RU2322987C2 - Agent for treatment of skin immune disease - Google Patents

Abstract

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to drugs used in treatment of skin immune diseases displaying sensitivity to corticosteroid therapy. The claimed agent consists of glucocorticosteroids, heparin and vitamin D that provide the synergistic effect. Agent is used topically as ointment, cream, gel and solution wherein even ten-fold decrease of dose of glucocorticosteroids enhances effectiveness of treatment, reduces risk for development of complications caused by using steroids, and additional use of vitamin D improved state of protective properties of skin and inhibits development of osteoporosis. Hypocalcemia found before treatment was not observed after using dermatological agents comprising vitamin D. Invention provides enhancing effectiveness of treatment of patients with dermatitis associated with immunological responses of delayed type, decreasing inflammation symptoms and simultaneous elimination of complications associated with use of glucocorticosteroids.

EFFECT: valuable medicinal properties and enhanced effectiveness of agent.

2 cl, 3 tbl, 4 dwg, 7 ex

Description

The invention relates to medicines and for the treatment of immune skin diseases sensitive to corticosteroid therapy - atonic dermatitis, neurodermatitis, urticaria, eczema, contact dermatitis, seborrheic dermatitis, psoriasis, exfoliative dermatitis.

A known method of treating immune skin diseases using dermatological agents containing glucocorticosteroids. Long-term use of these drugs for the treatment of immune dermatitis leads to the development of a number of complications, such as hirsutism, telangiectasia, photosensitive dermatitis, purpura, rosacea-like dermatitis, acne, changes in skin pigmentation, fibrosis and dystrophic changes in the skin, decreased immunity and the attachment of a secondary infection, high risk skin cancer development (Clinical Pharmacy and Therapeutics / editors, ETHerfindal, DR Gourley, LL Hart. - 5ch ed. 1998; Dahl R., Nielsen LP Steroids: An Overview; in TTHansel, PJ Bames (eds) New Drugs for Asthma , Allergy and COPD. London ,. - 2001, pp. 86-90; Savolainen, J., O. Kortekangas-Savolainen, M. Nermes, M.Via nder, A. Koivikko, K. Kalimo, and E. O. Terho. IgE, IgA, and IgG responses to common yeasts in atopic patients. // Allergy 1998.53: 506-512).

The use of heparin in the treatment of immune skin diseases such as psoriasis is known. In addition, heparin is a histamine antagonist and immunomodulator used in immunocomplex immunological reactions (Vinogradov V.V., Vorobyova N.F. Mast cells. Novosibirsk., - 1973; Subbotina O.A., Subbotina M.A. treatment with glucocorticosteroid ointments. Patent for the invention No. 2170092; 07/10/2001; Filimonkova NN, Kokhan MM. A method for the treatment of psoriasis. Patent of Russia No. 2004243 from 12.15.93).

The disadvantage of this method is that a parenteral route of administration is used in the treatment, which requires constant monitoring of the blood coagulation system. For immune skin diseases, local use of heparin is sufficient and this method of heparin use does not cause changes in the blood coagulation system and does not require complex invasive research methods (Clinical Pharmacy and Therapeutics / editors, ETHerfmdal, DRGourley, LLHart. - 5ch ed. 1998 )

The use of colecalciferol is known for children and adults, which prevents the development of osteoporosis in patients using steroid therapy, as well as to enhance the phagocytic activity of the immune system in immune diseases, in addition, a sufficient amount of colecalciferol prevents the development of skin cancer, which is especially susceptible to patients who use large doses of glucocortigosteroid dermatological agents (Clinical Pharmacy and Therapeutics / editors, ETHerfmdal, DRGourley, LLHart. - 5ch ed. 1998).

The disadvantage of this method is that the drug is used per os, which requires additional administration of the drug and its daily intake. Patients often do not attach importance to the importance of additional treatment and, as a rule, 98% of them develop osteoporosis and injuries associated with bone fractures. The simultaneous use of steroids and colecalciferol will have not only a local therapeutic effect on the immune system of the skin, but also a preventive effect to prevent the development of osteoporosis (Clinical Pharmacy and Therapeutics / editors, ETHerfindal, DR Gourley, LLHart. - 5ch ed. 1998; R. Dahl, LP Nielsen. Steroids: An Overview; in TTHansel, PJ Barnes (eds) New Drugs for Asthma, Allergy and COPD. London ,. - 2001, pp. 86-90).

The objective of the present invention is to increase the effectiveness of agents for the treatment of immune skin diseases with the simultaneous exclusion of complications associated with the use of glucocorticosteroids.

The problem is solved as follows.

The proposed tool for the treatment of immune skin diseases containing glucocorticosteroid, heparin or heparinoid and vitamin D, with the following content of active ingredients per 100 g of base:

glucocorticosteroid 0.002-0.1 g heparin 3000-10000 PIECES heparinoid 30-180 mg vitamin D 2500-33000 ME,

while the tool is made in a dosage form for external use.

The tool can be made in the form of any form: paste, ointment, cream, gel, spray, hydrogel or solution (table 1).

The claimed tool, in contrast to the known one, consists in the combined use of heparin and vitamin D glucocorticosteroids, which provides a synergistic effect, and the drug is used topically in the form of ointments, creams, gels or sprays, while even a ten-fold reduction in the dose of glucocorticosteroids increases the effectiveness of treatment, reduces the risk of complications caused by the use of steroids, and the additional simultaneous use of vitamin D improves the protective properties of the skin and prevents the development of osteoporosis.

Information confirming the effectiveness of the invention.

A glucocortocosteroid cream has been used in 75 patients with a common form of psoriasis.

In the first group, for 7 children with psoriasis, a cream containing 100 g of base was used (cetomacrogol 1000 - 1.8 g, cetostearyl alcohol - 7.2 g, chlorocresol - 0.1 g, sodium dihydrogen phosphate - 0.3 g, liquid paraffin - 6 g, white soft paraffin - 15 g, sodium hydroxide - qs purified water up to 100 g) betamethasone dipropionate 0.064 g,

In the second group of 10 children used a cream containing 100 g of the base (cetomacrogol 1000 - 1.8 g, cetostearyl alcohol - 7.2 g, chlorocresol - 0.1 g, sodium dihydrogen phosphate - 0.3 g, liquid paraffin - 6 g, white soft paraffin - 15 g, sodium hydroxide - qs purified water up to 100 g) betamethasone dipropionate 0.0064 g, heparinoid 120 mg and colecalciferol 33000 ME.

In the third group of 9 patients, a cream containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) mometasone furoate 0.1 g was used.

In the fourth group of 10 people used a cream containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) mometasone furoate 0.01 g, sodium heparin 10000 IU, colecalciferol 33000 ME.

In the fifth group of 10 patients, a paste containing 100 g of the base (zinc oxide, starch, olive oil) fluocinolone acetonide 0.025 g was used

In the sixth group of 11 patients, a paste containing 100 g of the base (zinc oxide, starch, olive oil) fluocinolone acetonide 0.0025 g, sodium heparin 6000 IU, colecalciferol 33000 ME was used.

In the seventh group of 10 patients, a hydrogel containing 100 g of the base (hydroxyethyl cellulose, 85% glycerol, water) methylprednisolone aceponate 0.1 g was used.

In the eighth group of 8 patients, a hydrogel containing 100 g of the base (hydroxyethyl cellulose, glycerol 85%, water) methylprednisolone aceponate 0.01 g, sodium heparin 6000 ME, and colecalciferol 33000 ME was used.

A cream with glucocortocosteroid was used in 30 children with severe atopic dermatitis.

In the ninth group, in 10 children, a cream was used containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone dipropionate 0.064 g.

In the tenth group, in 10 children, a cream was used containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone dipropionate 0.0064 g and heparin 180 mg

In the eleventh group, in children of 10 people with severe atopic dermatitis, a cream containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone d was used 0.0064 g, heparinoid 180 mg and colecalciferol 33000 ME.

The cream was applied twice a day. The result was recorded daily with measurement of the size of the damaged area of the skin, the degree of inflammation. The combination of glucocorticosteroids, heparin or heparinoid and colecalciferol was used in the form of hydrogels based on: carboxymethyl cellulose 600, hydroxyethyl cellulose 30000, polyacrylic acid, hydroxyethyl cellulose 300; ointments based on: petroleum jelly, lanolin, naphthalan, citronella oil, cocoa butter, castor, olive and peach oil, ichthyol, white clay, wax, paraffin, glycerol; in the form of pastes, lotions and solutions (table 1).

Studies have shown that the average duration of treatment with complex cream was significantly reduced in patients with psoriasis (2, 4, 6, 8 groups) to 14 days compared with 29 in the control groups (1, 3, 5, 7 groups) and gave a longer effect (figure 1).

In patients with severe atopic dermatitis, the average duration of treatment with complex cream was significantly reduced to 14-12 days (groups 10 and 11) compared to 27 days in the control group (group 9) and gave a longer effect (figure 2).

Hypocalcemia detected in patients with psoriasis before treatment in the 1, 3, 5, 7 groups - 1.94 mmol / L (n = 11) and in the 2, 4, 6, 8 groups - 1.82 mmol / L (n = 17), after treatment with a cream containing colecalciferol, groups 2, 4, 6, 8 were not observed and the blood calcium level returned to normal (in the 1, 3, 5, 7 groups after treatment - 1.75 mmol / L and in 2 , 4, 6, 8 groups - 2.27 mmol / l) (Fig.3).

Hypocalcemia detected in patients with atonic dermatitis before treatment (in the ninth group - 1.79 mmol / L, in the tenth group 1.82 mmol / L and in the eleventh group - 1.86), in patients of the eleventh group after treatment with a cream containing colecalciferol was not observed (in the ninth group after treatment - 1.78 mmol / L and in the tenth group - 1.83 and in the eleventh group -2.2 mmol / L) (tables 2, 3, Fig. 4).

Table 2.
The level of total calcium in the blood in children with severe atopic dermatitis (group 9) before and after treatment with a cream containing betamethasone dipropionate 0.064% 9 GROUPS TOTAL CALCIUM LEVEL IN BLOOD MOL / L A patient age Before treatment After treatment one 5 years 1.7 1,63 2 6 years 1.9 1.9 3 9 years 1,64 1.65 four 4 years 1.9 1.87 5 10 years 1.78 1.8 6 9 years 1.8 1.9 7 11 years 1.91 1.9 8 5 years 1,6 1,6 9 7 years 1.83 1.71 10 6 years 1.82 1.8 Average value 1.79 1.78

Table 3.
The level of total calcium in the blood in children (group 11) with severe atopic dermatitis before and after treatment with a cream containing betamethasone dipropionate 0.0064%, heparin, colecalciferol 330 IU / g 11 GROUP TOTAL CALCIUM LEVEL IN BLOOD MOL / L A patient age Before treatment After treatment one 3 years 1.95 2.1 2 5 years 1.76 2 3 7 years 1.87 2,3 four 11 years 1.91 2.2 5 17 years 1.65 1.9 6 10 years 1.97 2.2 7 12 years 1.94 2,3 8 9 years 1.83 2,5 9 5 years 1.82 2.1 10 7 years 1.85 2,4 Average value 1.86 2.2

Examples of specific applications of dermatological agents containing glucocorticosteroids, heparin and vitamin D ₃

Example 1. Child T. 13 years old, diagnosis: psoriasis, a common form. Before the appointment of a complex cream for 2 weeks, the use of a cream containing 0.064 g per 100 g of betamethasone base, had no effect. After changing the treatment to a cream, in which 100 g of heparoid base 120 mg, colecalciferol 33000 ME and a dose of betamethasone dipropionate 0.064 g, the condition improved from the first days from the start of treatment. A paste (zinc oxide, olive oil) containing betamethasone dipropionate 0.0024 g, heparinoid 30 mg, colecalciferol 2500 ME was used on the scalp. Complete remission of the disease was achieved on day 9 from the start of therapy.

Example 2. Patient D., 7 years old, diagnosis: Palmar-plantar psoriasis. On the left foot, a lotion was used containing 100 g of the base (zinc oxide, talc, 85% glycerol, ethyl alcohol, water) mometasone furoate 0.1 g, on the right foot was used lotion containing 100 g of the base (zinc oxide, talc, glycerol 85%, ethyl alcohol, water), mometasone furoate 0.1 g, sodium heparin 6000 ME, colecalciferol 2500 ME. Remission of the disease on the left foot was achieved on day 19, on the right foot on day 14.

The level of calcium in the blood before treatment 1.96 mmol / L, after treatment 2.2 mmol / L.

Example 3. Patient 34 years old, diagnosis: exfoliative dermatitis. The use of an ointment containing 100 g of the base (glycerol, petroleum jelly, cosmetic stearin “D”, peach oil, emulsifier No. 1, Lanette®, methylhydroxybenzoate, propylhydroxybenzoate, distilled water) methylprednisolone 0.1 g, sodium heparin 3000 IU, colecalciferol 33000 ME , on day 11 gave a good lasting effect.

Example 4. The patient is 19 years old, the diagnosis of contact dermatitis. A hydrogel was applied to areas of affected skin containing 100 g of the base (carboxymetholcellulose 600, glycerol 85%, water) fluocinolone acetonide 0.025 g, sodium heparin 6000, colecalciferol 5000 ME. A solution (glycerol 85%, ethyl alcohol 70%, water) containing fluocinolone acetonide 0.0025 g, sodium heparin 3000, colecalciferol 3300000 ME was used on the scalp. The patient's condition improved on day 14 from the start of the gel. Normalized blood calcium level from 1.93 mmol / L to 2.24 mmol / L

Example 5. Child G., 5 years old, diagnosis: atopic dermatitis, severe. The disease started at the age of three months and since then, a topical cream was used containing 100 g of base (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) methylprednisol aceponate 0.1 g. Against the background of the use of a dermatological agent, a child constantly has recurrent infections of the skin of Staphilococcus aureus (staphyloderma) and human papilloma virus (multiple warts). There was no complete remission of the disease. The level of total calcium in the blood is 1.72 mmol / L. Violation of calcium metabolism was accompanied by osteoporosis, curvature of the legs. After applying a cream containing 1005 g of mometasone aceponate 0.005 g, heparinoid 120 mg, and colecalciferol 33000 ME. After 14 days of treatment, the skin condition significantly improved, the level of total calcium in the blood increased to 2.1 mmol / L.

Example 6. Child M. 6 years old, the diagnosis of neurodermatitis, severe course. Long-term use of dermatological products from a month of age brought relief, but in the area of the flexion surfaces of the elbow and knee joints and the wrist region remained skin tightening and severe lichenification, cracks and crusts. The use of a lotion containing 100 g of base (polyethylene glycol, titanium dioxide, starch, water) methylprednisolone aceponate 0.01 g, heparin sodium 6000 IU, colecalciferol 2500 ME, gave a positive effect on day 9 from the start of therapy. Skin infiltration decreased after 18 days of treatment.

Example 7. Patient 17 years old, diagnosed with atopic dermatitis, severe course. Used dermatological products containing glucocorticosteroids from 6 months. Prior to the use of an ointment containing 100 g of base (glycerol, petroleum jelly, stearin, cosmetic “D”, peach oil, emulsifier No. 1, Lanette®, methyl hydroxybenzoate, propyl hydroxybenzoate, purified water) 0.0064 g of betamethasone dipropionate, 180 mg heparinoid and colecalciferol 30000 ME, the manifestations of dermatitis were in the form of hyperemia, infiltration, lichenification and crusts throughout the body. On examination, tremor of the hands was found, associated with prolonged hypocalcemia, the level of total calcium in the blood - 1, 67 mmol / l. After applying the cream, the skin condition improved, after 10 days there were only lichenification areas in the cubital folds and on the palms of the hands. The level of total calcium in the blood increased to 2.19 mmol / L.

Thus, the proposed method for the treatment of immune diseases of the skin ensures the effectiveness of treatment and prevents the development of side effects such as a decrease in the protective function of local immunity, impaired calcium metabolism, leading to osteoporosis and impaired development of the skeletal system in children.

Table 1.
Comparative composition of dermatological agents for the treatment of immunological skin diseases. group / patient diagnosis the basis glucocorticosteroids heparin sodium heparinoid vitamin D one 2 3 four 5 6 7 1 group cream psoriasis (n = 7) (cetomacrogol 1000-1.8 g, cetostearyl alcohol 7.2 g, chlorocresol 0.1 g, sodium dihydrogen phosphate 0.3 g, liquid paraffin 6 g, white soft paraffin 15 g, sodium hydroxide qs purified water up to 100 g) betamethasone dipropionate 0.064 g, 2 group cream psoriasis (n = 10) (cetomacrogol 1000-1.8 g, cetostearyl alcohol - 7.2 g, chlorocresol - 0.1 g, sodium dihydrogen phosphate - 0.3 g, liquid paraffin - 6 g, white soft paraffin - 15 g, sodium hydroxide - qs purified water up to 100 g) betamethasone dipropionate 0.0064 g, heparinoid 120 mg colecalciferol 33000 ME 3 group cream psoriasis (n = 9) (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) Mometasone furoate 0.1 g 4 group cream psoriasis (n = 10) (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) mometasone furoate 0.01 g, heparin sodium 10000ED colecalciferol 33000 ME. 5 group pasta psoriasis (n = 10) (zinc oxide, starch, olive oil) fluocinolone acetonide 0.025 g 6 group pasta psoriasis (n = 11) (zinc oxide, starch, olive oil) fluocinolone acetonide 0.0025 g heparin sodium 6000 units colecalciferol 33000 ME. 7 group hydrogel psoriasis (n = 10) (hydroxyethyl cellulose, glycerol 85%, water) methylprednisolone aceponate 0.1 g 8 group hydrogel psoriasis (n = 8) (hydroxyethyl cellulose, glycerol 85%, water) methylprednisolone aceponate 0.01 g heparin sodium 6000 ME colecalciferol 33000 ME 9 group cream Blood pressure (n = 10) (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone dipropionate 0.064 g, 10 group cream Blood pressure (n = 10) (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone dipropionate 0.0064 g, heparinoid 180 mg 11 group cream Blood pressure (n = 10) (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) betamethasone dipropionate 0.0064 g heparinoid 180 mg colecalciferol 33000 ME Baby T. 13 years old cream psoriasis betamethasone dipropionate 0.064 g heparinoid 120 mg colecalciferol 33000 ME Child T. 13 years pasta psoriasis betamethasone dipropionate 0.0024 g, heparinoid 30 mg colecalciferol 2500 ME

one 2 3 four 5 6 7 Patient D. 7 years
lotion psoriasis (zinc oxide, talc, glycerol 85%, ethyl alcohol, water) mometasone furoate 0.1 g heparin sodium 6000 ME colecalciferol 2500 ME 34 year old patient
ointment exfoliative dermatitis (glycerol, petroleum jelly, cosmetic stearin “D”, peach oil, emulsifier No. 1, Lanette®, methylhydroxybenzoate, propylhydroxybenzoate, distilled water) methyl prednisolone 0.1 g heparin sodium 3000 units colecalciferol 33000 ME 19 year old patient
hydrogel contact dermatitis (carboxymetholcellulose 600, glycerol 85%, water) fluocinolone acetonide 0.025 g heparin sodium 6000 colecalciferol 5000 ME 19 year old patient
solution contact dermatitis (glycerol 85%, ethyl alcohol 70%, water), fluocinolone acetonide 0.0025 g heparin sodium 3000 colecalciferol 330000 ME Child G., 5 years old
cream atopic dermatitis, severe form. (white petrolatum, white wax, propylene glycol stearate, stearyl alcohol, cetiret-20, hexylene glycol, titanium dioxide, aluminum starch octenyl succinate, distilled water) mometasone aceponate 0.005 g heparinoid 120 mg colecalciferol 33000 ME Child M. 6 years
lotion, neurodermatitis, severe (polyethylene glycol, titanium dioxide, starch, water) methylprednisolone aceponate 0.01 g heparin sodium 6000 units colecalciferol 2500 ME Patient 17 years old
ointment, atopic dermatitis, severe (glycerol, petroleum jelly, stearin, cosmetic “D”, peach oil, emulsifier No. 1, Lanette®, methylhydroxybenzoate, propylhydroxybenzoate, purified water) betamethasone dipropionate 0.0064 g heparinoid 180 mg colecalciferol 30000 ME

Claims (2)

1. The tool for the treatment of immune diseases of the skin containing glucocorticosteroid, characterized in that it is made in a dosage form for external use and additionally contains heparin or heparinoid and vitamin D with the following content of active ingredients per 100 g of base: glucocorticosteroid 0.002-0.1 g heparin 3000-10000 PIECES heparinoid 30-180 mg vitamin D 2500-33000 ME 2. The tool according to claim 1, characterized in that it is made in the form of a paste, ointment, cream, gel, hydrogel or solution.

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