Pharmaceutical composition having anti-inflammatory and antiallergic action

 

The invention relates to medicine and relates to a pharmaceutical composition with anti-inflammatory and antiallergic action, including betamethasone dipropionate, a hydrophobic component is a combination of petrolatum, paraffin wax and paraffin oil, antioxidant, water, propylene glycol, Trilon B, emulsifier and ether p-oksibenzoynoy acid. The drug is characterized by stability, high level of therapeutic activity, minor side effects. 3 C.p. f-crystals, 1 table.

The invention relates to medicine, specifically to anti-inflammatory and anti-allergic drug, which can be used for the treatment of inflammatory and allergic skin diseases, including acute, subacute and chronic contact dermatitis, occupational dermatitis, seborrheic dermatitis, atopic dermatitis, solar dermatitis, neurodermatitis, pruritus, disgestrotical dermatitis, acute and chronic forms of non-allergic dermatitis, psoriasis.

In the structure of skin diseases allergic skin diseases occupy a dominant place. The allergic affects up to 15% of the population of the planet. Data times is one), but about the weighting of the flow of allergic skin diseases. A clear trend of increasing severe clinical forms, leading to disability, the propensity for dissemination skin rashes, frequent relapses, low recovery rates put forward the problem of treatment of allergic pathology of the skin on one of the first places in modern clinical medicine.

In this regard, of particular importance are the issues of drugs for the treatment of acute and chronic dermatoses. Pathogenetically justified and effective in the treatment of allergic is therapy using glucocorticoids. Glucocorticoid influence the organism's complex multilateral influence, possess strong anti-inflammatory activity, which can't compete with other drugs, and immunosuppressive properties, which is the result of suppression of different stages of immunogenesis.

Betamethasone(9-fluoro-11,17,21 trihydroxy-16-methylpregna-1,4-diene-3,20-dione-17,21-dipropionate) is a fluorinated synthetic glucocorticoid is one of the most effective drugs in this group [Mashkovsky M. D. Drugs, so the economic effect and little has mineralokortikoidnoy activity. Various modifications of betamethasone (betamethasone dipropionate, valerate, disodium phosphate, acetate) are used as anti-inflammatory, antiallergic funds in the form of various dosage forms: tablets, injections, suspensions, creams, ointments.

Betamethasone, as with all glucocorticoids, when administered parenterally, with the goal of systemic therapy causes a number of side effects: Cushing's syndrome, diabetes, problems with gastrointestinal tract and others, and topical application of betamethasone is in some cases only acceptable.

In the United Kingdom patent 32123292, 1984 proposed topical preparations containing corticosteroids. As steroid can apply betamethasone dipropionate in the amount of 0.005-2 wt.%. The composition has anti-inflammatory action and further includes an emulsifier, a preservative, and, optionally, other auxiliary and/or active ingredients. However, specific examples of compounds on the basis of betamethasone dipropionate no.

In U.S. patent 4370322, 1983 proposed anti-inflammatory pharmaceutical composition in the form of ointments containing corticosteroids, such as betamethasone dipropionate and lipophile the global ingredients, for example, betamethasone dipropionate is 0.05 wt.%, beeswax - 10 wt.%, microcrystalline wax - 20 wt.%, dibutyltin rest. Known composition is characterized acceptable indicators of the release of the active substance and, accordingly, therapeutic efficacy, however, it can increase the side effects due to human respiration and thermoregulation of the skin, which creates a morphological basis for complications and recurrence of the pathological process.

In the United Kingdom patent 2122087, 1984, describes a pharmaceutical composition comprising a corticosteroid, such as ether betamethasone alcohol, for example ethanol, polyethylene glycol, a monoglyceride, a nonionic surfactant and/or water. The presence of glycols may result in long-term use of the drug to irritation and obessolivaniju skin and for dry skin - the lack of explicit actions and aggravation of the disease.

In U.S. patent 4489070, 1984, provides information about the pharmaceutical compositions on the basis of betamethasone dipropionate, offered under the trade name "Diprosone", which contains as inactive ingredients: purified water, a hydrophobic component (mineral oil, petrolatum), emulsifier (manservant (4-chloro-m-cresol) and propylene glycol. However, the known composition is not effective enough and to enhance therapeutic action features a pharmaceutical composition that includes betamethasone dipropionate, a hydrophobic component (petrolatum, white wax), 70% aqueous solution of sorbitol, pH regulator, emulsifier, preservative, preferably 4-chloro-m-cresol, propylene glycol, water and cyclomethicone (prototype, U.S. patent 4489071). The composition is more effective than the cream Diprosone", however, is characterized by instability indicators of quality during storage and, as a consequence, a small shelf life. In addition, the presence in the composition of 4-chloro-m-cresol additionally contributes to undesirable reactions, such as skin irritation.

It should be noted that the efficacy and adverse reactions of drugs glucocorticoids for cutaneous application depends largely on the release of the active substance from the basics and its penetration into the skin. To optimize these parameters it is possible, by varying the type and composition of the excipients.

The purpose of this invention is to provide anti-inflammatory and anti-allergic pharmaceutical composition with an optimal combination of excipients for soft Lek is a result, gained through the implementation of the present invention is the stability of the inventive pharmaceutical composition during storage at high therapeutic efficacy and lack of side irritants.

This technical result is achieved by the fact that the proposed pharmaceutical composition comprising as active ingredient betamethasone dipropionate and as excipients water, a hydrophobic component and additives target - propylene glycol, emulsifier, ether p-oksibenzoynoy acid, contains as the hydrophobic component is a combination of petrolatum, paraffin wax and paraffin oil, and optionally the target additives antioxidant and Trilon B in the following ratio of ingredients, wt.%: Betamethasone dipropionate - 0,02-0,2 Hydrophobic component (vaseline, solid paraffin, liquid paraffin) - 15,0-40,2 Antioxidant Is 0.01 To 0.5 Propylene glycol - 2,0-15,0 Trilon B Is 0.01-0.5 Emulsifier - 3,0-15,0 Ether p-oksibenzoynoy acid - 0,02-0,5 Water Up to 100 Declare qualitative and quantitative ratio of ingredients found experimentally and is optimal.

As a result of introduction into the composition of an antioxidant, trylon B and selection savlon azizia on the basis of betamethasone dipropionate, stable during storage and has a shelf life of not less than 2 years.

Experimental study of the biological effect of the claimed composition was conducted on the model DNCB-dermatitis in Guinea pigs. It is found that developed the drug has expressed specific anti-inflammatory, antiallergic and antipruritic effect, which is confirmed by morphological studies. It was established experimentally that the new composition refers to practically non-toxic substances: LD50of the drug in a single cutaneous application was more than 10.0 g/kg

Obtained in the experiment results show that the application of the new composition of rats for 28 days at doses of 1.0 g/kg 2.0 g/kg (1/10 and 1/5 of the maximum tested in acute experiments) does not have a negative impact on the General condition of the animals, functional characteristics of the Central nervous system, the electrophysiological activity of the myocardium, peripheral blood, do not cause pathological changes of basic biochemical parameters of blood of animals that characterize the metabolic processes in the liver, kidney, myocardium. The proposed composition in both the studied doses does not alter the relative mass of the inner and new members within 14 days of the effective therapeutic dose (0.5 mg/kg) betamethasone basis) do not cause significant decrease in the indices of cellular and humoral components of the immune system.

The obtained experimental results allow to conclude that the claimed composition exhibits a high therapeutic activity and no side effects.

The inventive composition can be obtained by the known methods used for the preparation of soft medicinal forms, such as the addition of betamethasone dipropionate, ether oksibenzoynoy acid and parts of propylene glycol to the previously prepared emulsion of a hydrophobic component, water and other special additives, or gomogenizirovannom solution of the active substance in propylene glycol with other ingredients. However, these methods are not exhaustive and are given only as examples. Non-aqueous hydrophilic solvent propylene glycol is a solvent of ether oksibenzoynoy acid and betamethasone in the technological process of preparation of the composition. The preferred amount of propylene glycol is 2.5-10.0 wt.%.

According to the invention the hydrophobic component of the framework includes a combination of petrolatum, paraffin wax and paraffin oil. It is preferable to use these ingredients in a mass ratio of 1:(2-4):(4-8), that allows you to improve soften the athel - Trilon B (or the disodium salt of ethylenediaminetetraacetic acid) improves therapeutic efficacy of the composition by binding metal ions, which inhibit the active substance, and at the same time synergistically potentiates the effect of the antioxidant. Examples of antioxidants include in the composition are sodium sulfite, sodium hydrosulfite, 2,3-dimethyl-1,4-di(3,4-dihydroxyphenyl)butane, monothioglycerol, nutrisearch, ntrihalomethylthio dehydrate and similar compounds, preferably sodium sulfite.

As the emulsifier can be used high molecular weight alcohols, their oxyalkylene derivatives, sodium salts of sulfonic ethers of these alcohols, the twins, spiny, zhirosahar or mixtures of these substances. Examples of emulsifiers are cetosteatil alcohol or emulsifier 1 (mixture of primary higher fatty alcohols with a number of carbon atoms of 16 to 20 and sodium salts of sulfonic ethers of such alcohols), or emulsifier brand "Lanette" (a mixture of high molecular weight alcohols with the number of carbon atoms from 14 to 20, mainly cetyl and stearyl, and, optionally, sodium alkyl sulphates (mainly nutriceuticals and netresearchserver)), or emulgirovannie acid, performing as part of the function of the preservative to use methyl and/or propyl esters of p-oksibenzoynoy acid, more preferably methyl ether.

More in detail the invention is illustrated by the following examples (see Table).

Example 1. The solution 102,5 mg of betamethasone dipropionate in parts of propylene glycol is added to the emulsion obtained consistent mixture of 4.8 g of vaseline, 9.6 g of solid paraffin, a 33.6 g of paraffin oil and 14.4 g of emulsifier (cetosteatil alcohol) aqueous solution semimodule sodium sulfite (0.32 g) and trylon B (0.16 g) and a solution of 0.32 g of methyl ester of p-oksibenzoynoy acid residue of propylene glycol (the total number of propylene glycol - 11.2 g) and stirred at 55-65oWith until smooth, then cool.

The resulting cream white meets pharmaceutical agent (in appearance, uniformity, and other indicators) and has a shelf life of more than 27 months. The study of microbiological purity (the State Pharmacopoeia XI edition - GF XI) and the effectiveness of antimicrobial preservatives (according to the requirements of the European Pharmacopoeia). Microbiological purity and effectiveness of preservatives polucheniem, in example 2, is used emulsifier brand "Lanette SX" and propyl ester of p-oksibenzoynoy acid, as in example 3, a mixture of methyl and propyl esters oksibenzoynoy acid (2:1) and these preservatives injected into the composition together with the active substance. The obtained composition satisfy the requirements of the pharmaceutical agent and have a shelf life of more than 24 months. The results of the preparation of compounds presented in the Table.


Claims

1. Pharmaceutical composition with anti-inflammatory and antiallergic action, including the active ingredient is betamethasone dipropionate, water, a hydrophobic component and additives target - propylene glycol, emulsifier, ether p-oksibenzoynoy acid, characterized in that it additionally contains as special additives antioxidant and Trilon B, and as the hydrophobic component is a combination of petrolatum, paraffin wax and paraffin oil, in the following ratio of ingredients, wt.%:

Betamethasone dipropionate 0,02-0,2

The hydrophobic component (a combination of petrolatum, solid paraffin, vaseline oil) 15,0-40,2

Antioxidant 0,01-0,5

Propylene glycol 2,0-15,0

Trilon B 0,01-0,5

Emulsifier 3,0-1 is the fact that it contains petrolatum, solid paraffin and vaseline oil mass ratio of 1:(2-4):(4-8), respectively.

3. The pharmaceutical composition under item 1 or 2, characterized in that it contains as an antioxidant, sodium sulfite.

4. The pharmaceutical composition according to any one of paragraphs.1-3, characterized in that it contains as ether p-oksibenzoynoy acid methyl ester p-oksibenzoynoy acid and/or propyl ester of p-oksibenzoynoy acid.

 

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