RU2489144C2 - Pharmaceutical composition for treating skin diseases and method for preparing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a combined pharmaceutical composition for treating skin diseases. The composition contains betamethasone, preferentially betamethasone dipropionate, urea and at least one adjuvant. As adjuvants, the composition contains a hydrophobic component, an emulsifier, a preserving agent, a buffer agent, a non-aqueous solvent and water. A method for preparing the declared composition consists in the fact that the melted hydrophobic component, emulsifier and water are emulsified, and then betamethasone and the preserving agent are introduced at temperature below 60°C, homogenised and added with a prepared solution of urea and the buffer agent.

EFFECT: pharmaceutical composition is characterised by high pharmacological activity, stability, uniform distribution of the active ingredients.

7 cl, 8 ex, 1 tbl

Description

The invention relates to medicine and pharmaceuticals, in particular, to a composition in the form of a cream for external use, which contains betamethasone and urea as an active ingredient and is intended for external use in the treatment of dermatoses with keratinization disorders: atopic dermatitis, diffuse neurodermatitis, simple chronic lichen ( limited neurodermatitis), seborrheic dermatitis, large plaque psoriasis in the stationary stage, psoriasis of the scalp, horny eczema, ichthyosis, etc.

The treatment of dermatoses is of particular importance in connection with an increase in their frequency, including among children, as well as in connection with the increase in severe, often torpid and therapy-resistant forms of these diseases, as well as complicated by various infections. The incidence of allergic dermatosis is 6-15%, psoriasis - 2-4% of the world's population, which determines the relevance of the problem and socio-economic significance.

The problem of treating dermatoses with keratinization disorders is complex and important in modern dermatology. Moreover, in the general structure of skin diseases, the proportion of psoriatic disease reaches about 9%, among those hospitalized in dermatological hospitals - 35-38% [Features of the clinical manifestations and course of psoriatic disease depending on the age of patients / Bratus-Sukhorukova E.Yu., Pogrebnyak L .A., Flat L.M., Tarnavskaya N.N. // Dermatovenerology, cosmetology, sexopathology. - 1999. - No. 2. - S.74-76], and seborrhea is the most common skin disease, its frequency of manifestations in people from 10 to 25 years, even according to the estimates of the most critical authors, does not fall below 85%.

For the external therapy of patients with psoriasis, neurodermatitis, dermatoses with the phenomena of hyperkeratosis, drugs are shown that have, on the one hand, keratolytic and keratoplastic properties, since the morphological essence of psoriasis is primarily the hyperproliferation of epidermal cells and impaired keratinization. To correct keratinization disorders in psoriasis and a number of other dermatoses with keratinization disorders, preparations containing keratolytics, in particular salicylic acid, are traditionally used [Dermatology. Atlas-directory / T. Fitzpatrick, R. Johnson, C. Wulf, M. Polano, D. Surmond. M .: PRACTICE, 1999. -1088 s]. On the other hand, drugs for the external treatment of dermatoses with keratinization disorders should have antipruritic, anti-inflammatory and antiproliferative effects. For this purpose, external treatment with glucocorticosteroids (GCS) is most often used.

Known compositions based on one of the most effective GCS - betamethasone. For example, the drug Diprosalik ointment (Schermg-Plow Labo N.V., Belgium) contains 0.064% betamethasone dipropionate and 3% salicylic acid on a vaseline hydrophobic basis [Russian Drug Register: Radar Drug Encyclopedia. - 15th edition Ch. ed. G.L. Vyshkovsky. - M.: “Radar-2007”, 2006]. One of the main disadvantages of this composition, as well as 2-10% salicylic acid ointments, is that it is prepared only on a hydrophobic petrolatum, which disrupts the thermoregulation of skin respiration, and therefore is unsuitable for use on large areas of affected skin for long periods period. Such external agents are extremely inconvenient for outpatient use, since they stain clothes, their use requires a violation of the usual rhythm of life for the period of application of the drug and subsequent thorough washing off. The hydrophobic base also makes them unsuitable for use on the scalp, especially on an outpatient basis, for the treatment of patients with exudative forms of psoriasis, pustular psoriasis, etc.

In this regard, practical medicine requires drugs with a similar complex effect, but containing hydrophilic excipients. A number of preparations on such a basis are known containing betamethasone, for example, the composition according to the patent of the Russian Federation No. 2225208 or the preparation Beloderm cream (Belupo, Croatia), which are practically equivalent in therapeutic effectiveness. The drug Beloderm contains betamethasone dipropionate and excipients.

Combination creams containing a corticosteroid in combination with urea are known. These are Hydrodexan cream (Roch Pharma) containing 1% hydrocortisone and 10% urea, as well as Prednikarb cream (ZAO Darnitsa Pharmaceutical Firm) containing 0.5% prednisolone and 10% urea [COMPENDIUM 2008 - drugs: B two volumes / Ed. V.N. Kovalenko, A.P. Viktorova. - K .: MORION, 2008 .-- 2270 s, 49; Rote Liste, 2000]. However, these drugs contain weak corticosteroids and are ineffective for external therapy of dermatoses.

It is also known that urea can form clathrate compounds (inclusion compounds) with many water-insoluble substances by incorporating these substances into the cavities of associates formed by urea molecules [Sweetman SC (Ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version, (2007)], which significantly complicates the development of pharmaceutical preparations containing urea.

Thus, the development of a drug based on the combination of a glucocorticosteroid with keratolytics for the treatment of inflammatory and allergic diseases, including those with violations of the keratinization process of the skin: subacute and chronic hyperkeratic and dry dermatoses such as psoriasis, atopic dermatitis, flat lichen, eczema, is still relevant. (including coin-shaped eczema, hand eczema, eczematous dermatitis), dyshidrosis, seborrheic dermatitis, common ichthyosis and other ichthyosiform dermatoses.

The objective of this invention is to create a new pharmaceutical composition for external use in the form of a cream with the optimal combination of excipients containing a combination of strong corticosteroids and urea, and intended for cutaneous treatment of dermatoses with impaired keratinization, and also to develop a method for producing such a composition.

To solve this problem, a pharmaceutical composition is proposed in the form of a soft dosage form for the treatment of skin diseases, which includes betamethasone dipropionate, urea, a hydrophobic component, emulsifier, preservative, a buffer substance, non-aqueous solvent and water, while the content of betamethasone dipropionate is 0.01-0 , 1 g / per 100 g of the composition and the composition has a pH from 4.5 to 7.1.

The preferred concentration of betamethasone dipropionate is 0.01-0.1 g / 100 g of the composition. Preferably, betamethasone dipropionate is used in a preferred concentration of 0.064% or 0.05 g / 100 g of the composition, calculated on betamethasone.

Betamethasone dipropionate (9-fluoro-11β-hydroxy-16β-methyl-3,20-dioxopregn-1,4-diene-17,21-diyl dipropionate) is a synthetic fluorinated glucocorticoid similar in structure and pharmacotherapeutic activity to dexamethasone and being its β -isomer [Vidal Handbook. Medicines in Russia: A Handbook. - M .: AstraPharm-Service, 2007 .-- 1632 p .; Mashkovsky M.D. Medicines - M.: Publishing House "New Wave", 2005. - 1200 p.].

Betamethasone dipropionate is used in the claimed composition in combination with urea, which significantly potentiates the pharmacological effect of the composition (anti-inflammatory, vasoconstrictor). Urea compares favorably with its safety, being a natural component of our body, and, in addition, exhibits an antimicrobial effect.

The presence of various pathological processes that occur in the dermis with chronic dermatoses, on the one hand, and the exogenous drying effect of external factors on the skin, on the other hand, make it necessary to have a moisturizer in the composition of the preparations. Urea can also serve as a humidifier, as it draws water from the environment and holds it in the stratum corneum of the epidermis, thereby helping to soften the skin and improve its elasticity.

Since topical application of urea is not absorbed into the systemic circulation, any systemic side effects are excluded. The only side effect, the manifestation of which is possible with the local use of soft drugs containing high concentrations of urea, is skin irritation. The preferred concentration of urea is 3-20 g / 100 g of the composition, more preferably 5 to 12 g / 100 g of the composition

The claimed composition is intended for skin application and local action. A comparative study of acute and chronic toxicity, locally irritating effect and immunotoxicity was conducted. In addition, a specific pharmacological (anti-inflammatory and vasoconstrictive) activity was studied in comparison with the prototype drug Beloderm cream (Belupo, Croatia).

It was found that with dextran exudative edema, double applications of the claimed composition (betamethasone dipropionate and urea) and the comparison drug in a total dose of 200 mg cream / rat (= 0.36 mg / kg for betamethasone) have a rapidly developing anti-inflammatory effect. The effect of the proposed drug 1 hour after application is 33.6%, slightly increasing by 3 hours to 43%. The effect of Beloderm cream is less pronounced and amounts to 22.2% by 1 hour, remaining at the same level for up to 3 hours (24.4%). The total effect of the new composition, calculated as the area under the time-effect curve, was 93.4, which is 1.6 times more than this indicator for the comparison drug (57.7).

With aerosil exudative edema, the anti-inflammatory effect of the proposed drug in the same dose was 1 hour after the induction of inflammation 36.1%, by 5 hours - 40.9%, by 24 hours - 16.7%. The effect of Beloderm cream after 1 hour corresponds to that in the case of the claimed composition, amounting to 36.7%, decreasing in the future: by 5 hours to 28.4%, by 24 hours - up to 3.1%. The total anti-inflammatory effect of the claimed composition was 719.3, which is also 1.6 times more than that for the drug Beloderm cream - 447.8.

With a single cutaneous application to the authors of the work on intact skin at a dose of 100 mg / person, the vasoconstrictor effect of the proposed composition and Beloderm cream 15 minutes after application is 43.6% and 45.5%, respectively. By the 30th minute, the activity of the new drug decreases by 1.2 times (to 37.2%), while the effect of the Beloderm cream decreases faster - by 1.7 times (to 26.3%).

In general, the results of a comparative study of the specific pharmacological activity of the drugs suggest that the compared drugs have a characteristic anti-inflammatory and vasoconstrictor activity. However, the claimed composition is characterized by higher activity, which is explained by the synergistic effect of urea on the pharmacological effect of betamethasone.

The results of the study of acute toxicity indicate that the claimed composition relates to practically non-toxic substances. Application of the drug in a dose of 1.50 g / kg on the entire surface of the animal’s body, with the exception of the head and tail, did not cause the death of the animals. According to the clinical symptoms of animal intoxication and the level of acute toxicity, the new drug corresponds to the comparison drug Beloderm cream.

The results obtained in a chronic experiment indicate that the cutaneous application of the claimed composition to rats for 1 month at doses of 0.150 g / kg (1/10 of the maximum tested in acute experiments) does not have a toxic effect on the general condition of animals, functional parameters of the central nervous system, and electrophysiological myocardial activity, peripheral blood parameters, does not cause pathological changes in the main biochemical blood parameters of animals that characterize metabolic processes in the liver, kidneys, myocardium.

The results of pathomorphological studies indicate that with a cutaneous application for 1 month in the studied doses, the proposed drug does not change such an indicator as the relative mass of the internal organs of rats. After exposure to the drug, morphological signs of cardiotoxic, nephrotoxic and hepatotoxic effects on the body of experimental animals are not detected. The inventive composition does not exhibit a locally irritating effect on the skin, which is histologically confirmed.

The results of immunotoxicity studies showed that cutaneous applications of the claimed composition for 14 days at a dose of 0.133 g / kg (1/10 of the maximum dose studied in an acute experiment in terms of mice) do not cause significant changes in indicators of the cellular and humoral immune system in mice .

The results of the study, obtained in a chronic experiment, indicate that, according to the toxicity parameters, the composition according to the invention corresponds to a comparative preparation.

As auxiliary substances, the composition also contains a hydrophobic component, an emulsifier, a preservative, a hydrophilic component (buffer substance, non-aqueous solvent and water). The preferred content of the ingredients of the composition is, g / 100 g of the composition:

Betamethasone dipropionate - 0.01-0.1 Urea 3-20 Hydrophilic component 34.0-90.5. Hydrophobic component 5.0-25.0 Preservative 0.01-3.0 Emulsifier 5.0-12.0,

and the composition has a pH of 4.5-7.1

As a hydrophobic component, petrolatum, petrolatum, squalane, isopropyl myristate, isopropyl palmitate, octyldodecanol, cyclomethicone and dimethicone can be used. It is preferable to use a combination of petrolatum, petrolatum and squalane in a concentration of% (g / 100 g of composition):

Petroleum jelly 5-9 Vaseline oil 5-9 Squalene 2-5

This composition of the excipients of the hydrophobic phase with different spreadability provides good spreadability on the skin

As an emulsifier, combinations of non-ionic emulsifiers of the 1st and 2nd kind from the number of ethoxylated alcohols of fatty acids can be used; esters of sorbitol and fatty acids; mixtures of mono - and diesters of diethylene glycol or glycerol of fatty acids, ethoxylated derivatives of glucose. It is preferable to use a combination of emulsifiers of macrogol 20 cetostearyl ether (emulsifier of the 1st kind) and cetostearyl alcohol (emulsifier of the 2nd kind) in a concentration (g / 100 g of composition):

Macrogol 20 cetostearyl ether 2-3 Cetostearyl alcohol 5-8

As a preservative, various types of parabens, phenoxyethanol-based preservatives, and imidourea can be used. The use of methyl paraben (nipagin) in a concentration of 0.1-0.3 (g / 100 g of the composition) is preferred.

The hydrophilic substance is selected from the group consisting of water, a non-aqueous solvent and a buffer substance. Preferably, the hydrophilic substance is a combination of a non-aqueous solvent and water, or a combination of water, a non-aqueous solvent and a buffer substance.

As a non-aqueous solvent, propylene glycol, glycerin, PEO-400, hexylene glycol, diethylene glycol monoethyl ether can be used. Preferably, propylene glycol is in a concentration of 3-7 (g / 100 g of the composition).

Initially, aqueous solutions of urea have a neutral pH. However, during their storage, the pH rises to 8.0-8.5. This is due to the property characteristic of urea - the ability of urea to hydrolyze in aqueous solutions with the formation of carbon dioxide and ammonia, which inevitably leads to an increase in pH [Neiland O.Ya. Organic Chemistry: Textbook. for chem. specialist. universities. - M .: Higher school, 1990. - 751 s]: Therefore, in a preferred embodiment of the invention, the claimed composition contains a buffering agent.

Preferably, buffering agents are those that provide a pH of the cream in the range of 4.5 to 7.1. As buffering substances can be salts of phosphoric, acetic, phthalic, citric, lactic acids, lactones, amino acids and their salts. It is preferable to use a buffer mixture based on organic buffer substances, mainly DL-pantolactone and arginine in a concentration of% (g / 100 g cream)

DL Pantolactone 0.5-3.5 Arginine 0.02-0.2

So, for example, when using organic buffer substances DL-pantolactone and arginine, a cream containing 10% urea and 2.3% DL-pantolactone initially has a pH of 3.43. When stored for 9 months, the pH of this cream reaches 6.23. With the introduction of arginine in creams containing 10% urea and 2.3% DL-pantolactone, their pH rises; in this case, the pH is higher, the higher the concentration of arginine (at a constant concentration of DL-pantolactone). With a low arginine content, the pH of creams during storage increases the more, the lower the concentration of arginine. Starting with an arginine concentration of 0.075%, the pH of the creams stabilizes and remains at approximately the same level during storage for 9 months. Thus, DL-pantolactone and arginine form a buffer mixture in urea solutions and stabilize the pH, apparently preventing hydrolysis of urea during storage. By varying the ratio between the components of the buffer mixture, you can control the pH of the cream.

Studies have been conducted to study the stability of betamethasone dipropionate. For these studies, formulations with a pH of 4.5 to 7.5 were developed; The pH was adjusted with a buffer substance. The concentration of beamethasone and its impurities in the cream was determined by HPLC.

Initially, after preparation of the preparation, impurities were formed in the sample that had an alkaline medium (pH 7.5). The sum of the peak areas of impurities relative to the peak area of betamethasone dipropionate was 8.17%.

At a pH of 7.0 to 4.5, impurities are not formed during the manufacture of the drug. After storage for 3 months at a temperature of 40 ° C, which corresponds to approximately 1 year of storage at a temperature of 25 ° C, the pH of the samples changed. In the sample, which had an initial pH of 7.5, the pH increased to 9.5, the medium became even more alkaline, which is apparently due to the hydrolysis of urea. In the sample with an initial pH of 4.5, the pH decreased to 4.01. For samples with a pH of 7.0 to 5.0, the pH is close to 6.0.

In the sample composition No. 1, which had an alkaline pH of the medium, the amount of impurities increased from 8.17% to 13.40%. After storage, peaks of impurities appeared on the chromatograms of samples Nos. 2–7 with a retention time shorter than the retention time of betamethasone dipropionate, however, the content of these impurities is insignificant.

It should be noted that approximately the same level of impurities (an increase from 0.1% to 0.7%) is observed for the experimental series of the preparation, which were developed in a homogenizing reactor and stored at a temperature of 25 ° C for 2 years. Moreover, during the shelf life the pH of these creams remained at about 6.0.

Preferably, the proposed therapeutic composition is made in the form of a cream and is a complex emulsion disperse system. The inventive composition is characterized by a uniform distribution and a minimum particle size of the hydrophobic phase of the emulsion. The particle size of the oil phase in the cream is not more than 15-20 microns, and the bulk is up to 10 microns.

The choice of ingredients and their ratio significantly affects the method of obtaining the drug. According to the proposed method, the melt of the hydrophobic phase, the emulsifier and part of the water is emulsified, then betamethasone dipropionate and the preservative are administered in the form of a solution or in the form of a suspension at a temperature below 60 ° C, preferably in the form of a solution, the urea solution prepared in advance is homogenized. In a preferred embodiment, urea is administered in conjunction with a buffering agent.

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

- the introduction of betamethasone dipropionate and a preservative into the finished emulsion at a temperature below 60 ° C, which on the one hand preserves the liquid consistency of the base and allows the active substances to quickly disperse throughout the volume, and on the other hand reduces the time it takes for high temperature to affect the active components.

- the introduction of a urea solution at the lowest possible temperature before thickening the cream, which ensures uniform distribution, the absence of hydrolysis of urea and rapid subsequent cooling of the cream.

As a result, the most uniform distribution of the active ingredients in the finished form is achieved, which is essential for drugs. Changing the loading order and temperature conditions, namely, the introduction of active substances at the initial stage at the time of emulsification, or after structure formation (thickening) of the cream, can lead to an inhomogeneous distribution of active components in volume and instability of both the composition itself and the active components during storage.

The following examples illustrate the invention. A typical example (example 1). In a laboratory reactor equipped with a stirrer, homogenizer and thermometer, purified water is sequentially loaded, a mixture of petroleum jelly, liquid paraffin and squalane (in a 2: 2: 1 ratio, hydrophobic component), a mixture of macrogol 20 cetostearyl ether and cetostearyl alcohol in equal proportions (emulsifier) . The mass is heated to 70 ° C, maintained until the components are completely melted and homogenized with vigorous stirring at a temperature of 70-75 ° C for 10 minutes, then the cream base is gradually cooled at an average stirring speed of 55 ° C. A solution of methyl paraben (preservative) and betamethasone dipropionate in propylene glycol heated to 60 ° C (non-aqueous solvent) is separately prepared, the resulting solution is added to the cream base with a temperature of 55 ° C, the mass is homogenized for 5-10 minutes. Cool the mass at an average stirring speed of up to 45 ° C and load a pre-prepared aqueous solution of urea and a solution of pantolactone (buffer substance). The resulting solution was loaded into the reactor at a temperature of 45 ° C and homogenized for 5 minutes. The homogeneous mass is gradually cooled to 25-27 ° C and Packed in tubes.

Examples 2-8 (Table) were similarly obtained, with the difference that isopropyl myristate (example 2), paraffin wax and paraffin oil (example 3), octyldodecanol (example 4), isopropyl palmitate (example 5), isopropyl myristate were used as the hydrophobic component and cyclomethicone (example 7) and isopropyl myristate, squalane and dimethicone (example 8); as a preservative propyl paraben (example 3), EuxylPE9010 (phenoxyethanol 90%, ethylhexyl glycerol 10%, example 5), imidourea (example 6), sodium benzoate (example 7), a mixture of methyl and propyl parabens in a ratio of 2 to 1 (example 8) ; as a hydrophilic non-aqueous solvent, butylene glycol (example 2), hexylene glycol (example 4), polyethylene oxide 400 (example 5), glycerin (example 6), diethylene glycol monoethyl ether (example 7) and dimexide (example 8); as an emulsifier, polyethylene glycol monoacetyl ether (example 2), cetostearyl alcohol (example 3), emulsifying wax (examples 4.7), Lanette emulsifier (a mixture of high molecular weight alcohols with carbon atoms from 14 to 20, mainly cetyl and stearic, and, optionally sodium alkyl sulfates, mainly sodium lauryl sulfate and sodium stearyl sulfate, example 5), Cremophor emulsifier (macrogol-glycerol hydroxystearate example 6), emulsifier No. 1 (a mixture of primary higher fatty alcohols with carbon atoms from 16 to 20 and sodium sulfo salts firs of such alcohols, example 8); as a buffer substance pantolactone and arginine in a ratio of 1.5 to 1 (example 2), nitrate buffer (citric acid / sodium citrate, example 3), lactate buffer (example 5), malic acid and sodium hydroxide (example 6), phosphate buffer (example 8)

Table Ingredients Content, g / 100 g of composition one 2 3 four Betamethasone (calculated on the basis of betamethasone) 0.01 0.02 0.05 0,07 Urea 3 8 10 12 Hydrophobic component Preservative 1,0 0.4 0.2 0.2 Non-aqueous solvent 2 four 5 6 Emulsifier 5 7 9 12 Buffer substance up to pH 7.1 up to pH 5.0 up to pH 4.5 up to pH 6.0 Water up to 100 up to 100 up to 100 up to 100 Ingredients Content, g / 100 g of composition 5 6 7 8 Betamethasone (calculated on the basis of betamethasone) 0.1 0,03 0.05 0.05 Hydrophobic component Urea twenty 7 12 9 Preservative 0.05 0.1 0.1 0.1 Non-aqueous solvent 10 four 5 6 Emulsifier 10 6 8 10 Buffer substance up to pH 5.5 up to pH 5.0 up to pH 6.5 up to pH 6.0 Water up to 100 up to 100 up to 100 up to 100

Claims (7)

1. The pharmaceutical composition in the form of a soft dosage form for the treatment of skin diseases, which includes betamethasone dipropionate, urea, a hydrophobic component, an emulsifier, preservative, a buffer substance, a non-aqueous solvent and water, while the content of betamethasone dipropionate is 0.01-0.1 g / 100 g of the composition and the composition has a pH from 4.5 to 7.1. 2. The pharmaceutical composition according to claim 1, characterized in that the urea content is 3.0-20.0 g / 100 g of the composition. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it contains propylene glycol as a non-aqueous solvent. 4. The pharmaceutical composition according to claim 3, characterized in that it contains as a hydrophobic component a combination of petroleum jelly, liquid paraffin and squalane. 5. A method of obtaining a composition for treating skin diseases, according to which the melt of the hydrophobic component, emulsifier and part of the water is emulsified, after which betamethasone dipropionate, preservative and non-aqueous solvent are introduced at a temperature below 60 ° C, the urea solution and the buffer substance prepared in advance are homogenized and introduced. 6. The method according to claim 5, in which betamethasone dipropionate is administered in the form of a solution. 7. The method according to claim 6, in which urea is administered together with a buffer substance.