RU2481845C2 - Stabilised topical composition possessing comedolytic and antibiotic action - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and cosmetics, more specifically to a topical pharmaceutical composition possessing comedolytic and antibiotic action, comprising an effective amount of the antibiotic clindamycin, salicylic acid and excipients. The pharmaceutical composition is presented in the form of a gel. The excipients are as follows: acrylate copolymer emulsion Salcare SC80, allantoin, antioxidant dihydroquercetin preservative Sharomix MCI, propylene glycol, cyclomethicone DC 345, tocopherol phosphate, UV filter Escalol 567, emulsifier DC 5329, trometamol and thermal water.

EFFECT: stabilised composition has strong comedolytic and antibiotic action, comprises the protective SPF factor which protects inflamed skin against the negative effects of UV radiation and has a shelf life of at least 3 years.

3 ex, 4 tbl

Description

The invention relates to the field of medicine and cosmetology, specifically to a pharmaceutical composition for topical application, having an anti-acne and antibiotic effect, containing an effective amount of the antibiotic clindamycin, salicylic acid and excipients. The pharmaceutical composition is made in the form of a gel (hereinafter referred to as gel).

Acne is an inflammatory disease of the skin caused by changes in pilosebial structures (composed of a hair follicle and sebaceous gland). Hyperkeratinization and the formation of plaques from keratin and sebum leads to an increase in the sebaceous glands, especially during skin maturation in the pubertal period. An increase in sebum production occurs with adrenarch, when the production of dehydroepiandrosterone increases. The accumulation of sebum can lead to the development of infection. The immune system destroys bacteria, and pus is "packed" in clusters under the epidermis. Patients try to get rid of pustules by removing them on their own and in non-sterile conditions. Such damage to the underlying layers violates the fine structure of the dermis and generates a weakened zone that bacteria attack. As a result, the immune system leads to the spread of acne. The term "acne" comes from the ancient Greek "άκμή" - the culmination of a skin break (Mayorova A.V. et al., 2005).

The causes of the disease remain unclear. The main role in the development mechanism is played by seborrhea, which reduces the bactericidal effect of sebum and leads to activation of coccal flora. An important role in the mechanism of acne is given to the bacteria Propionibacterium acnes and its metabolic products. Common acne (youthful acne, acne) develop in young men and women during puberty and gradually disappear by 25-30 years. The appearance and exacerbation of acne is also affected by menstruation, stress, heat, high humidity and genetic factors. Cosmetics containing lanolin and paraffin are also known to cause acne. Acne can also be a side effect of certain medications.

There are various types of acne: seborrhea, sebaceous gland hyperplasia, sebum hypersecretion, hyperkeratosis leading to the formation of comedones - sebum-horn plugs in the ducts of the sebaceous glands with partial or complete blockage of them, which have the appearance of black dots, are pathomorphologically observed.

For effective action on Propionibacterium acnes, antibiotics must be used. One of the best in terms of exposure is clindamycin.

Clindamycin (Clindamycin) is a 7-chlorodeoxyoxy derivative of lincomycin. Available in the form of hydrochloride - for oral administration and phosphate - for injection. In terms of chemical structure, mechanism and spectrum of antimicrobial activity, it is close to lincomycin, but it is more active (by 2-10 times) with respect to some types of microorganisms (especially bacteroids and non-spore-forming anaerobes). It penetrates well into body tissues and fluids, undergoes biotransformation in the liver, and is excreted in urine and bile (Mashkovsky M.D., 2007).

For effective treatment of acne, it is necessary that the keratinized layers of the skin descend much faster than the natural process. For this, hydroxy acids must be used. One of the most effective in this regard is salicylic acid.

Salicylic acid (Acidum salicylicum) - ortho-hydroxybenzoic acid. White fine needle crystals or a light, odorless crystalline powder. It is slightly soluble in cold water, soluble in hot water, easily soluble in alcohol. Applied externally as an antiseptic, distracting and keratolytic agent in ointments, pastes and alcohol solutions (Mashkovsky MD, 2007).

Salicylic acid is often used in combination with fruit acids to enhance exfoliation. In nature, it is contained in the form of esters in the birch bark and leaves of gaulteria (Hernandez E.I., 2003).

There are topical pharmaceutical compositions designed to treat acne. Such compositions are marketed in dosage forms of a cream, gel, ointment, powder or solution.

A known composition of clindamycin and benzoyl peroxide for the treatment of acne, a kit for preparing the composition, a method of preparation and a method of treatment (application for invention of the Russian Federation No. 94040385 of 11/10/1996), including clindamycin and benzoyl peroxide as active substances. Kits for preparing compositions include a solution of clindamycin in a first container, a suspension in a benzoyl peroxide gel in a second container.

The main disadvantages of this tool is the difficulty in use, lack of effectiveness in the treatment of acne due to the lack of modern excipients.

There are topical pharmaceutical compositions containing an anti-acne compound and an antibiotic compound (RF patent No. 2404759 of 11/27/2010) containing a therapeutically effective amount of adapalene, or its pharmaceutically acceptable salt, or ester, clindamycin, or its pharmaceutically acceptable salt, or ester and a hydrophilic matrix in an amount of from 0.1 to 5.0 wt.%, containing carbomer. The invention provides a constant and uniform release of the active pharmaceutical ingredients, increased effectiveness and less side effects.

The disadvantage of this invention is the use of carbomer 940 (Carbopol 940) and methyl paraben as a preservative.

Carbopol 940 has an aggregate state of the powder, which, when used, must be subjected to a preliminary stage of swelling. The carbomer swelling stage requires heating the water to 40 ° C and holding for 1-3 hours for a uniform process. After exposure, intensive mechanical mixing is required, requiring significant energy costs.

Parabens are ineffective against bacteria and are mainly active against fungi and are completely inactivated by nonionic surfactants, and also have estrogenic activity (Belikov O.E. et al., 2003).

If parabens are already used, then they must be used together (several types): they usually use para-hydroxybenzoic acid esters with various radicals (methyl, ethyl, propyl, butyl parabens), which have varying degrees of exposure to microflora, but not just one methylparaben.

Parabens are poorly soluble in water, so they are introduced into the lipid phase, from which it is slowly released and, basically, this effect is not enough. In the presented water recipe, almost 67 wt.% And the need to use a water-soluble preservative for effective protection follows logically.

The closest to the claimed technical essence and the achieved result, selected as a prototype, is Klindovit medicinal ointment (manufactured by Akrikhin OJSC, Russia), which has an antibacterial effect. The ointment contains the antibiotic clindamycin as an active pharmaceutical substance, it is based on: methyl parahydroxybenzoate (nipagin), allantoin, tocopherol phosphate disodium lauryl iminodipropionate, propylene glycol, macrogol 400 (polyethylene oxide 400), carbomer (copolymer, interpolymer, purified water, sodium).

Klindovit ointment is one of the most effective acne treatment products on the Russian market, but this product also has several drawbacks.

The main disadvantages of the prototype are insufficient transdermal penetration of the active substance - clindamycin, the use of p-hydroxybenzoic acid methyl ester (nipagin) as a preservative, which refers to parabens.

The polyethylene oxide 400 used as a base is obsolete and does not provide the necessary rheological characteristics (tactile sensations after application, the degree of stickiness).

The prototype also does not contain a UV filter to protect damaged skin from ultraviolet radiation, which is especially important in the treatment of inflammatory processes.

The technical result of the invention is achieved by using clindamycin and salicylic acid as an active ingredient, propylene glycol, Escalol 567 UV filter, cyclomethicone DC 345, allantoin, tocopherol phosphate, dihydroquercetin antioxidant, Salcare SC80 organic acrylate emulsion, silicon as an excipient -12 Dimethicone DC 5329, Sharomix MCI preservative, trometamol and thermal water.

Propylene glycol is used to dissolve clindamycin and salicylic acid. The process is carried out at a temperature of 40-50 ° C. Propylene glycol is used as a moisturizer and solubilizer in the manufacture of cosmetics and medicines. In this case, propylene glycol acts as a solubilizer and helps to improve the penetration of active substances through the stratum corneum of the skin (Stratum Corneum) into the dermis.

Allantoin (5-ureidohydantoin) - colorless crystals soluble in water. Allantoin has an astringent effect and is included in the list of local anesthetics, astringents and anti-inflammatory drugs of the World Health Organization as an astringent for external use.

Allantoin is also widely used in the cosmetic industry as part of various creams, has a double effect on the skin: softens the stratum corneum, contributing to the separation of dead cells, and stimulates tissue regeneration. It is usually introduced into the composition of cosmetics for narrowing pores, softening the skin, including those intended for the care of weathered or sunburned (inflamed) skin.

Tocopherol phosphate (Vitamin E) is a fat-soluble vitamin. It is an antioxidant that protects cells from pathological peroxidation, which leads to their aging and death. Peroxidation plays a large role in the development of malignant processes in the body, therefore, it is believed that antioxidants protect against cancer. With a lack of vitamin E, the cells become susceptible to the action of toxic substances, they are damaged faster, and immunity is weakened.

Vitamin E is necessary for all body tissues. It protects red blood cells, improving oxygen transport to tissues. Due to its effect on blood coagulation, it prevents the formation of blood clots in blood vessels. Used for the prevention of vascular atherosclerosis.

Tocopherol phosphate improves the nutrition of the skin and mucous membranes, which prevents dry skin and promotes "rejuvenation" of the body.

For stabilization, an Escalol 567 organic UV-filter Benzophenone-3 (INCI: Benzophenone-3), active in the “A” and “B” ranges of ultraviolet radiation, and the antioxidant dihydroquercetin are introduced into the gel.

The main parameters that determine the effectiveness of sunscreens are the minimum erythema dose (MED) and the sun protection factor - SPF (Sun Protection Factor).

Erythema, or redness of the skin, has a convenient quantitative characteristic - MED. The minimum erythema dose (biodose) is the dose of radiation that causes the minimum redness visible to the eye, which develops after a certain period of time after exposure (usually 24 hours). MED can also be defined as the exposure time sufficient to induce minimal erythema. In order to find out how effectively this product protects against sunburn, measure the DER of unprotected skin and compare it with the DER of the skin on which the test agent is applied. The SPF value shows how much the DER of protected skin exceeds the DER of exposed skin.

The native form dihydroquercetin obtained from Siberian larch (Larix sibirica Ledeb.) And Daurian larch (Larix Dahurica Nurcz.) Was used as an antioxidant.

Silicone oil is added to the gel - cyclomethicone DC 345 (INCI: Cyclomethicone). Cyclomethicone is a mixture of cyclic polydimethylsiloxanes with a low viscosity of 0.65 centistokes, which guarantees hydration and increased fluidity on the surface of the skin and, as a result, a decrease in the consumption of pharmaceutical gel.

The aqueous anionic acrylate emulsion of the Salcare SC80 copolymer (INCI: Steareth-10Allyl Ether / Acrylates Copolymer), which is a carbomer, was selected as the basis for the pharmaceutical gel. Salcare SC80 is compatible with a wide range of active pharmaceutical substances. Salcare SC80 is convenient to use in view of its emulsified form, allowing you to quickly get a clear gel.

To enhance the transfer of biologically active substances into the dermis, the PEG-12 Dimethicone silicone emulsifier (INCI: PEG-12 Dimethicone) was used. When emulsified, instead of micelles it forms vesicular structures - niosomes, which are able to transfer biologically active substances deep into the dermis.

Niosomes are vesicles consisting of a shell in the form of a water-insoluble double layer of a nonionic emulsifier (surfactant). In this case, surfactants are a group of dimethicone copolyols, which are esters of polyethylene glycol and polydimethylsiloxane base. Thus, dimethicone copolyols are a hybrid of silicon and carbon. Unlike liposomes made on the basis of phospholipids, niosomes have a number of advantages for the delivery of active pharmaceutical substances (APS). The presence of a covalent Si – O bond in the hydrophobic part of the polydimethylsiloxane emulsifier base molecule, which has great elasticity, allows targeted delivery of a wide range of APIs.

The use of the water-soluble preservative Sharomix MCI (INCI: 5-cloro-2-methyl-4-isothiazolinone and 2-methyl-4-isothiazolinone) allows better protection of the pharmaceutical gel than the use of a fat-soluble preservative (e.g. parabens), due to the high content of the aqueous phase and the ability of microorganisms to reproduce precisely in the aqueous phase and on the interface.

The concentration of hydrogen ions (pH) is stabilized by trometamol (2-amino-2- (hydroxymethyl) -1,3-propanediol), which, unlike other amine thickeners, such as di- and triethanolamines, does not have local irritating properties and is less toxic , which allows you to use it even in injectable preparations (for example, Trisamine solution for injection).

Thermal water contains mineral salts and various trace elements (bromine, iodine, iron, magnesium, sodium, etc.), the concentration of which corresponds to those in the human body, when environmental conditions are favorable to maintain balance. That is, thermal water is a way to maintain the natural composition of water in our body, which is disturbed by stress. Thermal water helps to maintain a normal rate of cellular metabolism, increases resistance to negative environmental influences, maintains skin hydration, as well as its protective properties at the required level and normalizes the water-lipid balance.

All products manufactured in the laboratory of NPO SayTEK LLC are made on the basis of thermal water extracted at well No. 1 in the village of Suvorovskaya in the Stavropol Territory.

The source of thermal mineral water Suvorovskaya No. 1 is a typical representative of alkaline low-mineral deep waters with a high flow rate and a temperature of 53-56 ° C. It was discovered and drilled in 1959 at a depth of 1253 m and from that moment it has half a century of tradition of improving people.

The possibility of carrying out the claimed invention is confirmed by examples of specific performance.

Example 1

As active pharmaceutical substances, the gel contains clindamycin and salicylic acid, which dissolve in propylene glycol at a temperature of 40-50 ° C.

The basis of the product includes: UV filter Escalol 567, cyclomethicone DC 345, antioxidant dihydroquercetin, allantoin, tocopherol phosphate, Salcare SC80 acrylate emulsion, PEG-12 silicone emulsifier Dimethicone DC 5329, Sharomix MCI preservative, trometamol and thermal water.

The phases of preparation and formulation of the gels in examples 1-3 are presented in table 1.

Phase A is prepared at room temperature by mechanical mixing of the following components in the mixer: Salcare SC80 copolymer acrylate emulsion - 1.0 wt.%, Allantoin - 0.1 wt.%, Dihydroquercetin antioxidant - 0.02 wt.%, Sharomix MCI preservative - 0.1 wt.%. Thermal water is introduced up to 100 wt.% Of the total mass of the gel (i.e., Phase A, B, C and D).

Phase B contains, as an active pharmaceutical substance, clindamycin in an amount of 0.5 wt.%, Salicylic acid, 4.0 wt.%, Dissolved in propylene glycol, 20.0 wt.% At a temperature of 40-50 ° C.

Phase B is added to Phase A cooled to a temperature of 30-50 ° C with mechanical stirring in a mixer.

Phase B is prepared separately by intensive mechanical mixing and includes the lipid components of the agent: cyclomethicone DC 345 - 5.0 wt.%, Tocopherol phosphate - 0.01 wt.%, Emulsifier DC 5329 - 1.0 wt.%. An Escalol 567 UV filter is added to the mixture in an amount of 40.0 wt.%, Providing an SPF of 40.

Phase B is introduced into the mixture (A + B) with vigorous stirring and room temperature.

Phase G consists of one component, trometamol, which, when added in an amount of 1.0 wt.%, Neutralizes the acrylate emulsion and, as a result, a gel consistency is formed. Trometamol is introduced into the mixture at the very least and is a pH regulator.

The resulting pharmaceutical gel is a soft consistency of white or white with a yellowish tint, with a weak specific odor, pH from 4.50 to 6.0.

Example 2

It is carried out analogously to example 1, only the following components are used in quantity: salcare SC80 copolymer acrylate emulsion - 2.0 wt.%, Allantoin - 2.0 wt.%, Antioxidant dihydroquercetin - 0.04 wt.%, Preservative Sharomix MCI - 0, 3 wt.%, Clindamycin - 3.0 wt.%, Salicylic acid - 8.0 wt.%, Propylene glycol - 10.0 wt.%, Cyclomethicone DC 345 - 15.0 wt.%, Tocopherol phosphate - 0.1 wt.%, emulsifier DC 5329 - 3.0 wt.%, trometamol - 2.0 wt.%. An Escalol 567 UV filter is added to the mixture in an amount of 8.0 wt.%, Providing SPF 8 (Table 1).

Example 3

It is carried out analogously to example 1, only the following components are used in quantity: salcare SC80 copolymer acrylate emulsion - 3.5 wt.%, Allantoin - 1.0 wt.%, Antioxidant dihydroquercetin - 0.1 wt.%, Preservative Sharomix MCI - 0, 5 wt.%, Clindamycin - 5.0 wt.%, Salicylic acid - 0.5 wt.%, Propylene glycol - 15.0 wt.%, Cyclomethicone DC 345 - 20.0 wt.%, Tocopherol phosphate - 0.04 wt.%, emulsifier DC 5329 - 4.0 wt.%, trometamol - 2.5 wt.%. An Escalol 567 UV filter is added to the mixture in an amount of 1.0 wt.%, Providing SPF 1 (Table 1).

The developed gel passed physical-chemical, toxicological tests at the Federal State Health Institution “Center for Hygiene and Epidemiology in the Stavropol Territory” of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare. The research results testified to the safety of use and high quality of the gel.

Due to the presence of salicylic acid, an UV filter Escalol 567, an antioxidant dihydroquercetin, allantoin and an organosilicon emulsifier DC 5329 capable of forming niosome vesicles, the process of skin restoration (Acne treatment) was much faster than analogues.

Thus, the inventive stabilized composition has a pronounced anti-acne and antibiotic effect, contains a protective factor SPF, which reliably protects the inflamed area of the skin from the negative effects of ultraviolet radiation.

Information sources

1. Application for the invention of the Russian Federation No. 940403 85 of 11/10/1996.

2. RF patent No. 2404759 of 11/27/2010.

3. Mayorova A.V., Shapovalov B.C., Akhtyamov S.N. Acne in the practice of a dermatocosmetologist. M., “Klavel Firm”, 2005; 6-85.

4. Hernandez E.I. Cosmetic peeling: theoretical and practical aspects. Digest of articles. - M., LLC company Klavel, 2003. - 214 p.

5. Mashkovsky M.D. Medicines - 15th ed., - M.: RIA "New Wave", 2007. - 1206 p.

6. Belikov O.E., Puchkova T.V. Preservatives in cosmetics and hygiene products, M .: Izd. "School of cosmetic chemists", 2003. - 250 p.

Table 1. Preparation phases and formulation of a stabilized topical composition with anti-acne and antibiotic effects No. p / p Name of ingredient Content in wt.% Example 1 Example 2 Example 3 Phase A one Thermal water up to 100 by weight of the gel up to 100 by weight of the gel up to 100 by weight of the gel 2 Preservative (Sharomix MCI) 0.1 0.3 0.5 3 Acrylate Emulsion Copolymer (Salcare SC80) 1,0 2.0 3,5 four Antioxidant Dihydroquercetin 0.02 0.04 0.1 5 Allantoin 0.1 2.0 1,0 Phase B 6 Propylene glycol 20,0 10.0 15.0 7 Clindamycin 0.5 3.0 5,0 8 Salicylic acid 4.0 8.0 0.5 Phase B 9 Cyclomethicone (DC 345) 5,0 15.0 20,0 10 Organosilicon Emulsifier (DC 5329) 1,0 3.0 4.0 eleven UV Filter (Escalol 567) 40,0 8.0 1,0 12 Tocopherol phosphate (Vitamin E) 0.01 0.1 0.04 Phase G 13 Trometamol 1,0 2.0 2,5

Claims (1)

A stabilized topical gel composition with anti-acne and antibiotic effects, containing a therapeutically effective amount of clindamycin, tocopherol phosphate, allontaine, a base, preservative, propylene glycol solvent, characterized in that it additionally contains salicylic acid, antioxidant dihydroquercetin, UV cyclomethicone filter Escalol 567, silicone emulsifier DC 5329, as a base acrylate emulsion copolymer Salcare SC80, as a preservative Sharomix MCI, as solvent TBE - thermal water and the following component, in weight%:.
Clindamycin 0.5-5.0 Salicylic acid 0.5-8.0 Propylene glycol 10.0-20.0 UV Filter Escalol 567 1,0-40,0 Cyclomethicone DC 345 5.0-20.0 Silicone emulsifier DC 5329 1.0-4.0 Antioxidant Dihydroquercetin 0.02-0.1 Allantoin 0.1-2.0 Tocopherol phosphate 0.01-0.1 Salcare SC80 Acrylate Emulsion Copolymer 1.0-3.5 Trometamol 1.0-2.5 Preservative Sharomix MCI 0.1-0.5 Thermal water Up to 100.0