corning)4,90
Laureth-4 (Volpo L4 - Croda)1,0
Tween 80 (Polysorbate 80 - Surfachem)1,00
The aqueous phase
Isopropanol3,00
Demineralized water6,00
Gidrirovannoe castor oil Polyoxyl 40 (Cremophor RH 40 - BASF)1,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)2,00
Triethanolamine (tea)to pH 7,29
Isopropanol (30,6% wt./wt.) in demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 115,80
GEL POLIARNAIA VARIANCE 227,10
GEL POLIARNAIA DISPERSION 319,70
WATER-based GEL37,40
* The content of calcipotriol in the final composition is equal to 39.9 ág/g
** The content of betamethasone dipropionate in the final composition is 536 ág/g (equivalent to 417 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

Measuring sustainability

Stability was tested by the method described in example 1A.

It was found that after storage for 3.5 months at 40°C in a sealed tube Eppendorf levels of calcipotriol and betamethasone, respectively 101% and 137% of the original levels. Currently, the test of the stability during storage.

EXAMPLE 17

GEL POLIARNAIA VARIANCE 1
Oil is the main phase %
The solution of calcipotriol* (0,02047%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90

The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

GEL POLIARNAIA VARIANCE 2
The oil phase%
A solution of betamethasone dipropionate** (0,2775%) isopropylmyristate (Lexol IPM NF - Inolex)89,10
Laureth-4 (Volpo L4 - Croda)0,90
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Dem is nerealizovannoe water 9,00

GEL POLIARNAIA DISPERSION 3
The oil phase% wt./wt.
Squalene (extracted from olive - A & E Connock)20,00
Dimethicone (Q7-9120, 100 CP - Dow Corning)35,00
Elastomer DC10 (Dow Corning)5,00
Cyclomethicone (STb5NF - Dow Corning)29,00
Laureth-4 (Volpo L4 - Croda)1,00
The aqueous phase
Poloxamer 188 (Pluronic F68 - BASF)1,00
Demineralized water9,00

WATER-based GEL% wt./wt.
Polyacrylic acid (Ultrez 10 - a Noveon)1,00
Triethanolamine (tea to a pH of 7.25
Demineralized waterup to 100%

The FINAL PRODUCT% wt./wt.
GEL POLIARNAIA VARIANCE 126,20
GEL POLIARNAIA VARIANCE 225,32
GEL POLIARNAIA DISPERSION 338,75
WATER-based GEL9,73
* The content of calcipotriol in the final composition is equal to 47.8 ág/g
** The contents of the BDP in the final composition is 626 µg/g (equivalent to 487 mg/g betamethasone).

Method get

The method of obtaining was similar to that described in above example 1 except that the final mixture of three gel poliamidowych dispersions 1, 2 and 3 were added to the neutralized water-based gel and mixed by simple stirring until the formation of homogeneous mixture poliamidowych dispersions.

A brief overview

# exampleStorage environmentStability (time)
Example 1Glass2 months (test in progress)
Example 1Plastic2 monthsand
Example 2Glass2 months* (test in progress)
Example 3Glass9 months
Example 4Glass4.5 months**
Example 5GlassThe test continues
Example 6Plastic3 months (test in progress)
Example 7Plastic3 months***
Example 8Glass3 months**** (unstable product)
Example 9The stack is about 18 months at room temperature
Example 10Glass6 months
Example 11Glass6 months
Example 12Plastic6 months
Example 13Plastic6 months
Example 14Plastic3.5 weeks
Example 15Plastic3.5 weeks
Example 16Plastic3.5 weeks
Sustainability has the above values; less than 5% loss of each drug compared with the initial levels. Storage at 40°C except where otherwise noted.
andLevels of calcipotriol and betamethasone dipropionate are 102% and 99% of the initial levels.
* The level of betamethasone = 95% of the initial level in the sample, tested for stability in storage during the most is his time.
** After storage for 6 months, the levels of calcipotriol and betamethasone dipropionate were, respectively, 42% and 65% of the initial level.
*** The level of calcipotriol = 86% from the initial value after storage for 4 months at 40°C.
**** After storage for 3 months, the levels of calcipotriol and betamethasone dipropionate were, respectively, 91% and 70% of the initial level.

1. The composition is intended for topical application, which comprises a continuous phase and at least one dispersed phase, with the specified composition contains at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D and at least one corticosteroid, and the corticosteroid is mainly in the dispersed phase, and vitamin D or an analogue of vitamin D is mainly in the dispersed phase.

2. The composition according to claim 1, in which the corticosteroid is betamethasone, clobetasol, clobetasone, desoximetasone, diflucortolone, diflorasone, fluocinonide, flumetazon, fluocinolone, fluticasone, fluprednidene, halcinonide, hydrocortisone, mometazon, triamcinolone, esters or mixtures of these substances.

3. The composition according to claim 2, in which the corticosteroid is betamethasone or a complex ester.

4. The composition according to claim 1, in which the vitamin D or an analogue of vitamin D is vitamin D, calcipotriol, seocalcitol, calcitriol, tacalcitol, maximalization, paricalcitol, falecalcitriol, 1α,24S-dihydroxy-vitamin D2, 1(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)phenyl)methoxy)methyl]-9,10-scoprega-5(Z),7(E),10(19)-triens or a mixture of these substances.

5. The composition according to claim 4, in which the vitamin D or an analogue of vitamin D is calcipotriol.

6. The composition according to claim 1, in which the dispersed phase comprises oil.

7. The composition according to claim 6, in which the oil comprises a monoglyceride, diglyceride, triglyceride, isopropylmyristate or a mixture of these substances.

8. The composition according to claim 1, which comprises less than 5 wt.% water based on the total weight of the composition.

9. The composition according to claim 8, in which the continuous phase is non-aqueous phase.

10. The composition according to claim 1, which includes at least 5 wt.% water based on the total weight of the composition.

11. The composition according to claim 10, which includes at least 10 wt.% water based on the total weight of the composition.

12. The composition according to claim 11, which comprises at least 15 wt.% water based on the total weight of the composition.

13. The composition according to claim 1, which comprises 5-50 wt.% water based on the total weight of the composition.

14. The composition according to claim 1, in which the continuous phase comprises a compound of the formula R1 -OH, where R1means1-C10alkyl, and/or the compound of the formula HO-R2-H, where R2means (C2H4)nor (C3H6)nwhere n is 1-100.

15. The composition according to 14, in which the continuous phase comprises propylene glycol, glycerin, ethanol, isopropyl alcohol, or a mixture of these substances.

16. The composition according to claim 1, in which the pH value is 7.0-8.5 in.

17. The composition according to item 16, in which the pH value of the aqueous phase is equal to 7.25 to 7.75.

18. The composition according to claim 1, which further includes a gelling.

19. The composition according to claim 1, which further includes power penetration.

20. The composition according to claim 1, which is designed for use in a method of therapeutic treatment of the human or animal.

21. The composition according to claim 1, which is designed for use in the treatment of psoriasis.

22. The use of a composition according to claim 1 for the preparation of drugs for the treatment of psoriasis.

23. A method of obtaining a composition according to claim 1, which includes the following stages:
(i) obtaining a hydrophilic solvent, optionally containing at least one vitamin D or an analogue of vitamin D, and/or at least one corticosteroid and/or surfactant;
(ii) obtaining a hydrophobic solvent, optionally containing at least one vitamin D or an analogue of vitamin D, and/or n is at least one corticosteroid and/or surfactant;
(iii) mixing the hydrophilic solvent and a hydrophobic solvent in acceptable conditions with the formation of a composition containing at least one polyamoury dispersion, at least one vitamin D or an analogue of vitamin D and at least one corticosteroid.

24. A method of obtaining a composition according to claim 1, which includes the following stages:
receiving the first polihronova dispersion containing vitamin D or an analogue of vitamin D;
receiving the second polihronova dispersion containing corticosteroid; and
mixing these first and second poliamidowych dispersions with the formation of the composition.

25. The method according to item 23, which further includes:
obtaining a third or subsequent polihronova dispersion containing the active agent; and
mixing a specified third or subsequent polihronova variance with those of the first and second poliarnoye dispersions.

26. The method according to paragraph 24, in which the above first and second Polyarnaya dispersion is mixed with another hydrophilic solvent having a pH value in the range from of 7.25 to 7.75.

27. The composition according to claim 1, which is stable, and the resistance measured in the form of no more than 5% reduction in the number of vitamin D or analogue of vitamin D and not more than 5% reduction in the number of corticosteroid relative to the initial amount is at after storage for 3 months in a tightly closed glass containers at 40°C.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method of treating psoriasis. The invention refers to medicine, specifically to dermatology, and may be used for treating the patients suffering psoriasis. That is ensured by conducting detoxification, hyposensitising therapy, prescribing antihistamine preparations, vitamins, cytostatics, physiotherapeutic therapy, ointment applications. The conducted therapy is combined with additionally prescribed oral 40% alcoholate (1:10) containing herbal phytoecdysteroids in mass fractions 50 drops 3 times a day 15 minutes before meal daily for 30 days: Rhaponticum carthamoides roots and rhinzomes - 3, pot marigold blossom - 1, wild camomile blossom - 1.

EFFECT: method enabled considerably improved therapeutic effect in the patients due to evident immunomodulating, adaptogenic, sedative and anti-inflammatory effects of herbal phytoecdysteroids.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dermatology and can be applied for external treatment of psoriatic onychodystrophy. For this purpose mixture of gel tisol and ointment daivonex is applied on nidus of affection in ratio 1:2 with following keeping under adhesive plaster during 8-10 h two times per day. Course of treatment constitutes not less than 14 days.

EFFECT: method ensures reduction of treatment terms and duration of remission and obtaining high therapeutic effect.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and concerns preparing an agent for treating various dermatopathies: psoriasis, eczema, atopic dermatitis, ulcers incl. trophic and other diseases accompanied by inflammation or skin flaking. According to the first version, the composition contains ethoxylated alcohol, glycerol monostearate, higher fatty alcohols C16-C18 and cocoglycerides, as well as glycerol, olive oil and water. According to the other versions, it contains naphthalan oil or pentoxifylline or urea. All the versions provide a liposomal form of the composition improving healing, soothing and trophic effects.

EFFECT: composition is hypoallergic, easy-to-use.

12 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: invention describes a novel useful vitamin D3 derivative, which has excellent vitamin D3 activity, and has relatively low action on system calcium metabolism compared to other traditional vitamin D3 derivatives. The invention includes a 9,10-secopregnane derivative of general formula [1] and a pharmaceutical composition containing said derivative as an active ingredient. [Formula 1]

.

In general formula [1], the next part of the structure between position 16 and position 17 denotes a single bond or a double bond. Y denotes a single bond, alkylene, alkenylene or phenylene; R1 and R2 are identical or different and each denotes hydrogen, alkyl or cycloalkyl; or R1 and R2, taken together with an adjacent carbon atom, form a cycloalkyl; R3 denotes hydrogen or methyl; Z denotes hydrogen, hydroxy or -NR11R12, where R11 and R12 assume values given in the claim.

EFFECT: obtaining a useful D3 derivative.

14 cl, 73 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is pharmaceutical composition for treating psoriasis, which includes, at least, one excipient and active agents counted per total composition weight: clobetasol propionate: 0.05-5%, minoxydyl: 0.05-7% and 11-alfa-hydroxyprogesteron: 0.05-12%. Composition can also include other excipients, vitamins and/or mineral compounds. It is demonstrated: 11-alfa-hydroxyprogesteron reduces grease-secretion on affected region, which increases action of other active agents. Efficiency of composition is manifested 2-4 days after beginning of treatment, it does not change skin colour, side effects are manifested in light degree.

EFFECT: composition retards accelerated growth of skin cells, as well as suppresses development of other abnormal phenomena developing in case of psoriasis vulgaris.

15 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular for treatment of psoriasis. Medication for treatment of psoriasis, which contains solution of phospholipids in 70% ethyl alcohol and water solution of sodium deoxyribonucleate, components being taken in specified ratio.

EFFECT: medication is efficient for treatment of psoriasis.

4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmaceutical application and represents a gel or viscous composition applicable for local wound healing on injured skin, containing erythropoein (EPO) and at least one swelling gel-forming polysaccharide in the concentration of 0.4-4 wt %/wt specified from one or more than one member of the group consisting of: hydroxyethyl cellulose, hydroxymethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose which can be prepared by mixing EPO in a lyophilised or suspended form with the pre-swelled polysaccharide of viscosity less than 5000 mPa*s, and initiating complete swelling wherein completely swelled polysaccharide has viscosity 20000-60000 mPa*s, and EPO is found in the concentration of 100-500 IU/g of the gel composition wherein said mixing is ensured by EPO diffusion in a gel for at least 24 h.

EFFECT: invention provides stabilisation of the active compound and its uniform release, as well as effective therapy of injuries or pathologically induced skin injury.

13 cl, 17 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid dispersion wherein revaprazan particles are surface-modified by a water-soluble polymer, a water-soluble saccharide, a surfactant or their mixture wherein the water-soluble polymer is specified in a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, a water-soluble polyacrylic acid copolymer, polyvinyl alcohol or their mixture, and wherein the water-soluble saccharide is specified in a group consisting of lactose, white sugar, saccharose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and their mixture. The invention also refers to a method for preparing said solid dispersion. The present invention also presents a pharmaceutical composition containing the solid dispersion, and the method for producing the pharmaceutical composition.

EFFECT: invention provides improved solubility of revaprazan and reduced adhesion and agglutination properties.

16 cl, 4 dwg, 7 tbl, 55 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a biodegradable plaster containing at least one bioadhesive layer, and at least one non-bioadhesive layer with the bioadhesive layer containing at least one polyarphon dispersion, and at least one bioadhesive polymer with the polyarphon dispersion containing at least one pharmacologically active substance.

EFFECT: biodegradable plaster can deliver drugs, including poorly water soluble ones.

21 cl, 8 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. An oil-in-water emulsion and a method for preparing it for ophthalmic application is characterised by at least one prostaglandin as an active agent, and a surface-active ingredient containing a combination of at least two non-ionic surfactants.

EFFECT: group of inventions provides treating glaucoma and is characterised by high chemical stability of the prostaglandin active agent that enables long-term storage of the emulsion at room temperature.

30 cl, 7 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic industry and represents an oil-in-water or water-in-oil cosmetic emulsion which contains one or more vegetable oils, one or more polyols, partial esters of polyols and esters of aliphatic alcohols and fatty acids being a part of the oil used in the given composition in the form of triglycerides.

EFFECT: invention provides a wider range of the compositions for preparing cosmetic emulsions.

19 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: declared invention refers to an agent for treating ulcer including as an effective ingredient composite hydrotalcite in the form of particles, which contains zinc in the form of a solid solution and presented by formula (MgaZnb)1-xAlx(OH)2(An-1)x/n·H2O, wherein An-1 means CO32-, SO42- or Cl-, n is equal to 1 or 2, and x, a, b and m have the values fulfils the following conditions 0.18≤x≤0.4, 0.1≤a≤1, 0≤b≤0,5, 0≤m<1. Said agent may be presented in the granular or fine-grained form, suspension form or tableted form. The invention also refers to a method of treating peptic ulcer by the oral introduction of an effective amount of said hydrotalcite.

EFFECT: declared invention has an effective effect in treating peptic ulcer in an individual or a mammal, nor damaging a mucous membrane of internal walls of stomach, and possesses low probability of side effects.

17 cl, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a medicine for treating depression. The oral medicine for treating depression prepared from a jujuba extract containing jujube cyclic adenosine monophosphate (jujuba cAMP) and an additional ingredient taken from a group consisting of a pharmaceutically acceptable carrier, an additive, an adjuvant and combination thereof. A method for preparing jujube cyclic adenosine monophosphate (jujuba cAMP) taken as an ingredient of the medicine for treating depression, involving the stages: (a) jujube extraction in water and alcohol to produce a primary extract, (b) primary extract purification to produce a secondary extract wherein the jujuba cAMP concentration in the secondary extract is higher than that in the primary extract wherein the stage (b) is performed by jujuba cAMP chromatography of the primary extract with the use of macroporous resins bound with an aldehyde group.

EFFECT: medicine is effective for treating depression, has no side effects.

16 cl, 7 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to suspension for visualisation of transparent tissue of eye, which contains finely dispersed particles of biodegradable macromolecular compound and salt, selected from salt of divalent metal in amount 0.1-1 wt/vol.% or salts of trivalent metal in amount 0.01-1 wt/vol.%. Said suspension is intended for pouring into eye to come in contact with transparent eye tissues with the purpose to improve their distinguishability. Invention also relates to ophthalmologic preparation which contains hard particles of biodegradable macromolecular compound and water medium, which contains said salts of divalent or trivalent metal, solid and water media being placed separately and without allowing contact with each other. Invention also relates to methods of obtaining suspension for eye visualisation, which include obtaining solid composition, containing finely dispersed particles of biodegradable macromolecular compound or finely dispersed particles of biodegradable macromolecular compound and 0.1-1 wt/vol.% of salt of divalent or 0.01-1 wt/vol.% of salt of trivalent metal, and suspending said solid composition in water solution.

EFFECT: invention ensures obtaining suspension for visualisation of transparent eye tissue, which can be applied as convenient and safe means for improvement of distinguishability of transparent eye tissues when performing surgical operation on them.

21 cl, 1 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, and represents a sterile injectable water-based composition in the form of gel for iintra-articular injection containing hyaluronic acid of molecular weight 0.1 to 10×106 Da in the amount of 1-100 mg/ml of water or one of its salts and optionally one or more other natural polysaccharides specified in a group consisting of chondroitin sulphate, keratan, keratan sulphate, heparin, heparan sulphate, cellulose and its derivatives, chitosan, xanthan, alginate and their salts, and also one or more polyalcohols in the amount of 0.0001-100 mg/ml of water, prepared by making a water-based formulation containing hyaluronic acid or one of its salts, optionally one or more other natural polysaccharides, and also one or more polyalcohols, sterilising it with wet steam; the prepared gel shows a coincidence frequency of the elasticity modulus G' and the viscosity modulus G" within the range 0 to 10 Hz preferentially 0.41 Hz ±0.41 Hz with G" exceeding G' if the coincidence frequency is found to be high.

EFFECT: invention provides higher degradation resistance of the gel, and also makes the gel visco-elastic.

11 cl, 8 ex, 11 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition effective for injections in the form of a water suspension for prolonged release of a bisphosphonate agent. Said pharmaceutical composition contains a combined dispersion complex containing a salt of a bisphosphonate agent and a salt of pentavalent phosphorus oxoacid, and the complex has solubility in physiologic saline less than 0.05 wt % at bisphosphonic acid. The invention also refers to a pharmaceutical composition effective for injection which contains the combined dispersion complex containing a calcium salt in the amount less than 50 wt %, a calcium salt of pentavalent phosphorus oxoacid with the solid substance having an average particle size 1-100 mcm, the calcium to phosphorus mass relation is equal to 0.5-3; and the composition has pH equal to 6-9.5 if the complex is suspended in an aqueous medium. The invention also refers to a method of treating or preventing of bone diseases in patients with, e.g. osteoporosis, implying the intramuscular introduction of said compositions in a patient's body.

EFFECT: invention aims at preparing the composition low soluble in the physiological medium and provides prolonged slow release of the bisphosphonate agents.

24 cl, 8 tbl, 3 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: there are described new transdermal preparations combining a non-steroid anti-inflammatory drug (NSAID), such as flunixin. There are also described methods of using and introducing such preparation in treating inflammatory conditions in cattle, including a cattle respiratory disease. The transdermal liquid preparation containing: a) first and second skin penetration intensifiers; b) an aprotonic primary solvent; and c) a therapeutic effective amount of flunixin or its pharmaceutically acceptable salt. The transdermal liquid preparation contains a combination of two agents.

EFFECT: improved penetration.

25 cl, 5 dwg, 9 ex

Up!