RU2197247C2 - Agent for treatment of dermatological diseases - Google Patents

Abstract

FIELD: medicine, dermatology, chemical-pharmaceutical industry. SUBSTANCE: agent comprises fluocinolone acetonide, nipagine, propylene glycol, solid paraffin, vaseline, vaseline oil, emulsifier = 1 or emulsifying cetostearyl alcohol, Trilon B and purified water and components are taken in the definite ratio. Invention provides possibility to enhance the level of specific activity of fluocinolone acetonide due to increase of its concentration without or at significant reduction of toxic properties of this substance. EFFECT: enhanced effectiveness of agent and treatment.

Description

 The invention relates to medicine and the pharmaceutical industry, in particular to the creation, production and use of glucocorticosteroid-based agents for the treatment of dermatological diseases.

 The drug "Lokacorten" based on flumetasone pivalate is known, which is close in its chemical structure and specific activity to fluocinolone acetonide. Lokacorten is used in the form of 0.02% ointment or cream in the treatment of eczema, neurodermatitis, pruritus, inflammatory reactions of the skin and mucous membranes. The drug has a number of contraindications: it can not be used for skin tuberculosis, syphilitic skin lesions, conjunctival lesions, skin reactions after vaccination, etc. [1].

 The known drug "Fladex" in the form of an ointment containing (wt.%) The active substance of plant origin, fladescan (1.00-2.00), medical vaseline (15.00-20.00), stearic acid (2.00- 5.00), propylene glycol (10.00-18.00), emulsifier 1 (5.00-8.00), nipagin (0.06-0.07), nipazole (0.03-0.04) and purified water (rest). The drug is used to treat dermatoses of various etiologies, but the level of its specific activity is insufficient for the treatment of skin diseases, which require the use of corticosteroid-based drugs [2].

 The drug "Gossypol" is known in the form of a 3% liniment, containing as an active component a substance from seeds or roots of cotton, and castor oil, sorbic acid, emulsifier 1 and purified water as auxiliary substances. The drug is used in the treatment of psoriasis, herpes zoster, ordinary vesicle. The disadvantages of "Gossypol" include the presence of cumulative properties and toxic effects when used [3].

 The known drug "Oxycort" in the form of an aerosol containing hydrocortisone 0.1 g, oxytetracycline hydrochloride 0.3 g and a solvent up to 75 g. A drug with anti-inflammatory, antibacterial and anti-allergic properties is used in the treatment of superficial and deep burns, infected wounds [4].

 Known drug "Cortifoam" in the form of an aerosol containing 10% hydrocortisone acetate and 90% of the base, including solvents, emulsifiers, preservatives, propellant, foam stabilizer and water [5].

 Known hydrocortisone ointment 1% containing 1 g of hydrocortisone acetate, 45 g of petroleum jelly, 10 g of anhydrous lanolin, 5 g of pentol, 3 g of stearic acid, 0.08 g of nipagin, 0.02 g of nipazole and 35.9 g of distilled water. Hydrocortisone ointment is used in the treatment of eczema, pruritus, dermatitis, allergic dermatoses, etc. The drug is contraindicated in severe systemic diseases and infection of the skin surface [6].

 Known drug "Flucinar" containing fluocinolone acetonide on a gel basis, which has anti-inflammatory, anti-allergic, antiexudative and antipruritic effect. The drug is used to treat psoriasis, lichen planus, seborrheic dermatitis and is not prescribed for bacterial, viral, fungal skin diseases, tuberculosis and skin tumors, during pregnancy, etc. [7].

 Closest to the claimed is a drug containing (wt.%) Fluocinolone acetonide (0.02-0.03), 1,2-propylene glycol (4.97-4.98), lanolin (4.0-6.0 ), ceresin (9.0-11.0) and petroleum jelly (the rest). The tool has anti-inflammatory and antipruritic activity inherent in corticosteroids, and does not cause obvious disorders of organs and systems. But the basis of the drug, containing lanolin, ceresin and petrolatum, does not allow, if necessary, to effectively increase the level of activity of fluocinolone acetonide by increasing its concentration without manifesting the toxic properties of this substance [8].

 The basis of the invention is the task of creating funds based on fluocinolone acetonide for the treatment of dermatological diseases by selecting such a composition of components that would provide the opportunity to increase the level of specific activity of fluocinolone acetonide by increasing its concentration without manifesting or with a significant decrease in the toxic properties of this substance.

The problem is solved in that the tool for the treatment of dermatological diseases containing fluocinolone acetonide, propylene glycol and petrolatum, in accordance with the invention additionally contains nipagin, solid paraffin, paraffin oil, emulsifier 1 or cetostearyl emulsifying alcohol, Trilon B and purified water in the following ratio of components , wt.%:
Fluocinolone acetonide (European Pharmacopoeia, 1997, p. 864) - 0.025-0.2
Nipagin (European Pharmacopoeia, 1997, p. 1173) - 0.05-0.25
Propylene glycol (European Pharmacopoeia, 1997, p. 1398) - 2.0-10.0
Hard paraffin (European Pharmacopoeia, 1997, p. 1289) - 3.0-12.0
Vaseline (British Pharmacopoeia, 1999, p. 1091) - 1.0-4.0
Vaseline oil (European Pharmacopoeia, 1997, p. 1290) - 6.0-24.0
Emulsifier 1 (VFS 42-2121-92) or
Emulsifying cetostearyl alcohol (European Pharmacopoeia, 2000, p. 519) - 4.0-10.0
Trilon B (European Pharmacopoeia, 1997, p. 1491) - 0.05-0.5
Purified water (VFS 42-2619-89) - The rest
The technical result that is obtained by carrying out the invention is to provide an opportunity to increase the level of specific activity of fluocinolone acetonide by increasing its concentration without manifestation or with a significant decrease in the toxic properties of this substance.

 We give specific examples of the invention.

Example 1. Propylene glycol, fluocinolone acetonide, nipagin are loaded into reactor 1. The resulting mixture was dissolved at a temperature of 60 ^o C and stirred. Trilon B, paraffin wax, petroleum jelly, liquid paraffin, emulsifier 1 are loaded into reactor 2, the water is purified and heated to a temperature of 70 ^{° C.} with stirring until the components of the base are dissolved or melted, respectively. The resulting mixture is emulsified, then cooled to a temperature of (55 ± 2) ^o C. The solution from reactor 1 is introduced into the emulsion and cooled to 25 ^o C. with constant stirring ^. The resulting cream is Packed in tubes.

The inventive tool has the following ratio of components, wt.%:
Fluocinolone acetonide - 0.025
Nipagin - 0.05
Propylene glycol - 2.0
Hard paraffin - 3.0
Vaseline - 1.0
Vaseline oil - 6.0
Emulsifier 1 - 4.0
Trilon B - 0.05
Purified Water - Else
Example 2. Propylene glycol, fluocinolone acetonide, nipagin are loaded into reactor 1. The resulting mixture was dissolved at a temperature of 60 ^o C and stirred. Trilon B, paraffin wax, petroleum jelly, liquid paraffin, emulsifier 1 are loaded into reactor 2, the water is purified and heated to a temperature of 70 ^{° C.} with stirring until the components of the base are dissolved or melted, respectively. The resulting mixture is emulsified, then cooled to a temperature of (55 ± 2) ^o C. The solution from reactor 1 is introduced into the emulsion and cooled to 25 ^o C. with constant stirring ^. The resulting cream is Packed in tubes.

The inventive tool has the following ratio of components, wt.%:
Fluocinolone acetonide - 0.1
Nipagin - 0.1
Propylene glycol - 4.0
Hard paraffin - 9.0
Vaseline - 3.0
Vaseline oil - 18.0
Cetostearyl emulsifying alcohol - 7.0
Trilon B - 0.1
Purified Water - Else
Example 3. Propylene glycol, fluocinolone acetonide, nipagin are loaded into reactor 1. The resulting mixture was dissolved at a temperature of 60 ^o C and stirred. Trilon B, paraffin wax, petroleum jelly, liquid paraffin, emulsifier 1 are loaded into reactor 2, the water is purified and heated to a temperature of 70 ^{° C.} with stirring until the components of the base are dissolved or melted, respectively. The resulting mixture is emulsified, then cooled to a temperature of (55 ± 2) ^o C. The solution from reactor 1 is introduced into the emulsion and cooled to 25 ^o C. with constant stirring ^. The resulting cream is Packed in tubes.

The inventive tool has the following ratio of components, wt.%:
Fluocinolone acetonide - 0.2
Nipagin - 0.25
Propylene glycol - 10.0
Hard paraffin - 12.0
Vaseline - 4.0
Vaseline oil - 24.0
Emulsifier 1 - 10.0
Trilon B - 0.5
Purified Water - Else
The qualitative and quantitative composition of the claimed means completely solves the task of the invention to create a highly effective means in the form of a cream based on fluocinolone acetonide.

 The active substance of the claimed agent fluocinolone acetonide is a synthetic fluorinated derivative of prednisolone and belongs to the pharmacotherapeutic group of glucocorticosteroid drugs. Glucocorticosteroid-based drugs are effective anti-inflammatory drugs that exhibit a powerful and rapid inhibitory effect on the inflammatory process at all stages of its development, exhibit anti-allergic properties, have a complex and multidirectional effect on energy metabolism, on plastic processes, on the functions of a number of organs and systems. These agents are widely used in clinical practice, in particular, in dermatology in the treatment of complex inflammatory and allergic skin diseases. But having a high level of pharmacotherapeutic activity, drugs based on glucocorticosteroids, including fluocinolone acetonide, can cause undesirable reactions in the patient’s body. With internal administration and with parenteral administration, the most characteristic negative changes are observed in the gastrointestinal tract, cardiovascular system, musculoskeletal system, endocrine and immune systems. With topical use of glucocorticosteroids, patients may experience atrophy of the skin and subcutaneous fat, striae, impaired epithelization, delayed healing of wounds and ulcerative lesions, skin rashes, exacerbation or development of secondary infectious complications.

 The problem of negative side effects becomes especially relevant when it becomes necessary to treat patients with drugs with a high concentration of glucocorticosteroids for long periods. The inventors solved this problem by selecting the qualitative and quantitative composition of the auxiliary components of the claimed agent. So, the function of the oil phase is performed by solid paraffin, petrolatum and petrolatum, the quantitative content of which and the ratio between them are determined experimentally. These same components are responsible for the mitigating effect of the claimed drug. Emulsifier 1 and cetostearyl emulsifying alcohol provide stability and a greasy consistency. If the quantitative content of these components is violated, the dosage form of the product becomes unstable, delaminates or exhibits a tendency to harden the mass, which loses its greasy consistency. Propylene glycol simultaneously serves as a preservative, which exhibits an antimicrobial effect, and as a solvent for fluocinolone acetonide. In case of violation of the quantitative content of this component, the effect of microbial contamination, locally irritating action, and destabilization of the dosage form can be observed. Nipagin acts as a preservative and its presence and quantitative content in the dosage form is regulated by pharmacopoeial requirements. Trilon B, being a complexing agent, increases the stability of the agent. In the experiment, data were obtained that the introduction of Trilon B in the inventive composition to a certain extent increased the therapeutic effect of the drug. Purified water - a hydrophilic solvent that plays the role of a dispersion medium in an emulsion of the first kind, together with other components ensures uniform distribution of the cream over the skin surface and the necessary wettability effect of the affected tissue. It should be noted that the relative multicomponent nature of the claimed drug does not cause technological difficulties in the production of the drug.

In the process of preclinical studies, the study was conducted:
- specific pharmacological activity;
- specific general resorption effects;
- bioavailability and pharmacokinetics;
- acute toxicity;
- subchronic toxicity, including pathomorphological studies;
- local irritating effect;
- immunotoxicity.

 The results of pharmacological and preliminary clinical studies have confirmed the optimality of the qualitative and quantitative composition of the claimed drug, which allows the use of fluocinolone acetonide in high concentrations and for a long time without the manifestation of toxic effects. We studied the specific pharmacological activity of the drug (anti-inflammatory and vasoconstrictor) and specific general resorptive systemic effects on the effects on the adrenal gland mass and animal body weight. Studies were carried out in comparison with several drugs based on fluocinolone acetonide, in particular, ointment "Flucinar" (Jelfa, Poland), which contains 0.025% fluocinolone acetonide.

 Studies have shown that under conditions that differ in the pathogenesis and duration of acute dextran and aerosilic inflammation of the foot of rats, the claimed anti-inflammatory agent significantly exceeds the reference drug. So, with dextran inflammation, the antiexudative activity of the claimed drug after 1 and 3 hours after the start of treatment is 45.9% and 50.9%, respectively, while the effects of the comparison drug are 25.9% and 29.5%. With aerosil inflammation, the claimed agent suppressed inflammatory edema 5 and 24 hours after its application to the affected tissues by 50.0% and 61.1%, while Flucinar ointment was 34.5% and 39.7%.

 The vasoconstrictive effect of the claimed drug was studied in its authors-volunteers photoplethysmographically according to indicators of peripheral microvasculature of the skin (when applied to the skin at a dose of 25 mg). The results of the study indicate that the vasoconstrictor effect of the claimed drug within 1 hour after application is 41.5-59.0%, and the comparison drug is 17.7-29.7%.

 In the study of general resorption systemic effects, it was found that the comparison drugs have specific general resorption effects that are characteristic of glucocorticosteroid-based drugs, which is manifested in a decrease in the weight of the adrenal glands and the body of experimental animals. With cutaneous applications of the studied drugs for 7 days, the corresponding effects of the claimed drug were 7.5% and 26%, and the comparison drug - 12.2% and 48.4%.

 Pharmacokinetic studies indicate that with subcutaneous use of the claimed drug there is a very slight transdermal absorption of fluocinolone acetonide in the systemic circulation, which ensures minimal general resorption effects or their absence with a significant level of pharmacotherapeutic activity of the drug.

 Pathomorphological studies have confirmed the absence of changes in the relative mass of the histostructure of the internal organs when applying the claimed drug in a dose of 100 mg / kg In a therapeutic dose, the drug does not affect the cellular and humoral links of the immune system, causing a decrease in these indicators with a 10-fold excess of the therapeutic dose.

 Thus, the claimed agent fully fulfills the task of the invention to create a highly effective agent based on fluocinolone acetonide, the composition of the components of which allows, if necessary, to increase the level of specific activity due to a significant increase in the concentration of the active substance without manifesting its toxic properties.

LITERATURE
1. Mashkovsky M.D. Medicines M .: Medicine, 1977, v. 1, p. 583.

 2. Patent of Ukraine 17253 A, cl. A 61 K 35/78. Publ. bull. "Promislova power", 1997, 5.

 3. Mashkovsky M.D. Medicines - Kharkov: Torsing, 1997, v. 2.- S. 362.

 4. Mashkovsky M.D. Medicines M .: Medicine, 1977, v. 2, p. 163.

 5. Physicianis' Desk Reference. - 46 edition. - New York, 1992 .-- P. 1827.

 6. Pharmacopoeia article FS 42-1961-83. Hydrocortisone ointment. Mashkovsky M.D. Medicines M .: Medicine, 1977, v. 1, p. 575.

 7. Reference "Vidal". M .: AstraPharmService, 1995.- S. 939-940.

 8. Patent of the Russian Federation 2106860, cl. A 61 to 9/06, 31/57. Publ. bull. "Inventions", 1998, 8 (prototype).

Claims (1)

An agent for treating dermatological diseases containing fluocinolone acetonide, propylene glycol and petroleum jelly, characterized in that it further comprises nipagin, solid paraffin, liquid paraffin, emulsifier 1 or cetostearyl emulsifying alcohol, Trilon B and purified water in the following ratio, wt. %:
Fluocinolone acetonide - 0.025-0.2
Nipagin - 0.05-0.25
Propylene glycol - 2.0-10.0
Hard paraffin - 3.0-12.0
Vaseline - 1.0-4.0
Vaseline oil - 6.0-24.0
Emulsifier 1 or cetostearyl emulsifying alcohol - 4.0-10.0
Trilon B - 0.05-0.5
Purified Water - Else