RU2548714C2 - Pharmaceutical composition for treating acne and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and represents a pharmaceutical composition in the form of gel, which contains clindamycin phosphate, a combination of gel-forming polymer and hydrophilic dispersion phase, pH control agent, allantoin and lauryliminodipropionate sodium tocopheryl phosphate; the ingredients of the composition are taken in certain ratio, in g per 100 g.

EFFECT: invention provides the high level of antibacterial activity and stability.

5 cl, 1 tbl

Description

The invention relates to the field of medicine and pharmaceuticals, specifically relates to a composition in the form of a gel for external use, containing clindamycin phosphate as an active substance, a broad-spectrum antibiotic. The main purpose of this composition is the treatment of inflammatory and non-inflammatory forms of acne (common acne) and rosacea.

Acne (acne vulgaris) is one of the most common dermatoses. Acne is a polymorphic multifactorial disease of the hair follicles and sebaceous glands, which occurs in 80% of adolescents and young adults (in girls - 10-17 years old, boys - 14-19 years old). Usually, by 20 (sometimes by 30) years the effects of acne subside, but in some cases persist after 40 years. Sometimes acne first appears after 25 years. Among the various clinical varieties of acne, acne vulgaris (acne vulgaris) is most commonly found. This dermatosis affects up to 35% of male adolescents and 23% of female adolescents. Only over the age of 24 years, this figure drops to 10% or lower.

Acne develops against the background of seborrhea, and one of the main etiopathogenetic factors that determine the development and progression of this dermatosis is the multiplication of opportunistic microflora in clogged sebaceous glands with subsequent inflammation. Violation of the skin microbiocenosis plays an important role in the pathogenesis of acne and may contribute to the development of infection in the sebaceous glands. A regular secretion from inflamed and non-inflamed follicles in acne of propionobacteria and epidermal staphylococcus has been established. In severe forms of dermatosis, a mixed infection with the presence of opportunistic and transient microflora is observed.

In the early stages of the disease, the main pathogenetic factor is blockage of the sebaceous glands; however, against the background of existing microbial dysbiosis, an infectious factor quickly joins. Therefore, the elimination of violations of the skin microbiocenosis must begin as early as possible, before the appearance of inflammatory elements. The spectrum of influence on microbiological disorders in the foci of inflammation expanded with the advent of external antibacterial agents. It is very important that external agents, without affecting the body as a whole, can affect the pathogen directly in the lesion.

An integral part of acne therapy is currently antimicrobial agents that contain broad-spectrum antibiotics as the active substance, such as clindamycin, erythromycin, tetracycline, chloramphenicol, in the form of alcohol solutions (lotions), gels, creams. In this case, the leading role belongs to dosage forms with clindamycin.

Clindamycin phosphate is an antibiotic that belongs to lincosamides and has an antibacterial effect. After clindamycin is applied to the skin, phosphate is rapidly hydrolyzed in vivo in the ducts of the sebaceous glands by phosphatases to form clindamycin, which has a higher antibacterial activity.

Clindamycin has an antimicrobial effect on propionobacteria, staphylococcus and other bacteria involved in the pathogenesis of acne. According to reference data, with topical application in the form of a gel, the average absolute bioavailability is less than 3% of the dose of clindamycin. Clindamycin rapidly accumulates in comedones of patients with acne. The average concentration of antibiotic in the comedone content after application of the gel is significantly higher than the BMD for all strains of Propionibacterium acnes, the causative agent of acne (0.4 μg / ml). With external use of clindamycin, the amount of free fatty acids on the surface of the skin decreases, which also helps to clear it of acne.

For patients with inflammatory manifestations of acne, external antibiotic therapy is very important because it allows you to quickly eliminate microbiocenosis disorders, reduce the risk of side effects and the timing of taking systemic drugs, and increase the duration of clinical remission. When prescribing therapy, it is necessary to take into account the duration of the process, its prevalence, severity, as well as the type of skin lesion and the formation of sebum. It is necessary to pay attention to the depth of the skin lesions, complications, hyperpigmentation, cicatricial changes, as well as the physical characteristics of the patient, hormonal disorders, anamnestic data, previously used therapy and its adequacy, as well as cosmetics used by patients. Of great importance is the assessment of the psycho-emotional sphere, social status, social adaptation of the patient. This makes it necessary to create a wide range of drugs for external use, which would be different in the mechanism of action and type of dosage forms.

There are various pharmaceutical formulations based on clindamycin or its derivatives, made in the form of soft dosage forms (gels, creams). US Pat. No. 4,262,075 discloses a pharmaceutical composition in the form of a gel for external use containing clindamycin phosphate, zinc acetate and a carrier base in the form of a combination of a hydrophobic and hydrophilic component. A pharmaceutical composition for treating acne in the form of a cream comprising clindamycin or a derivative thereof as an active ingredient is described in US Pat. No. 3,996,516. As auxiliary substances, it contains 2-pyrrolidone or its N-alkyl substituted, preferably N-methyl-2-pyrrolidone, and a base including hydrophobic, hydrophilic components and an emulsifier.

The patent of the Russian Federation No. 2205011 (prototype) describes a pharmaceutical composition comprising a clindamycin salt or ester, a base that is a combination of hydrophobic and hydrophilic components and an emulsifier, and additionally sodium benzoate. The known composition is characterized by an effective antibacterial effect. However, the known composition, like other analogues, does not provide a sufficient sebomodulating effect.

In recent years, the possibilities of pharmacotherapy of dermatoses have expanded significantly, which is associated not only with the achievements of fundamental biomedical disciplines, which made it possible to study important aspects of the pathogenesis of common dermatoses, but also with the introduction into medical practice of new drugs based on a new generation containing new excipients, which have a directed effect on the elimination of pathological processes that occur in the skin [Fitzpatrick D.E., Elling D.L. The secrets of dermatology. - St. Petersburg: Binom, Nevsky Dialect, 1999 .-- 512 p .; Dermatology. Atlas-reference book / T. Fitzpatrick, R. Johnson, C. Wulf, M. Polano, D. Surmond. M .: PRACTICE, 1999. - 1088 p.].

Such auxiliary substances include, for example, substances that moisturize and soften 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.]. A rational combination of such excipients with medicinal substances creates the prerequisites for rational drug external therapy. To reduce skin irritation, especially under the influence of ultraviolet rays in the summer, it is recommended to introduce cosmetic excipients with dermatoprotective properties and eliminating the irritating effect of the drug into the topical treatment of acne. Such substances, for example, are derivatives of vitamin E. The use of these substances eliminates the irritating effect, reduces erythema, including those caused by ultraviolet radiation. However, substances that soften the skin, such as derivatives of vitamin E, are hydrophobic in nature and do not show the corresponding activity in the composition of dosage forms on a gel (hydrophilic) basis. The additional presence of a derivative of vitamin E, which is poorly soluble in water, also determines the difficulty of stabilizing the composition

The objective of this invention is to create a pharmaceutical composition for external use in the form of a gel that combines antibacterial and sebomodulating properties, containing clindamycin phosphate in a therapeutically effective concentration and intended for the cutaneous treatment of inflammatory and non-inflammatory forms of acne (common acne) and rosacea, as well as developing a method for producing such a composition.

To solve this problem, a pharmaceutical composition for treating acne in the form of a soft dosage form, preferably in the form of a gel, having antibacterial and sebomodulating activity, which includes therapeutically effective amount of clindamycin phosphate, special additives, a pH regulator and a base, is proposed. The latter includes a hydrophilic dispersion phase, a gelling agent and, optionally, a preservative.

Preferably, the ingredients are contained in the following ratio, wt.%

Clindamycin phosphate (in terms of clindamycin) 0.5-2.0 Special additives 0.2-5.0 PH regulator To pH 4.0-7.0 The basis Rest

Clindamycin phosphate in a therapeutically effective amount is used as the active ingredient in the composition.

As special additives, substances with anti-inflammatory, emollient and dermatoprotective properties (allantoin together with bisabolol and / or derivatives of vitamin E), plant extracts and essential oils with anti-inflammatory and antiseptic properties in concentration (g / 100 g of the composition) can be used:

Special additives 0.2-5.0

It is preferable to use as special additives a combination of allantoin and a derivative of vitamin E (lauryliminodipropionate sodium tocopheryl phosphate) in a concentration (g / 100 g of the composition):

Allantoin 0.05-1.0 Vitamin E Derivative 0.15-4.0

It is permissible to use various agents as a pH regulator, preferably sodium or potassium hydroxide, triethanolamine, diethanolamine, trometamol, most preferably sodium hydroxide. The amount of pH adjuster is selected so as to achieve a pH of from 4.0 to 7.0, more preferably from 4.5 to 6.5.

The antibacterial effect in vitro by agar diffusion method showed the high efficiency of the proposed combination in relation to clinical strains of propionobacteria, which play an important role in the etiopathogenesis of acne, as well as clinical and reference strains of staphylococci, Micrococcus luteus, obligate anaerobic bacteria (Clostridium perfhngens, Pepto Bacto Peptostreptococcus and Streptococcus pyogenes strain). As a result of the studies, it was found that the claimed composition significantly increases the antibacterial effect of clindamycin phosphate in relation to a number of the studied strains (S.aureus ATCC 6538 P, the clinical strain of staphylococcus M. luteus ATCC 9341) compared with formulations in which there was no tocopheryl lauryliminodipropionate sodium phosphate or pH regulator, i.e., the claimed combination of clindamycin phosphate, allantoin and laurylimino dipropionate tocopheryl sodium phosphate in the claimed pH range exhibits a synergistic action.

When studying the claimed composition in the treatment of acne of varying severity, its high clinical efficacy and safety was demonstrated, which allows us to recommend its wider use as an antibacterial, anti-inflammatory and anti-comedogenic / comedonolytic drug of choice in the treatment of acne of various severity.

Clindamycin phosphate in powder form is used to prepare a patentable composition. The composition is prepared on a gel basis, which is a complex dispersed system, which is both a solution, a colloidal solution and an emulsion of the first kind (type m / v) due to the presence of special additives.

The additional presence of a derivative of vitamin E, which is poorly soluble in water, caused difficulties in stabilizing the composition and required the presence of a gel-forming polymer

As gelling agents can be used derivatives of polyacrylic acid or cellulose derivatives in a concentration (g / 100 g of the composition):

Gelling polymer 0.3-1.6

It is preferable to use polyacrylic acid derivatives (carbomers) and combinations thereof as gelling agents. In particular, it is preferable to use a combination of a high molecular weight copolymer of acrylic acid and long chain methacrylate, a crosshair of allyl ether-cross-linked pentaerythritol (carbomer 1342 or carbomer type B copolymer, for example Pemulen TR-1), and a copolymer containing a polyethylene glycol block copolymer and carboxylic fatty acid ester type A, for example Carbopol Ultrez 10) in a concentration (g / 100 g of the composition):

Carbomer copolymer type B 0.1-0.6 Carbomer interpolymer type A 0.2-1.0

Carbomer 1342 contains alkyl radicals in the molecule, due to which it emulsifies and solubilizes water-insoluble substances, and carbomer interpolymer type A additionally contains nonionic surfactants, which also provide emulsification and solubilization, the polymer is easily dispersed in water without the formation of lumps.

These substances in the indicated concentrations give a plastic type of flow with thixotropic properties, characteristic of gels applied externally, which ensures good extrusion of the claimed composition from the package.

The hydrophilic dispersion phase may consist of water and non-aqueous solvents at a concentration of% (g / 100 g gel)

Non-aqueous solvents 5.0-20.0 Water 70.0-92.0

Non-aqueous solvents may be polyhydric alcohol (glycerol, propylene glycol, hexylene glycol), PEO-400, diethylene glycol monoethyl ether, DMSO, ethyl alcohol and N-methylpyrrolidone. It is preferable to use a combination of osmotically active components of polyhydric alcohol and PEO-400 at a concentration of% (g / 100 g of gel)

Polyhydric alcohol 0,0-19,5 PEO-400 1.0-15.0

Propylene glycol is preferably used as the polyhydric alcohol. PEO-400 and propylene glycol contribute to the penetration of clindamycin phosphate into comedones, and on the other hand, due to osmotic activity, they contribute to the manifestation of anti-inflammatory and sebomodulating effects.

As a preservative, various types of parabens, benzoic acid, sorbic acid, phenoxyethanol preservatives, and imidourea can be used. Preferably, methylparaben is used as a preservative in a concentration of 0.05-0.3% (g / 100 g of the composition).

In the claimed composition for topical use, methylparaben is used in concentrations from 0.02% to 0.3%. Methylparaben has a wide spectrum of antimicrobial activity against bacteria and fungi. Moreover, its effect is enhanced in the presence of one of the auxiliary ingredients of the claimed composition is a non-aqueous propylene glycol solvent.

The effectiveness of the preservative effect of the samples of the laboratory series of the proposed drug was investigated. Studies on the effectiveness of preservatives were carried out in accordance with EU standards. A gel sample was used in which the contents of clindamycin phosphate (in terms of clindamycin) and methyl paraben were in the amount of 9.0 mg per 1 g and 2.55 mg per 1 g, respectively. As follows from the research results, according to the effectiveness of the antimicrobial preserving action, the developed drug meets the requirements of criterion A of the European Pharmacopoeia [European Pharmacopoeia 5. - 2005].

The choice of ingredients and their ratio significantly affects the method of obtaining the drug.

A method of obtaining the claimed composition consists in adding a gelling polymer to a salt or ester of clindamycin and special additives in part of the hydrophilic dispersion phase, then subsequently a special additive with hydrophobic properties, preferably tocopheryl phosphate lauryl iminodipropionate, and a pH regulator solution, after which they are mixed until homogeneous condition, adding, if necessary, a preservative.

In a preferred embodiment of the proposed production method, in the main apparatus, a solution of the active substances in a mixture of purified water and non-aqueous solvents is prepared by heating. A gel base is prepared separately by dispersing the appropriate gelling agents in water (carbomer 1342 / carbomer copolymer type B and carbomer interpolymer type A). After that, the polymer dispersion is introduced into a solution of the active substance, preservative and special additives, mixed until smooth, while cooling the base. Homogenize the mass to evenly distribute the components throughout the volume.

A special additive with hydrophobic properties is introduced into the obtained gel base, homogenized, and then the pH regulator solution is added and the mass is mixed under vacuum until all components are uniformly distributed. Chilled gel to room temperature and unload in prepared containers. The resulting product is a viscous homogeneous gel.

Distinctive features of the claimed method for producing the composition are:

- active substances (clindamycin phosphate and special additives) are dissolved in a mixture of purified water and non-aqueous solvents, which allows to reduce the dissolution time and heating temperature,

- the completeness of dissolution of the active substances (clindamycin phosphate and a special additive) is controlled before the introduction of the polymers, which avoids the partial presence of the active substances in the undissolved state and ensures their uniform distribution when the base is thickened,

- a special additive with hydrophobic properties is pre-mixed with water to achieve high fluidity of the emulsion and, accordingly, better mixing with the base.

Changing the loading order can lead to an inhomogeneous distribution of active components by volume

The following examples illustrate the invention.

A typical example.

1. Preparation of clindamycin phosphate and allantoin solution.

In a laboratory reactor equipped with a stirrer, a homogenizer and a thermometer, the bulk of the purified water, non-aqueous solvents, such as PEO and propylene glycol, are loaded, and the mass is heated to 60-65 ° C. Clindamycin phosphate is then charged; allantoin and, if necessary, methylparaben. Mixing is carried out until completely dissolved. Then cool the solution with stirring to 45 ° C.

2. Preparation of carbomer dispersions.

Part of the purified water is charged into a separate container, and a carbomer type B copolymer is loaded with stirring. Mixing is carried out until a uniform dispersion is obtained. A portion of the purified water is charged into a separate container, and a carbomer of type A interpolymer is loaded with stirring. The extract is allowed to swell without stirring.

3. Getting the gel.

In a reactor with a solution of active components with a temperature of 45 ° C, carbomer dispersions are charged. Stir the mass for 15 minutes and load the emulsion of the vitamin E derivative (lauriminodipropionate sodium tocopheryl phosphate, trade name - Vital ET). Stir while cooling to a temperature of 30 ° C. Then add a solution of pH regulator (NaOH) and homogenize the mass until smooth. Mix the gel, achieving a uniform distribution of the components at room temperature.

4. Unloading the gel.

Specific embodiments of the invention are presented in table 1. The resulting compositions have a shelf life of at least 2 years and 3 months when stored at 25 ° C.

As a gelling polymer in examples 1, 4, 5, a combination of carbomer of the copolymer type B and carbomer of the interpolymer type A in a ratio of 0.1 to 1.0, 0.6 to 0.6 and 0.3 to 0.2, respectively, are used, in example 2 - carbomer 1342, in example 3 - hydroxypropylmethyl cellulose. Sodium hydroxide is used as a pH regulator in example 1, potassium hydroxide in example 2, triethanolamine in example 3, diethanolamine in example 4, and trometamol in example 5. Methylparaben is used as a preservative in Example 1, an equal proportion of methylparaben and propylparaben is used in Example 2, benzoic acid in Example 3, and sorbic acid in Example 5. Diethylene glycol monoethyl ether is used as non-aqueous solvent in example 1, in a mixture of glycerol and polyethylene oxide 400 (PEO-400) in a ratio of 1 to 15.0 in example 2, a mixture of propylene glycol and PEO-400 in a ratio of 6.0 in example 3 to 6.0, in example 4, N-methylpyrrolidone, in example 5, a mixture of hexylene glycol and PEO-400 in a ratio of 19.0 to 1.0.

Selection of packaging materials

As a result of marketing research and the needs of clinicians, it is preferable to dose the gel with clindamycin for external use in aluminum tubes of 30 g, each gel tube is placed in a cardboard box.

The gel is dosed 30 g into an aluminum tube according to TU 64-7-678-90 or another with an internal coating with varnish based on glue BF-2, approved for medical use by the Ministry of Health of the Russian Federation.

When extruding the gel, aluminum tubes are irreversibly deformed, as a result of which air suction does not occur. By preventing the ingress of air, there is less chance of oxidation, decomposition of the active substance, less likelihood of microbiological contamination of the finished product after opening the tube. Packaging in such tubes meets the pharmacopoeial requirements [European Pharmacopoeia 5. - Semi-Solid Preparations for Cutaneous Application. - P.624-626]. The membrane and latex ring in the tail ensure the tube is impermeable to air. This is especially important for soft medicines containing water. In addition, such tubes can avoid the effects of light on the gel, which is important for maintaining the declared concentration of the active substance throughout the shelf life.

Each tube, together with instructions for use, is placed in a pack of cardboard for consumer packaging subgroups chrome or chrome ersatz according to GOST 7933-89.

Claims (5)

1. The pharmaceutical composition in the form of a gel for the treatment of acne (acne), which includes clindamycin phosphate and a base that is a combination of a gel-forming polymer and a hydrophilic dispersion phase, characterized in that it additionally contains a pH regulator and special additives - allantoin and lauryliminodipropionate tocopheryl phosphate sodium, with the following ingredients, g / 100 g of the composition:
Clindamycin phosphate (in terms of clindamycin) 0.5-2.0 Allantoin 0.05-1.0 Lauryliminodipropionate tocopheryl sodium phosphate 0.15-4.0 PH regulator To pH 4.0-7.0 The basis Rest 2. The pharmaceutical composition according to claim 1, characterized in that it further comprises a preservative. 3. The pharmaceutical composition according to claim 2, characterized in that it contains polyethylene oxide 400, propylene glycol and water as a hydrophilic dispersion phase, and a combination of carbomer copolymer type B and carbomer interpolymer type A as a gelling polymer. 4. The pharmaceutical composition according to claim 3, characterized in that it contains the ingredients of the base in the following ratio, g / 100 g of the composition:
Carbomer copolymer type B 0.1-0.6 Carbomer interpolymer type A 0.2-1.0 Propylene glycol 0,0-19,5 PEO-400 1.0-15.0 Water 70.0-92.0 5. The pharmaceutical composition according to claim 4, characterized in that it contains methyl parahydroxybenzoate as a preservative.