The solution for the treatment of skin diseases, the method of its production and a method of treatment of skin diseases

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry, concerns the solution of isotretinoin (13-CIS-retinoic acid) and treatment of skin diseases. The invention lies in the fact that as the active ingredient solution containing 13-CIS-retinoic acid at concentrations of 0,02-0,03%, stabilized with a mixture of butylacetyl-butylacetamide in equal proportions. The method of obtaining the solution includes dissolving the active ingredient in alcohol-glycolic environment, contribute stabilizer and isotretinoin, the mixture is stirred at room temperature in a stream of inert gas until complete dissolution of the components. Treatment of diseases of the skin by applying to the affected skin areas of the proposed solution late in the evening and/or early in the morning for 12-18 weeks. The invention enables the creation of highly effective, low-toxic stable product for external use. 3 S. and 1 C.p. f-crystals, 13 tab., 3 Il.

The invention relates to chemical-pharmaceutical industry, refers to a stable solution of isotretinoin (13-CIS-retinoic acid) and treatment of skin diseases.

Derivatives of vitamin a (retinoic acids with the surface layers of the skin, anti-inflammatory action and therefore pathogenetically most closely preparations for treatment of acne, seborrhea, rosacea [1-4].

Problems of creation of preparations containing analogues of retinoic acid, are associated with relatively high toxicity of these compounds, their instability to the effects of oxygen and light, hard soluble not only in water, but in most organic solvents.

In medical practice known medicines containing retinoic acid or its derivative used to treat acne and seborrhea [1, 2].

The closest in technical essence and the achieved result is the drug company Hoffmann-La Roche, presented in the patent [5]. Solution for acne treatment is protected by a patent in 1973. Described in the patent drug called Airol (Airol) firm Hoffmann-La Roche continues to produce and present [6]. The specified medication is a topical solution containing all - TRANS retinoic acid (tretinoin) at a concentration of 0.05%; the solvent used is a mixture of ethyl alcohol and propylene glycol. The drug is highly effective in curing adsto Airol "stimulates normal mitotic activity of the skin, reduces the thickness of the stratum corneum, causing expansion and loosening of the epithelium around comedones, which contributes to their dump. The product gives good cosmetic results and can be used in combination with diet and oral drugs [6] . Similar drug Retin-Athe Swiss company ilag AG Products represents a 0.1% solution of tretinoin, stable butylacetyl and sorbic acid. Its pharmacological properties, indications for use and side effects of the same drug have Irol.

The disadvantages of the drug Airol (prototype) should be attributed to the high toxicity and a strong irritant effect tretinoin used as active compounds (table. 1-3). In addition, the concentration of this relatively toxic retinoid preparation Airol high (0,05%), drug Retin-Aeven higher (by 0.1%).

To stabilize tretinoin used or dl--tocopherol, or butylacetyl. However, as shown by their own research (table. 4, 5), one antioxidant is often not enough to prevent the oxidation of the substance.

Getting the closest to the technical sush.], according to which TRANS-retinoic acid is dissolved in alcohol. This method of dissolution requires a long time and heat.

However, this method of obtaining a solution retinoid not take into account either the low solubility of the isomers of retinoic acid, especially in ethyl alcohol 95%, or their instability to oxidation.

There is a method of use of a medicinal product does not meet the modern requirements of clinical pharmacology primarily because as the active ingredient uses relatively toxic, with strong local irritant action of tretinoin. While less toxic and do not have explicit local irritating action of isotretinoin is almost not used for external application in the treatment of skin diseases.

It is associated with widespread among foreign authors belief that isotretinoin should be used orally, and more toxic, and more effective tretinoin, used for outdoor applications. However, our own studies have found (PL. 6-8) expressed substations action of isotretinoin, which it has when applied to the skin of rats, manifested in the ed is nami and differentiating the sebocyti, in the direction of increasing the share of first. Therefore, topical application in the treatment of acne it is advisable.

Well-known indications for use drugs cannot be considered satisfactory because narrowed range of nosological forms of diseases (in the instructions for use of the drug Airol [6] indicated only eels), while the solution of isotretinoin is effective in the treatment of seborrhea, rosacea and perioral dermatitis. Moreover, the method of application does not take into account the biorhythm dividing epithelial cells and their differentiation.

The present invention is the development of highly efficient, low-toxic stable product for external use, which allows you to expand the use of the drug on the basis of retinoic acid in the treatment of a wide range of skin diseases: seborrhea, rosacea, dermatitis.

To achieve the objectives of the proposed group of inventions, United by a common inventive concept.

Drug for the treatment of diseases of the skin contains as the active ingredient of isotretionin dissolved in alcohol and glycol, environment, and stabilizer, represent the governmental funds the following, wt.%:

Isotretinoin - 0,02-0,03

Butylacetyl - 0,02-0,03

Butylacetamide - 0,02-0,03

Propylene glycol, or ethylene glycol, or onomatology ether - 50,0-60,0

Ethyl or propyl - Rest

According to the invention is a method of obtaining the solution of the proposed structure is that of pre-mixed alcohol and glycol in the mixture make a first stabilizer, a mixture of butylacetyl and butylacetamide in equal proportions, and isotretinoin, the mixture is stirred at room temperature in a stream of inert gas until complete dissolution of the components.

According to the invention a preparation containing isotretinoin, is used to apply externally, and not oral, not only to treat acne, but also in the treatment of other skin diseases: seborrhea, rosacea, perioral dermatitis. In accordance with the biorhythm of dividing epithelial cells solution was applied to the affected areas before going to sleep and/or early in the morning for 12-18 weeks.

The invention is illustrated by the following studies.

Research confirming the lower toxicity of 13-CIS isomer of retinoic acid and its more weakly expressed irritant effect. Ieoi 19,01,0, All - TRANS and 13-CIS-retinoic acid was investigated in the form of methyl esters. These compounds are stable, more soluble and easier to use than crystalline isomers of retinoic acid. The substance was administered intraperitoneally, once in the form of water-alcohol solutions. The maximum tolerated (MTD) and isoeffective (LD50) doses were estimated on the 15-day survival on the methods of Datman-Lablanca and the Litchfield-Wilcoxon signed.

From the results shown in table. 1, it is seen that MTD 4.5 times, and LD50almost 1.5 times higher in the 13-CIS isomer of retinoic acid, in comparison with all-TRANS-isomer.

Studies of chronic toxicity were performed on male mice (C57B1/6xCBA)F1mass 19,01,0 g, which on the shorn skin interscapular region of the back was applied of 0.25% stable BOT and BOA alcohol-glycol solutions 13-CIS - and all-TRANS retinoic acid in 0.2 ml 3 times per week. Results General toxic effect was evaluated on 15, 30, 60, 90, 120, 150 and 180-day experience.

As you can see from the data table. 2, the survival of animals to 180 th day in the case of isotretinoin is more than twice higher compared to tretinoin.

The research is Kah-female albino animals weighing 240-270, Mow areas interscapular region of the back daily for 2 weeks was applied for 0.2 ml of 0.25% alcohol-glycol solutions of tretinoin and isotretinoin, stable butylacetophenone (BOT) and butiloksianizol (BOA). The results were evaluated by external evidence and on the basis of histological changes of the skin. Evaluation criteria and the results are presented in table. 3.

From these data it is seen that alterimage effect on the structure of the skin in animals treated with isotretinoin, is expressed to a lesser degree by all criteria, compared with tretinoin.

With less toxicity and slight irritant effect compared with tretinoin, isotretinoin manifests expressed dermatotropnoe action. Under his influence increased proliferative activity of the epidermis, sebocyti and excretory ducts of the sebaceous glands causes terminal differentiation sebocyti, activated intradermal immune response.

The study of specific pharmacological activity of the drug for the claimed composition (example 1) performed on the intact skin of laboratory animals. Evaluation of the pharmacological action of the drug was carried out on the basis of morphological bodily rats male Wistar with an average weight of 170 g

Each group consisted of 7 animals of both sexes.

1. Control - intact animals.

2. Control - based solution.

3. Experimental a solution of 13-CIS-retinoic acid (CR) 0,025%.

4. Experienced solution CR of 0.05%.

Mow the surface of the skin of the interscapular region of the back 5 times a week for 2 weeks caused investigational drugs in the amount of 0.3 g

Throughout the experiment the animals from the control and experimental groups did not differ from each other. Visually macroscopic signs of irritant actions were noted.

Statistical processing of the research results was performed using the least squared differences and t-student criterion. The comparison was carried out with a group of intact animals. Statistically significant believed the results with a confidence level of at least 95% (tables marked with an asterisk).

In the study sections of the skin revealed that under the influence of isotretinoin is a series of changes.

The histostructure of the sebaceous glands in animals of the experimental groups is polymorphism. Their profiles are non-uniformly reduced in size; square separate sebaceous> Some hair follicles are detected reduced residues of secretory departments, consisting of several deformed sebocyti. The cells themselves wrinkled; their cytoplasm between lipid inclusions of moderately basophilia sometimes loses a honeycomb structure. Some sebaceous glands seem destructive modified, shrink and look like a cluster of undifferentiated sebocyti. When this cell borders lose their distinct shape, and contours of individual secretory departments appear blurred (Fig. 2).

Core sebocyti look more often located than in intact animals, indicating a decrease of the cell volume. For basal sebocyti characterized by intensive basophile cytoplasm, they often acquire a cubic shape. In General, different basophilia border with connective tissue peripheral areas secretory departments of the sebaceous glands in animals of experimental groups expressed better than in the control. Not synthesizing lipid sebocyti be similar to other cells of epidermal origin and can sometimes be indistinguishable from the cells of the outer root sheaths. Visually, the ratio of basal and differentone individual sebaceous gland is reduced to such an extent, that presents a cluster of undifferentiated epithelial cells around the duct. Sometimes, the sebaceous glands are somewhat orgasimic from the dermal connective tissue.

Morphometric studies have confirmed the results of the visual assessment (table. 6).

From the table it follows that the preparation of the inventive composition and 0.05% solution of isotretinoin significantly reduce the average size of the profiles of the sebaceous glands in the cut compared to the control. Significantly increased market share in the area of the sebaceous glands in the undifferentiated (basal) sebocyti, and consequently reducing the area occupied by cells at different stages of differentiation.

Thus, as a result of exposure solutions isotretinoin both concentrations is a significant shift in the ratio of the area occupied undifferentiated sebocyti and cells at different stages of differentiation, in the direction of increasing the proportion of undifferentiated forms; however, the maximum effect is achieved by application of the drug for the claimed composition.

Considering that morphological and morphometric parameters of the sebaceous glands in oslavany to stay at a lower concentration of the substance (0,025%).

The epidermis of rats after application of the solutions isotretinoin both concentrations unevenly thickened; the number of rows of cells in granular layer increases and is 3-10 layers. Visually the number of keratohyaline in the epidermis increases; its granules are sometimes found in the cells not only of the granular layer, but also prickly, including epithelial cells, comprising the wall of the hair funnel and outer root sheaths (Fig. 3).

Visual observations were confirmed in morphometric studies (table. 7, 8).

Thus, the solutions of isotretinoin have on the skin of rats expressed substations effect, resulting in the reduction of sebaceous glands and statistically significant change in the ratio of the area occupied undifferentiated and differentiating the sebocyti, in the direction of increasing the share of the first.

The specific activity of the solutions isotretinoin in respect of the sebaceous glands within the used concentrations and periods of study do not depend significantly on the quantity of the substance, therefore, the use of a solution of lesser concentration (0,025%) is safer and more profitable economically.

Sebaceous galeata of the proposed structure is appropriate.

Clinical study of the drug confirms this conclusion. Tests were performed on 52 patients with papules-pustular form of acne. Age from 13 to 35 years. Disease duration from 6 months to 16 years. The clinical picture was typical: the presence of comedones, papules, pustules, spots and scars.

Clinical evaluation of the treatment results are presented in table. 9.

Positive clinical effect was achieved in 47 patients (90.4 percent). The 4 people came complete clinical recovery, in 23 patients - a significant improvement by the end of the first month remained isolated papules or pustules were observed spots and scars, fresh elements appeared rarely. The number of comedones sharply reduced, normalized oiliness of the skin.

Thus, the preparation of the inventive composition has a pronounced therapeutic activity, which proves the feasibility of establishing dosage forms with isotretinoin not only for the system, but also for external use.

A solution containing 13-CIS-isomer of retinoic acid, is effective in the treatment of papular-pustular forms of acne. The best result is when the predominant clinical picture of comedones and pustules. In the early days when the final outcome of treatment.

The efficacy and safety of products containing retinoids, depends on the preservation of the substance within the expiration date. Isotretinoin, like all retinoids, unstable with respect to oxygen in the air, but the introduction to the basis of preparation of the necessary amount of antioxidants prevents its oxidation.

The effect of various combinations of antioxidants on the safety of 13-CIS-retinoic acid has been studied in experiments with accelerated aging. The substance was injected in the base containing stabilizers or a mixture of them, and kept in conditions of free access of air at a temperature of 60oC. the results Obtained are presented in table. 4. Quantitative determination of isotretinoin was performed by HPLC. (Chromatograph conditions were as follows: column 25,H,46 cm, filled with sorbent type ULTRASPHERE-ODS (5 μm), mobile phase (PF) alcohol methyl - 4% aqueous solution of acetic acid (9:1), the speed PF 1.0 ml/min, UV detector, 356 nm). Statistical processing of the research results was performed using t-student criterion. Compare the results of determination of isotretinoin during storage and at the time of manufacture. Statistically significant believed the results with a confidence level of at least 95% (tables marked mesh of butylacetyl and butylacetate in the ratio of 1:1.

The results of the storage solution of the inventive composition (example 1) within two years are presented in table. 5. Thus, the equilibrium mixture of butylacetyl and butylacetate in the amount of from 0.02 to 0.03 wt.% each protects isotretinoin from oxidation.

Furthermore, the method of obtaining the drug also plays an important role in ensuring the stability of the substance. In alcohol-glycol medium containing antioxidants, isotretinoin is not prone to oxidation. To avoid the destruction of the substance at the time of dissolution, the process of preparation of the drug need to quickly in a stream of inert gas without heating.

Isotretinoin hardly soluble in alcohol, particularly 95%, containing 5% water. In the glycol solubility isotretinoin above, but because of the viscosity of the process of obtaining a homogeneous solution is also slowing. The best option is to introduce a substance prepared in advance in alcohol-glycol mixture, as in this case, isotretinoin dissolves easier and faster. If the required amount of antioxidants in alcohol-glycol mixture was added previously, and the process of dissolution of lead in a stream of inert gas, the risk of oxidation of the substance will minidose (PL. 5).

Studies suggest that the optimal time of administration of the drug - late at night or early in the morning.

The study of circadian rhythm proliferative activity of the epidermis conducted on rats male Wistar rats weighing 120,010,0, Animals were killed every hour, took the skin back and counted the number of fissile (metaphase) cells. The results of the study are summarized in table. 10. It is obvious that the peak of the proliferative activity occurs at night: the cells begin to divide after midnight and complete this process by the morning.

Pharmacokinetic studies, put on rats male Wistar rats weighing 180,0-220,0 g, showed that a single application to the skin of 0.025% solution of isotretinoin reliably increased and the maximum concentration of active substance in the blood is found over 0.75 hour. Less than 2 hours concentration isotretinoin decreases and after 2 hours reaches the level of intact animals. Because the drug is used for local treatment, its concentration in the skin reaches its maximum value earlier.

Since the peak of the proliferative activity occurs at night, of course b is updaet with this assumption. Time use of the drug after 23 hours, i.e. before going to sleep is optimal (table. 11).

In clinical trials involved young people aged 15 to 20 years with youthful acne, localized on the face. All patients inflicted 0.025% solution of isotretinoin on the affected areas once a day. The best effect was achieved when the treatment was performed no earlier than 23 hours.

Studies have shown that the solution of isotretinoin may be effective in the treatment of such skin diseases for which treatment drug Airol not used: rosacea, perioral dermatitis, and seborrhea.

Rosacea (acne rosacea) is an inflammatory process in the skin of unknown etiology that occurs in persons older than 30 years. Clinically expressed papules-pustular lesions, telangiectasia, congestive erythema, violation of saloobrazovanie. The traditional approach to treatment assignment metronidazole inside and in the composition of external agents, vitamins, alcohol solutions and mash with resorcinol, sulfur, antibiotics. In recent years, applied retinoic ointment 0.1% and 0.05%, the containing 13-CIS-retinoic acid (isotretinoin). However, a number of patients who have expressed the oiliness of the skin, application of ointments rather than the a - 6 men and 8 women aged from 31 to 55 years. All patients had previously received conventional treatment without significant improvement. All patients on the face there were multiple papules and pustules located on the nose, cheeks, chin, telangiectasias in the area of the nose and around it. The drug was applied to affected areas morning and night. Efficacy of therapy was evaluated by dynamic changes of the clinical signs recorded 1 time per week. In all patients after 2-3 days of treatment was observed the reaction of deterioration, consisting of redness and peeling. The reaction took place without additional treatment, lasted 5-7 days. Improvement occurred by the end of the second week of treatment is decreased redness, papules became more flat, disappeared pustules, after 3-4 weeks of treatment showed a significant improvement was reducing the oiliness of the skin. Course duration - 2-3 months. At the end of the treatment course appointed retinoic ointment low concentrations (0.01%) as maintenance therapy. The results of the treatment after 1-month course given in table. 12.

As can be seen from the table, a positive effect was achieved in all patients, of whom the vast majority (92,9%) there was complete resolution vysypanie indicators that proves the safety of therapy.

Example 1.

Patient F. C. , 38 years, with 36 years of age suffer from skin disease. Earlier treatment is repeated courses trykhopol, homeopathic medicines, externally - benzyl benzoate emulsion, various ointments, was unsuccessful. Examination revealed erythema of the entire face, peeling, cheeks and chin small papules and pustules, telangiectasia on the nose and around it. After treatment of 0.025% solution of isotretinoin in 4 weeks on the man's face remained isolated papules, telangiectasias, 8 weeks - only telangiectasia. Drug treatment stopped, prescribed maintenance therapy.

Perioral dermatitis clinically characterized by symmetrically arranged multiple small papules located around the mouth, nasolabial folds, chin and periorbital. The disease occurs mostly in women who use cosmetics, is often associated with prolonged use of corticosteroid ointments. Effective treatments for the disease have not been developed, usually apply the same tools and rosacea. We observed three patients in the e 1-2 months. Analysis and treatment method were the same as in rosacea. All patients received a favorable result. By the end of the first month decreased the number of papules and erythema, papules became paler and flatter. After 2 months in two patients observed complete regression of lesions. One patient after 1 month developed dry skin, the treatment solution of isotretinoin stopped, however, by this time, there was significant improvement.

Example 2.

Patient K. T. , 38 years. Suffering from skin disease with 37 years of age, when there was occurrence of the lesion redness and small nodules on my chin. Were treated with corticosteroid ointments for 4 months. After a temporary improvement of the lesions was significantly more they spread to other areas of the face. Diagnosed with perioral dermatitis applied different tonic, vitamins, metronidazole, externally - alcoholic solutions of complex composition, and cosmetics. The treatment did not lead to success. Examination revealed multiple small papules and small blisters located on a background of erythema around the mouth, nasolabial folds, cheeks. Treatment of 0.025% solution isotretino the Naya bluish coloration of the skin. The drug was applied in the first month, 2 times a day, then once daily in the evening.

Seborrhea is a skin disease, which is based on the violation of the secretory function of the sebaceous glands expressed through increased allocation of qualitatively altered sebum. The disease is characterized by the tendency to chronicity, frequent relapses. Most often it is recorded in the period of puberty. Often affects the face, chest, back and scalp. Usually for the treatment of patients use a tonic, trace elements (arsenic, phosphorus, iron, zinc), vitamins, antibiotics. It is used externally sinistrality cream, alcohol solutions with chloramphenicol, ester, boric acid, sulfur, tar, medicated shampoos.

The study included 8 patients with seborrhea - two men and six women aged from 16 to 37 years. All patients had lesions on the face, pronounced the oiliness, erythematous-squamous lesions on the cheeks and forehead, covered with yellowish greasy scales. Similar lesions of the skin were also on the chest. 4 patients had a lesion of the scalp in the form of excess oil and hair loss, flaky skin (dandruff). Was cherthala full effect - resolution of lesions, reduce oil secretion. The results of treatment are presented in table. 13.

Example 3.

Patient Y. M. , 31. He complained of a rash on the face during the year, dandruff, increased oiliness of skin and hair. The use of metronidazole, homeopathic medicines, vitamins, alcohol solutions and corticosteroid ointments have been ineffective. When viewed from the facial skin is greasy, chin area and cheeks lesions of erythema, against which there are scales yellowish color. Hair greasy, a small amount of dandruff. Assigned 0.025% solution of isotretinoin, multivitamin. The improvement in the reduction of erythema and desquamation was noted after 2 weeks of using the drug. After 6 weeks the rash has resolved, the oiliness of the skin decreased.

The invention is illustrated in the examples.

Example 4.

Mix 40 ml of 95% ethyl alcohol with 60 ml of propylene glycol, after cooling in the resulting homogeneous mixture is injected 0,025 g butylacetyl and butylacetate, stirred in a stream of inert gas until complete dissolution of antioxidants, then stopping stirring and turning off the current of inert gas, add 0.025 g of isotretinoin. Paramashiva is. Store protected from light place at a temperature not higher than the 22oC.

Example 5.

Carried out analogously to example 4. Instead of 95% ethyl alcohol used alcohol propyl.

Examples 6-7.

Carried out analogously to example 4. Instead use propylene glycol ethylene glycol or its onomatology ether.

Thus, a highly effective, low-toxic stable preparation containing from 0.02 to 0.03% of isotretinoin, and developed a method thereof. The drug is characterized by what is isotretinoin used to treat skin diseases externally. The drug is designed to treat acne and other skin diseases for which therapy solution isotretinoin has not been: seborrhea, rosacea, perioral dermatitis. With proper use of the drug (after 23 hours) efficacy of the medicinal product is increased.

Sources of information

1. Patent Germany 2751391, MKI2A 61 K 31/215, publ. may 24, 1978

2. The application of EPO 0274104, MKI4A 61 K 7/48, publ. 13 Jul. 1988

3. The application of EPO 0552624, MKI5A 61 To 31/20, publ. 28 Jul. 1993

4. Kligman A. M., Fulton, J. E., Plewig G. Topical Vitamin A Acid in Acne Vulgaris // Arch. Derm., vol. 99. April 1969, p. 469-476.

5. U.S. patent 3729568, La Roche AG, Basel, Switzerland, S. 7-8.

7. Farrell L. N., J. S. Strauss, A. Stranieri, M. The treatment of severe cystic acne with 13-cis retinoic add // J. Am. Acad. Dermatol., vol. 3, 1980, p. 602-611.

8. Jones D. H., Blanc D., Cunliffe W. J. 13-cis retinoic acid and acne // Lancet, 1980/11, p. 1048-1049.

9. Plewig G. , Gollnick H. , Meigel W. et. al. 13-cis-Retinsaure zur oralen Behandlung.

1. The solution for the treatment of diseases of the skin, containing retinoic acid and alcohol-glycol Wednesday, characterized in that it additionally will win the stabilizer, which is a mixture of butylacetyl and butylacetate in the ratio of 1: 1, and as the active component contains 13-CIS-retinoic acid, isotretinoin in the following ratio of ingredients, wt. %:

Isotretinoin - 0,02-0,03

Butylacetyl - 0,02-0,03

Butylacetamide - 0,02-0,03

Propylene glycol, or ethylene glycol, or onomatology ether - 50,0-60,0

Ethyl or propyl - Rest

2. The solution on p. 1, characterized in that it is designed for the treatment of seborrhea, rosacea and dermatitis.

3. A method of obtaining a solution for the treatment of skin diseases, including the dissolution of the active ingredient in alcohol-glycolic environment, characterized in that alcohol-glycolic environment consistently contribute stabilizer, representing the room temperature in a stream of inert gas until complete dissolution of the components.

4. A method of treatment of skin diseases by applying it to the affected areas of the skin, characterized in that on the affected skin put a solution on p. 1 late in the evening and/or early in the morning for 12-18 weeks.

 

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