Comedolytic pharmaceutical composition and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a composition for treating acne, rosacea and hyperpigmentation, in the form of a gel which contains anchoic acid, a hydrophobic ingredient, a non-aqueous solvent, an emulsifying agent, a gel-forming polymer, a preserving agent, a pH control agent and additionally methylpyrrolidone with anchoic acid having a particle size of less than 100 mcm, while anchoic acid is related to methylpyrrolidone as 1:0.025 to 1:4.

EFFECT: invention provides easy penetration of anchoic acid through a horny layer and its resolution into the oil grand ducts and between skin cells, providing high concentration of anchoic acid that promotes better antibacterial, keratolytic and de-pigmentation effects.

5 cl, 2 tbl, 1 ex

 

The invention relates to the field of medicine and pharmaceutics specifically relates to compositions in the form of a gel for external use containing as an active ingredient azelaic acid, and can be used as a tool with antibacterial, protivougrevoe and depigmentation effects, preferably for the treatment of inflammatory and non-inflammatory forms of acne (normal acne and rosacea.

The main purpose of this composition is the treatment of inflammatory and non-inflammatory forms of acne (normal acne and rosacea. Acne (common acne) is one of the most common dermatoses. Acne is polymorphic multifactorial disease of the hair follicles and sebaceous glands, which occurs in 80% of adolescents and young adults (girls - 10-17 years, boys - ages 14-19). Typically, 20 (or even 30) years of phenomena acne subside, however, in some cases retained after 40 years. Sometimes acne first appear after the age of 25. Among the various clinical types of acne are most often found acne vulgaris (acne vulgaris). This dermatosis affects up to 35% of adolescents male and 23% female. Only at the age of 24 years, this figure drops to 10% and below.

A significant place in the treatment of acne belongs rationally selected external therapy. External therapy occur is what justification is seen as an extremely important part of a comprehensive treatment of dermatological patients. When prescribing therapy must take into account the length of the process, its prevalence, severity, and type of skin lesions and the formation of sebum. You must pay attention to the depth of lesion of skin, complications, hyperpigmentation, scar changes, as well as on the physical characteristics of the patient: hormonal disturbances, historical data, previous therapy and its adequacy, as well as on cosmetic products used by the patients. Of great importance is the evaluation of emotional, social status, social adaptation of the patient. This makes necessary the creation of a wide range of drugs for external use, which would be different in mechanism of action and type of dosage forms.

In recent years significantly expanded opportunities pharmacotherapy dermatosis, which is associated not only with the achievements of fundamental biomedical disciplines, which allowed us to study important aspects of the pathogenesis of common dermatoses, but with the introduction into medical practice of new drugs on cream and cream-gel foundations of a new generation with new auxiliary substances, which have a direct effect on the elimination of pathological processes in the skin [Fitzpatrick B., Boathouse DL ecrecy dermatology. - SPb.: Binom, Nevsky Dialect, 1999. - 512 S.; Dermatology. Atlas-guide / Theatric, R. Johnson, Kwolf, Molano, Dsurmod. M: PRACTICE, 1999. - 1088 S.; Leather / edited Aminha, Approve. - M., 1982. - 336 S.]. Such excipients include, for example, substances, moisturizing and softening the skin [Handbook of Pharmaceutical Excipients: Second Edition / Ed. by Aniey Wade and Paul J. Weller. Washington/London: Amer. Pharm. Association / The Pharm. Press, 1994. - 651 p.]. Rational combination of such auxiliary substances with medicinal substances creates preconditions for rational drug external therapy.

The treatment of one of the most common dermatoses - acne vulgaris (vulgaris, or seborrheic acne) is still a challenging task, despite the fairly numerous studies devoted to the study of disease pathogenesis and the development of new methods of pharmacotherapy. Acne vulgaris occur in 80-90% of adolescents in the pubertal period that determines the urgency of the problem and its socio-economic importance [Jansen T., Plewig G. Acne in childhood: Note the specific therapeutic norms. TW Padiatr 1997; 10: 336-341; Males A.V., Szymanowski D. Skinoren in the treatment of acne vulgar // journal of dermatology and venereology. - 1998. - N-6. - P.39-41].

Azelaic acid - active substance having antibacterial activity, which results in stunted growth of propionic bacteria involved in is the education of acne. In addition, azelaic acid slows the formation of fatty acids, which contribute to the formation of acne, prevents the formation of comedones. Products with azelaic acid is indicated for the treatment of inflammatory and non-inflammatory forms of acne (normal acne and rosacea.

Azelaic acid is active against Propionibacterium acne and Staphylococcus epidermidis, playing a significant role in the formation of acne. At low concentrations of azelaic acid almost completely inhibits protein synthesis in the cells of P. acnes, exerting a bacteriostatic effect, while increasing its concentration addition is the inhibition of DNA synthesis and RNA and develops bactericidal effect. Activity increases at lower pH. The transport of dicarboxylic acids characterized by the uptake and the strong dependence on the pH (in the absence of a transmembrane pH gradient disappears). Outside the cell pH is about 5.6, and inside the bacterial cell pH>7,0. Transfer azelaic acid is in the protonated form; therefore, the more acidic the environment is outside the cells (acidification occurs when inflammation), the stronger azelaic acid will penetrate through the plasma membrane. Once inside the bacteria in large numbers, azelaic acid acidic intracellular environment that may play a role in its antibact the branches.

Azelaic acid is moderate cytotoxic effect (due to inhibition of the synthesis of cellular proteins), manifested by normalization of keratinization in the wall of the hair follicles. Azelaic acid reduces the growth of keratinized skin cells, which seal the pores of the skin and thus cause the formation of black and white comedones.

In U.S. patent 4386104 described pharmaceutical composition for treating acne comprising azelaic keyslot, titanium dioxide and salicylic acid. However, it is not effective in the absence of a second active ingredient is salicylic acid.

The literature describes a pharmaceutical composition of azelaic acid in the form of a gel, which contains as an auxiliary ingredients polyhydric alcohol (propylene glycol), polymer gelling (polyacrylic acid), a hydrophobic component (lecithin, triglycerides), emulsifier (Polysorbate 80), preservative (benzoic acid and Trilon B), pH Adjuster (sodium hydroxide) and water (Reference Vidal. Drugs in Russia, M: Attraversare, 2011, s). However, for known compositions may be irritant side steps, redness and peeling skin, burning, articlemy, itching, and in some cases of contact dermatitis and folliculitis, which is caused, on the one with the pile, high concentration part of azelaic acid and, on the other, lack of efficiency in relation to other species of bacteria related illness.

Because therapeutic concentration of azelaic acid in external dosage forms starts from 5-10% or more, i.e. introduces a significant percentage of the total mass of poorly soluble powder, it imposes certain difficulties in the development of dosage forms based on it. To obtain a stable system requires careful selection of excipients and formulations prepared. Substances included in the composition of the dosage form should be inert, to provide the required properties and the stability of the composition, not to be subjected to hydrolysis in the presence of high concentrations of acid.

Inertness towards azelaic acid were taken into account in the selection of the ingredients of the inventive composition with the objective of ensuring the quality of the finished product, especially the physical and chemical stability that is a prerequisite for the conclusion of a new product on the market and guarantee safety for the consumer.

Technology should not lead to recrystallization of the active substance due to the ability of azelaic acid partially dissolve in water at high t is mperature, as well as to provide a uniform distribution of particles throughout the volume of the dosage form. In the development of composition and technology necessary to prevent coagulation of the particles of the dispersed phase at the expense of increasing the viscosity of the medium (a hydrodynamic barrier), and to introduce substances that reduce the interfacial tension in the interaction of particles of the dispersed phase with the environment (due to adsorption and solvation).

The objective of this invention is to provide pharmaceutical compositions for external application in the form of a gel is hydrophilic on the basis of an optimal combination of excipients, including azelaic acid in therapeutically effective concentrations (5-20%) and intended for cutaneous treatment of inflammatory and non-inflammatory forms of acne (normal acne and rosacea, as well as in the development of a method of obtaining a composition.

To achieve this goal features a pharmaceutical composition in the form of a gel, which includes azelaic acid, a hydrophobic component, a non-aqueous solvent, emulsifier, gelling polymer, a preservative and a pH Adjuster, characterized in that azelaic acid has a particle size less than 100 microns, and further includes the organic, and the ratio of azelaic acid to organic is from 1:0.025 to 1:4

Preferred is oncentrate active substance - azelaic acid is 5.0 to 20.0 wt.% of the total weight of the composition, more preferably the use of azelaic acid at a concentration of 10.0% to 20.0 wt.%.

The claimed value of the active substance and additives target of methylpyrrolidone found experimentally and is optimal. We offer therapeutic composition is made in the form of a gel and is a complex dispersed system.

Study was made of specific antibacterial action of the inventive composition compared with the prototype in vitro by the method of diffusion in agar using standard and clinical strains of bacteria (Table 1). The results of studies in vitro (method of diffusion in agar) showed that the inventive composition has a wide range of effective antibacterial action against all bacteria, taken in the experience and play an important role in the etiopathogenesis of acne, particularly in relation to clinical strain Propionobacterium acnes. While the claimed composition was significantly more effective against strains of Staphylococcus aureus 1722, Bacillus cereus ATCC 10702, Staphylococcus saprophyticus ATCC 15305.

Table 1
Test microorganismsDiameter (mm) PR is stunting
The claimed compositionthe placeholder
Staphylococcus aureus ATCC 6538 P18,02±0,0817,92±0,09
Staphylococcus aureus 192517,12±0,0716,98±0,06
Staphylococcus aureus 62017,70±0,0617,63±0,06
Staphylococcus aureus 172216,95±0,1616,43±0,10
Staphylococcus saprophyticus ATCC 1530516,43±0,0715,05±0,08
Staphylococcus epidermidis MB17,13±0,0717,05±0,06
Streptococcus faecalis No. 416315,67±0,0715,43±0,08
Micrococcus luteus ATCC 934125,40±0,1325,12±0,11
Bacillus cereus ATCC 1070218,98±0,0817,55±0,08
Propionobacterium acnes (clinically. strain)20,17±0,2020,02±0,20

A study was conducted acute and on the acute toxicity and irritant actions of the proposed drug. The results of studies of acute toxicity indicate that the investigational drug for acute effects when applied to the skin of rats at a dose of 3.5 g/kg does not cause the death of experimental animals, has no toxic effect on the movement of their body, does not change the relative weight of internal organs of rats. The results of the study of subacute toxicity within 1 month showed that the investigational new composition in an average dose of 0.35 g/kg (1/10 of the maximum dose received in an acute experience) has no toxic effect on the General condition, behavior, electrophysiological activity of the myocardium, the functional state of the Central nervous system, peripheral blood counts, liver function and kidney of experimental rats. The results of pathological studies suggest that subacute exposure does not change the coefficients of the weight of internal organs of rats. Studied composition does not cause visible changes in the morpho-functional state of the Central (thymus) and peripheral (spleen) organs of the immune system. The study drug does not cause change in different areas of the cortex of the adrenal glands and related changes mineralocorticoid synthesis. The claimed composition has not shown mestnorazdrajatego action on the skin of rats in subacute experiment, that was confirmed histologically.

One aspect of the invention is the particle size of the azelaic acid. Preferably the use of azelaic acid with a particle size of not more than 100 μm. With the introduction of the azelaic acid is larger than 100 μm is probable that an unstable product that does not match modern requirements for dosage forms. The gel particles azelaic acid more than 100 μm may have inferior organoleptic properties, not to take the test "uniformity" in accordance with GF X (section Ointment). Preferred is the use of micronized substance azelaic acid with the following grain size distribution: 100% of the particles should not be larger than 50 microns and at least 30% of the particles should not be larger than 30 μm. Due to this, azelaic acid easier to penetrate through the thick Horny layer (Stratum comeum) and dissolves in the ducts of the sebaceous glands and between the cells of the skin. This creates the necessary concentration of azelaic acid that promotes manifestations antibacterial, keratolytic and depigmenting effects.

An important point when using external funds is to prevent overdrying. This is achieved, firstly, through the use of the composition of the soft drug what s means substances, which when absorbed into the skin bind and retain it moisture; such substances include, for example, propylene glycol. Secondly, softening and moisturizing the skin provide due to hydrophobic solvents (emollient), creating the skin occlusive film and preventing moisture evaporation. Emolliency give a cream-gels well as other important functional characteristics associated with raspadaemosti, slide, touch sensations on the skin, etc.

As the hydrophobic component can be used natural and synthetic oils in combination with dimethiconol, preferably oil with a degree of spreading from 300 to 1000 mm2/10 min, which ensures a good distribution on the surface of the skin, quick and easy absorption, the creation of a uniform protective oil film. The use of oils with less effective flowing property will hamper on the skin to leave it feeling greasy. The preferred concentration of the hydrophobic component is from 0.7 to 20.0 wt.%. The use of oils with a higher degree of spreading will lead to excessive distribution over the surface of the skin and make a point of application.

Preferably used in the inventive compositions of squalane (hydrogenated squalene) and Dimethicone, b is more preferably in the following concentrations wt.%:

Squalane0,5-11,5
Dimethicone0,2-8,5

Squalane is a chemically stable substance, resistant to oxidation [Handbook of Pharmaceutical Excipients: Second Edition / Ed. by Aniey Wade and Paul J. Weller. Washington/London: Amer. Pharm. Association / The Pharm. Press, 1994. - 651 p.]. In addition, squalane is a natural component of the skin. Dimethicone is a hydrophobic nonaqueous solvent and performs the function of emollient. Dimethicone facilitates easy absorption of the gel when rubbing into the skin and the absence of whitish marks and greasy after application of the drug.

As the emulsifier can be used in combination of nonionic emulsifiers or individual emulsifiers from among ethoxylated alcohols fatty acids; esters of sorbitol and fatty acids; mixtures of mono - and diesters of diethylene glycol or glycerin fatty acid, ethoxylated derivatives of glucose. Preferred is the use of the emulsifier of macrogol 20 cetosteatil ether (emulsifier of the 1st kind) at a concentration wt.% 1,0-10,0, this surfactant has a saturated alkyl chain and is stable to peroxide oxidation.

As preservative can be used in different types of parabens, benzoic acid, Sora is andnew acid, preservatives on the basis of Phenoxyethanol, imagemotion, as well as complexing agents from Talanov used to bind metal ions, preferably in a concentration of from 0.01 to 2.0 wt.%. Most preferably used as the preservative benzoic acid at a concentration of 0.02-0.5 wt.% and disodium edetate (Trilon B) at a concentration of 0.02-0.5 wt.%.

As follows from the results of studies on the effectiveness of preservative action samples laboratory series claimed compositions containing as preservative benzoic acid and Trilon B in the above concentration, the efficiency of the antimicrobial preservative action of the composition is far superior to the requirements of the criterion And the European Pharmacopoeia [European Pharmacopoeia 5. - 2005].

As the polymer (gel) can be used derivatives of cellulose hydroxypropylcellulose, sodium carboxymethylcellulose, methylcellulose), derivatives of polyacrylic acid (various types carbonero), derivatives of starch (hydroxypropylcellulose), preferably at a concentration of 0.4-5.0 wt.%:

Pets using the polymer as a pH Adjuster and without. Most preferably used as the gel-derived polyacrylic acid, preferably of carbomer interpolis the RA type a, (g/100 g of composition), such as the brand Carbopol Ultrez 10, preferably in a concentration of 0.5-2.0 wt.% in combination with the pH Adjuster (neutralizer). As a result, the optimal value of the structural viscosity of the composition, that is, PA·s (at a gradient of shear rate) - 5,5-6,5 (28,09 c-1), 2,6-3,3 (82,27 c-1and 2,0-2,6 (122,9 c-1)

The hydrophilic phase may comprise water, nonaqueous solvents, pH Adjuster (buffering agent).

As the nonaqueous solvent can be polyhydric alcohol (glycerol, propylene glycol, hexyleneglycol), PEO-400, diethylene glycol monotropy ether, DMSO, ethyl alcohol. Preference is given to using, in combination with N-organic polyhydric alcohol, the concentration of the polyhydric alcohol is 1.0 to 15.0 wt.%. As the polyhydric alcohol is preferable to use propylene glycol.

As pH Adjuster (neutralizing substances) can be used in weak acids (such as citric, lactic), inorganic salts (such as potassium phosphate, sodium phosphate) and base (e.g. sodium hydroxide, potassium hydroxide), mono - and diethanolamine, trometamol.

Preferably with the introduction of the polymer of carbomer interpolymer (derived poly (acrylic acid) used as a controller matria hydroxide. The preferred pH of the inventive compositions is from 4.0 to 5.5, more preferably from 4.5 - to 5.0.

The main component of the dispersion medium is water, the water concentration is adjusted depending on the amounts of other excipients.

Additionally, the claimed composition may contain an anti-inflammatory supplements (anti-inflammatory substance), which can be derived vitamins: vitamin E (for example tocopherol phosphate; lauramidopropyl Tocopheryl phosphate sodium, vitamin C and its derivatives, provitamin B5 (dexpanthenol). Pets are not incorporated in a gel anti-inflammatory supplements.

Introduced into the composition of N-organic in addition to the function of penetrant active substances is also osmotically active component and theoretically can greatly enhance the effect of a polyhydric alcohol, in particular propylene glycol, so for example the composition of these substances (for example 3) evaluated the correctness of the choice of the composition due to the measurement of the kinetics of water absorption [Methodical recommendations on experimental (preclinical) study of drugs for the local treatment of wounds / Bmezine, Sviridova, Team and others - M.: SSSR, 1989. - 47].

Studies have shown that the claimed composition has moderate about onirovanie osmotic activity absorbing for 6 hours to about 50% water. Kinetics and mass of absorbed water in the developed drug and reference drug (prototype) is almost identical. It is known that the dehydrating action on the skin depends on the osmotic activity of the drug. The results of the study of the kinetics of water absorption indicate acceptability of the chosen excipients in a new composition in relation to the dehydrating action and suggest that its dehydrating effect on the skin will be approximately that of the drug crawney. At the same time, the penetration of azelaic acid in the skin in the case of the proposed drug may be more pronounced due to the presence of N-methylpyrrolidone.

The claimed composition is prepared in a cream-gel base, representing a complex dispersed system, which is simultaneously the emulsion of the 1st kind (type of oil/water)solution, colloidal solution and suspension (compared to azelaic acid). The optimal selection of ingredients prevents stratification and preserves the uniform distribution of the dispersed phase within the framework supports a pH in the range sufficient to maintain stability and high activity of azelaic acid.

The choice of ingredients and their ratio significantly affect the pic is b getting medicines. The proposed ratio of the active substance and the target additives found experimentally and is optimal, providing the pharmaceutical composition according to all modern requirements for LF and shelf life at least 2 years.

The selected composition provides the following physico-chemical properties of the gel: uniform distribution and a sufficiently small particle size of the dispersed phase of the emulsion, homogeneous distribution of particles azelaic acid cream-gel base, comparable with the distribution and size of particles in the reference drug; the particles do not gather in conglomerates; structural viscosity, providing physical stability of the suspension of azelaic acid and the emulsion during storage, and proper extrusion of the gel from the tube and gel-like consistency.

The method of obtaining the claimed composition is in an aqueous solution of the preservative injected gel-forming polymer, an organic, non-aqueous solvent, if necessary, anti-inflammatory agent, emulsifier, azelaic acid, homogenized, then add a hydrophobic component, a pH Adjuster and homogenize the mixture.

According to a preferred variant of the method of obtaining prepared gel base, dissolved in parts of water preservative (for example, benzoic sour is at and sodium ADETEF), then in a solution of preservatives injected polymer, mix until smooth, add organic and non-aqueous solvent and stirred until complete mixing of components with a dispersion of the polymer. Separately, prepare the mixture of emulsifier and water, heated to 60-65°C and maintained until complete melting/dissolving the emulsifier, and after cooling the resulting solution to room temperature, add to the dispersion of carbomer and homogenized mass until smooth. In the resulting basis add portions azelaic acid, homogenized mass, then enter the hydrophobic component (oil) and a pH Adjuster (neutralizing agent) and homogenized. The pH Adjuster (neutralizing agent) is introduced into the composition predpochtitelno in the form of a solution. The resulting product is a viscous homogeneous gel is white in color.

The distinguishing features of the claimed method of producing the composition is that the solutions of preservative and emulsifier is prepared and administered before gelation, which accelerates dissolution; suspension of azelaic acid is prepared in a dispersion of carbomer - gel with relatively low structural viscosity, which is easily mixed with the powder and allows to obtain a stable homogeneous suspension; before suspendirovanie azelaic acid gel whodatnationman and emulsifier, well moisten the powder and prevent the formation of conglomerates; the process of introduction of azelaic acid in the finished gel base is held at room temperature (without heating); emuleret hydrophobic substances to enhance the structural viscosity of the gel due to the neutralization of carbomer a pH Adjuster.

Change the boot order and temperature regimes, namely the introduction of the active substance at the initial stage at the time of emulsification or after structure formation (thickening) of the composition, can lead to inhomogeneous distribution of the active component of displacement and instability of the composition, and components during storage.

The following examples illustrate the invention.

A typical example. In a laboratory reactor equipped with a stirrer, a homogenizer and a thermometer, load sequentially purified water (40% of the total) and preservative (benzoic acid and disodium ADETEF). Stir while heating until complete dissolution. Include cooled to room temperature (20-25°C) and is dispersed in the solution of the polymer (carbomer interpolymer type a). Stirred until complete wetting and obtain a homogeneous dispersion. Loaded into the reactor N-organic and non-aqueous solvent (propylene glycol), mix. In a separate container prepare a solution of em is ligature: to the residue purified water type emulsifier (macrogol 20 cetosteatil ether), heat the mixture up to 60-65°C and maintained until complete dissolution of the emulsifier. Cool the solution to 25°C and slowly added to the polymer dispersion, avoiding foam formation. Generate a vacuum of the order of 800-600 mbar and homogenized mass until smooth. In the reactor relieve the vacuum and download portions azelaic acid by stirring while the homogenizer between loading portions. After loading all azelaic acid mass is homogenized until smooth. Then download the hydrophobic component (Dimethicone 100 cst and squalane), homogenized mass. In a separate container prepare a solution of sodium hydroxide in the remaining 20% of water, which is loaded into the reactor. Mix the gel when the homogenizer until smooth. Unload gel and Packed in tubes.

Examples of carrying out the invention is presented in table 2.

The obtained gel is for external use is metered into the tube in aluminum on THE 64-7-678-90 or another internal coating with lacquer-based glue BF-2, approved for medical use health Ministry. Aluminum tube during extrusion of the gel irreversibly deformed, due to which they are not sucking air. Packing in such tubes meets pharmacopoeial requirements [European Pharmacopoeia 5. - Semi-Solid Preparations for Cutaneous Application. - P.624-626]. Membrane and latte the red ring in the tail provide proof tubes for air. Each tube together with instructions for use are placed in the cardboard pack for consumer packaging subgroups chrome or chrome-ersatz according to GOST 7933-89. In the selected package has shelf life of the drug for 2 years and 3 months when stored at 25°C.

Table 2
ComponentsExamples, wt.%
12345
Azelaic acid5,010,015,018,020,0
Preservative2,01,00,20,010,05
The hydrophobic phase (oils)6,00,72,015,020
Emulsifier3,01,0 1,86,010,0
Polymer2,52,01,41,00,4
The organic (azelaic acid/organic20,0 (1:4)15,0 (1:1,5)12,0 (1:0,8)9,0 (1:0,5)0,5 (1:0,025)
Nonaqueous solvent8,015,010,01,05,0
The pH Adjusterto pH 4,0to pH 5.0to pH 4,8to pH 5,5to pH 4.5
Water100100100100100

As the gel-forming polymer in example 1 is used carbomer interpolymer type A, example 2 - carbomer 1342, in example 3 - oksipropilmetiltselljuloza, in examples 4, 5 apply the combination to Romer copolymer type B and carbomer interpolymer type a in the ratio of 0.1 to 1.0, and 0.3 to 0.2, respectively.

As a pH-regulator in example 1 is used sodium hydroxide in example 2 potassium hydroxide in example 3 - trometamol, in example 4 - diethanolamin, in example 5 is triethanolamine.

As a preservative in example 1 used a combination of benzoic acid and trylon B in equal proportions, in example 2 - combination of methyl paraben and propyl paraben in equal proportions, in example 3 - methylparaben, in example 4 - benzoic acid and example 5 - sorbic acid.

As the nonaqueous solvent in example 1 use propylene glycol in example 2, a mixture of glycerol and polyethylene oxide-400 (PEO-400) at a ratio of 1 to 15.0 in example 3, a mixture of propylene glycol and PEO-400 in the ratio 6,0 6,0, in example 4 - monotropy ether of diethylene glycol, in example 5, a mixture of hexyleneglycol and PEO-400 in relation to 19,0 1,0.

As the hydrophobic component used a combination of squalane and Dimethicone in the ratio of 1 to 17 (example 3), 1 to 2 (example 1), 1 : 1 (example 4), 5 : 1 (example 5), of 57.5 1 (example 2). As emulsifier use of macrogol 20 cetosteatil ether.

1. Pharmaceutical composition for the treatment of acne, rosacea and hyperpigmentation in the form of a gel, which includes azelaic acid, a hydrophobic component, a non-aqueous solvent, emulsifier, gelling polymer, a preservative and a pH Adjuster, different those who, that azelaic acid has a particle size less than 100 microns and the composition further includes an organic, and the ratio of azelaic acid to organic is from 1:0.025 to 1:4.

2. The pharmaceutical composition according to claim 1, characterized in that it contains as a hydrophobic component, a combination of squalane and dimeticone.

3. The pharmaceutical composition according to claim 1, characterized in that it further contains an anti-inflammatory agent.

4. A method of obtaining a composition described in claim 1 in which the aqueous solution of the preservative injected gel-forming polymer, an organic, non-aqueous solvent, emulsifier, azelaic acid, homogenized, then add a hydrophobic component, a pH Adjuster and homogenize the mixture.

5. The method according to claim 4, in which the pH Adjuster is injected in the form of a solution.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dermatology, and can be used for selecting a therapeutic approach to acne in females by examining biological fluids and prescribing preparations depending on the clinical findings. The biological fluids are blood and urine; blood serum hormones and steroid urine profile are tested, and the derived values are compared to the standard norms specific for the absence of acne, while the preparations are prescribed according to the comparison results. Specifically, if observing an increase of blood luteinising hormone up to 16 mIU/ml, testosterone up to 4 ng/ml, an increase of urine androsterone up to 20 mcmole/24 hours, etiocholanolone up to 11 mcmole/24 hours, total 17-ketosteroids up to 35 mcmole/24 hours, van de Calseyde's discriminant up to 3, the combined oral contraceptive Jess with the anti-androgenic effect. If also observing an increase of immunoreactive protein up to 12.90 mcUnit/ml and insulin-line growth factor 1 up to 361.04 ng/ml, the combined oral contraceptive Jess and Metformine or Metformine are prescribed. If observing a decrease of blood oestradiol up to 140 pmole/l or an increase of the concentration of luteinising hormone up to 7 mIU/ml, dihydroepiandrosterone sulphate up to 4 mmole/l, 17 - hydroxyprogesterone up to 4 nmole/l and testosterone up to 4 nmole/l in blood and an increase of urine androsterone up to 17 mcmole/24 hours, etiocholanolone up to 17 mcmole/24 hours, 11 - ketoandrosterone up to 2.5 mcmole/24 hours, 11 - ketoetiocholanolone up to 2.5 mcmole/24 hours, 17 - ketosteroids up to 50 mcmole/24 hours and van de Calseyde's discriminant up to 3, the glucocorticoid Metypred is prescribed. The high blood concentration of luteinising hormone up to 15 mIU/ml, dihydroepiandrosterone sulphate up to 6.82 mcmole/l, 17 - hydroxyprogesterone up to 4 nmole/l and an increase of urine androsterone up to 19.5 mcmole/24 hours, etiocholanolone up to 16 mcmole/24 hours, dihydroepiandrosterone up to 7 mcmole/24 hours, 17 - ketosteroids up to 45 mcmole/24 hours and van de Calseyde's discriminant up to 3.5 enables using the combined oral contraceptive Jess and the glucocorticoid Metypred. And the preparation Dostinex is prescribed in observing the above values in a combination with an increase of blood prolactin up to 750 IU/ml and a decrease of blood oestradiol up to 95.48 pcg/ml.

EFFECT: method enables providing higher therapeutic selectivity and clinical effectiveness in acne without the need of thorough examination to be conducted.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, in particular represents composition for topic application, which includes, into physiologically acceptable medium at least one derivative of naphthoic acid, benzoylperoxide and at least one film-forming component.

EFFECT: invention is characterised by the fact that said compound of naphthoic acid and benzoylperoxide are in dispersed in said composition form.

23 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an herbal formulation of topical nanoemulsion for treating acne-related skin disorders. The above formulation contains an aqueous phase comprising a therapeutic agent, rose water and/or lemon juice, and an oil phase containing an essential oil, a non-ionic surfactant and an accessory surfactant. The aqueous and oil phases are related within the range of 1:1 to 1:2, while a particle size of the herbal formulation is less than 5 nm. The essential oil is presented by tea tree oil, basil oil, rosemary oil, lavender oil, jojoba oil, bergamot oil, clove oil and peppermint oil. The invention also refers to a method for preparing the herbal formulation which involves providing the aqueous and oil phases, mixing the above phases to produce a mixture to be emulsified with the non-ionic surfactant to prepare a macroemulsion. The prepared macroemulsion is mixed with ethanol to produce a nanoemulsion with a particle size less than 5 nm.

EFFECT: invention provides the herbal formulation with good penetration, prolonged effect causing no irritation.

8 cl, 4 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of the following formula , in which n equals integer number from 1 to 15, m equals 0, 1, 2 or 3, and R represents hydrocarbon chain of polyunsaturated fatty acid, selected from omega-3 and omega-6 polyunsaturated fatty acids, and to method of obtaining them.

EFFECT: development of pharmaceutical or cosmetic composition based on said compounds and to method of acne or seborrheic dermatitis treatment for cosmetic purposes.

16 cl, 4 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I)

where Y represents a group of formula -(CR9R10)n-; X represents -C(=O)-; Z represents a group of formula -(CR13R14)q-; R1 is selected from a group, consisting of (a) C2-C12alkenyl, substituted with 4-chlorophenyl; or (b) C6-C10aryl, optionally substituted with one or two halogen atoms; R2 and R3 represent H; R4 is selected from a group, consisting of H, C1-C12alkyl, optionally substituted with hydroxyl, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted with an amino group or pyperidine, C-bound C1-C18heteroaryl, selected from pyridine and imidazole, C(=O)R15, C(=O)NR16R17 and ONR16C(=NR17)NR18R19; each R5a and R5b represents H, each R6, R7 and R8 is independently selected from a group, consisting of H, C1-C12alkyl and C6-C18aryl, each R9 and R10 represents H; each R13 and R14 represents H; R15 represents H, each R16, R17, R18, R19 and R20 is independently selected from a group, consisting of H, C1-C12alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or any two of R16, R17, taken together with atoms, to which they are bound, form a cyclic group, containing 5 carbon atoms, or n equals to 1; q represents an integer number, selected from a group, consisting of 1, 2, 3, 4 and 5; r equals to 1; or its pharmaceutically acceptable salt.

EFFECT: invention relates to a pharmaceutical composition for treatment of MC5R-associated conditions, which contains a formula (I) compound and a pharmaceutically acceptable carrier, a diluent or a filling agent.

23 cl, 6 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to a composition, possessing immunomodulating and anti-inflammatory properties. The dermatological composition, possessing immunomodulating and anti-inflammatory properties, as an active ingredient, contains an extract of the aboveground part/parts of oat, collected before ear formation. The cosmetic composition, possessing immunomodulating and anti-inflammatory properties. Application of the extract of the aboveground part/parts of oat, collected before ear formation, possessing immunomodulating and anti-inflammatory properties, as a medication.

EFFECT: composition and extract possess expressed immunomodulating and anti-inflammatory properties.

15 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic industry and represents a non-foaming cosmetic composition of an oil-in-water emulsion containing (i) retinol, (ii) at least one polar emollient specified in a group consisting of propylene glycol stearyl ester, propylene glycol isostearate and mixtures thereof (iii) at least one non-polar emollient specified in a group consisting of aromatic or linear esters, Gerbe ester, mineral oils, squalane, isohexadecane, squalene, liquid paraffin and mixtures thereof with the weight ratio of the above polar emollient and the above non-polar emollient is found within the range of approximately 95 to 5 to approximately 40 to 60.

EFFECT: provided considerable reduction of retinoid-caused skin irritation and higher efficacy or retinoid.

11 cl, 3 ex, 7 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a method of treating acne. The method of treating acne by prescribing line seed oil 10 ml 2 times a day, sodium selenite 90 mcg 1 time a day, tocopherol acetate 100 mg 2 times a day for 1 month.

EFFECT: method of treating acne is effective and enables reducing the length of treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and dermatology, and represents a water-based formulation for local application for treating acne, containing water, a water-miscible organic solvent and benzoyl peroxide, wherein the organic solvent concentration is 1-4 times higher than the benzoyl peroxide concentration in the formulation; the water and organic solvent concentrations are related as at least 7:1, preferentially at least 10:1, more preferentially at least 20:1; the benzoyl peroxide concentration in the formulation makes less than 5.0 wt %, but at least 1.0 wt %.

EFFECT: invention provides the clinical effectiveness with the reduced active agent concentration, as well as reduced irritant action.

27 cl, 4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to biopharmaceutics, and can be applied for the preservation of an immunogenic composition in the suitable condition for introduction to an animal. For this purpose the claimed composition contains an antigen of foot-and-mouth disease (FMD) and an emulsion, which is a single emulsion at the first temperature lower than the temperature of the animal body, and the said emulsion is used at the second temperature between the first temperature and the body temperature. The method includes: provision of the composition, freezing the composition and storing the frozen composition until it is required for introduction to the animal. A group of inventions also relates to a method of testing the immunogenic composition.

EFFECT: group of inventions makes it possible to reach an increase of the storage term of a vaccine against FMD, based on the emulsion as an adjuvant, and it is possible to apply the process of slow freezing, without rendering an impact on adjuvant properties of the emulsion.

13 cl, 6 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining suspension of polymorphic form I of salt of methanesulfonic acid and dabigatran etexilate of formula I . Method is characterised by the following: polymorphic form I of dabigatran etexilate methanesulfonate with melt temperature tmelt 180±3°C is suspended in mixture with talc in solution of hydroxypropylcellulose in isopropyl alcohol at temperature in the range from 12 to 22°C with obtaining suspension by method of circulation dispersion at temperature not higher than 30°C. Invention also relates to obtained in said way suspension for obtaining dabigatran etexilate methanesulfonate pellets. Invention also relates to dabigatran etexilate methanesulfonate pellets used for thrombin inhibition, and to method of obtaining said pellets by dispersion of said suspension on isolated tartaric acid cores in fluidised bed.

EFFECT: claimed invention provides industrial method of obtaining pellets of dabigatran etexilate methanesulfonate, presents only in one polymorphic form.

27 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is described is using a pharmaceutical composition in the form of an orally disintegrated tablet containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active substance and crospovidone as a disintegrating agent in ratio 2:1 respectively, as a motor stimulating and anorectic agent.

EFFECT: preparing motor stimulating and anorectic agent.

16 dwg, 34 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical oil-in-water emulsion contains mometasone or mometasone furoate, propylene glycol and water. The propylene glycol concentration makes from 20 to approximately 45 wt %. A mass ratio of propylene glycol and water in the oil-in-water emulsion makes from 1:1 to approximately 1:3. A portion of mometasone or mometasone furoate is found insoluble in the emulsion.

EFFECT: composition is characterised by stability and therapeutic effect.

27 cl, 6 dwg, 5 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an herbal formulation of topical nanoemulsion for treating acne-related skin disorders. The above formulation contains an aqueous phase comprising a therapeutic agent, rose water and/or lemon juice, and an oil phase containing an essential oil, a non-ionic surfactant and an accessory surfactant. The aqueous and oil phases are related within the range of 1:1 to 1:2, while a particle size of the herbal formulation is less than 5 nm. The essential oil is presented by tea tree oil, basil oil, rosemary oil, lavender oil, jojoba oil, bergamot oil, clove oil and peppermint oil. The invention also refers to a method for preparing the herbal formulation which involves providing the aqueous and oil phases, mixing the above phases to produce a mixture to be emulsified with the non-ionic surfactant to prepare a macroemulsion. The prepared macroemulsion is mixed with ethanol to produce a nanoemulsion with a particle size less than 5 nm.

EFFECT: invention provides the herbal formulation with good penetration, prolonged effect causing no irritation.

8 cl, 4 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a pharmaceutical submicron suspension and to a method for preparing the submicron suspension and is applicable for ophthalmic (local or intravitreal) and nasal application. The ophthalmic aqueous pharmaceutical submicron suspension contains a hydrophobic therapeutic agent prepared in the form of submicron particles with the hydrophobic therapeutic agent presenting nepafenac; where a low-molecular charged polymer contains one or more cellulose polymers which jointly or individually have a molecular weight of less than 200000 kilodalton, and wherein the low-molecular charged polymer has an average degree of polymerisation (DP) making approximately min. 100 and up to approximately 4000; and one or more additives. The low-molecular charged polymer inhibits submicron particle aggregation in the suspension; the submicron particles have an average hydrodynamic radius making less than 1 mcm, and the low-molecular charged polymer represents carboxymethyl cellulose.

EFFECT: using the group of inventions enables preparing the high-active therapeutic agent for ophthalmic application.

16 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a formulation of a perfluorinated blood substitute emulsion for biomedical applications, containing: perfluorinated hydrocarbons, emulsifying agents and an electrolyte solution differing by the fact that it contains a binary mixture of two perfluorinated hydrocarbons in ratio 1.55 to 1.99 in the concentration of 5 - 1000 g/l, with an average particle size of a perfluororganic compound of 25 - 250 nm; a binary mixture of the emulsifying agents in ratio 1.55 to 1.99 that are non-ionic block copolymers of ethylene oxide and propylene oxide - proxanoles: proxanole-268/proxanole-168; proxanole-268 in the concentration of 1 - 200 g/l with the molecular weight of 7 - 14 thousand Da; proxanole-168 in the concentration of 1 - 200 g/l with the molecular weight of 5 - 7 thousand Da; the electrolyte solution: NaH2PO4 - 0.18-0.25 g/l; NaCl - 5.5-6.5 g/l; and/or KCl - 0.37-0.41 g/l; and/or MgCl2 - 0.17-0.21 g/l; and/or NaHCO3 - 0.35-0.7 g/l; and/or glucose - 1.5-2.5 g/l.

EFFECT: invention ensures formulating the perfluorinated blood substitute with better aggregation and sedimentation stability and lower toxicity.

2 cl, 9 ex

FIELD: medicine.

SUBSTANCE: agent contains 0.2% Pyriton, an emulsifier, an emollient - isopropyl myristate, and a solvent. The emulsifier is presented by glycerol cocoate PEG-7; the emollient is presented by triglycerides of caprylic and capric acids; the solvent is water. Besides, the agent additionally contains glycerol, cyclomethicone, urea, allantoin and a flavouring agent. All the ingredients of the agent are taken in certain mass ratio.

EFFECT: invention enables eliminating side effects, recovering physiological properties of skin and providing high patient's satisfaction upon completion of the treatment.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a cream for external treatment of Graham-Little-Piccardi-Lasseur syndrome, which contains lanolin, peach oil and distilled water, and is characterised by that it further contains chloroquine, wherein components of the cream are in a defined ratio given in g%.

EFFECT: inhibiting progression of scarring without marked side effects.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of cosmetology, namely to a cosmetic composition for peroral introduction, which contains a combination of lycopene, vitamin C, vitamin E and at least one polyphenol compound, obtained from pine bark, in which the ratio of weight content of polyphenol compound to the sum of weight contents of lycopene, vitamin C and vitamin E constitutes from 0.3 to 0.7, as s single active ingredient.

EFFECT: invention is intended for prevention and/or treatment of wrinkles in the area of eyes and mouth angles, small wrinkles, eye bags and dark circles under eyes.

22 cl, 2 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically to a conjugate of a version of exendin with a PEG molecule, and can be used in medicine. The above conjugate involves exendin with the amino acid sequence SEQ ID NO: 4 and one PEG molecule with molecular weight 21 kDa to 29 kDa conjugated with a cysteine residue in exendin. The invention also refers to a method for preparing an exendin conjugate, a pharmaceutical composition and a kit for lowering blood glucose providing using the exendin conjugate.

EFFECT: invention enables preparing the exendin conjugate with PEG with GLP-1 receptor agonist activity with maintaining the maximum effect on the stimulation of cAMP (Emax) production in PEGylation.

7 cl, 44 dwg, 5 tbl, 26 ex

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