UA62992C2 - Drugs for treating psoriasis, lichen rubber planus, and external diffuse otitis - Google Patents

Abstract

The invention relates to the medicine, in particular to the drugs for the topical application for treating psoriasis, lichen rubber planus, and external diffuse otitis. The drug contains the original non-steroid compound û N-[4-difluoromercaptophenyl] anthranilic acid with the base comprising lanoline and vaseline.

Description

The invention relates to medicine, in particular to medicinal products and can be used for local application in the treatment of psoriasis, lichen planus, and diffuse otitis externa.

In modern dermatological practice, a number of drugs of both resorptive and local type of action are used for the treatment of psoriasis and lichen planus. Along with agents that act on the nervous system (sedatives, tranquilizers, hypnotics), metabolism (hormones, trace elements, vitamins (1, 2, C), sensitization processes (calcium gluconate and chloride), etc., the need for widespread use of agents is not excluded , which are permanent components of the treatment of patients with psoriasis. Among the external means of disease therapy, salicylic, butadione, zinc oxide, zinc-sulphate, psoriasin, antipsoriatic, embiquin, anthramine, anthrasulfon, moldranat ointments are the most widely used, as well as ointments containing include glucocorticoid hormones (kenacort, prednisolone, polcortalone), tar, oil, etc. (4, 5, 6, 7, 8, 9).

In the treatment of diffuse otitis externa, in most cases, ointments are used, which include agents with an anti-inflammatory effect (butadione, mefenamic acid), astringents and antiseptics (xeroform, dermatol, resorcinol, zinc oxide), as well as corticosteroids and antibiotics (10 ).

It should be noted that the use of these drugs quite often leads to the development of severe complications, the occurrence of resistance to therapy in some cases, does not prevent the development of relapses that occur shortly after the end of the course of treatment.

595 salicylic ointment, which has keratolytic, distracting, and antiseptic properties, was used as a prototype for treatment in stationary and regressive stages of psoriasis and lichen planus (11).

The disadvantage of this ointment is a significant irritating effect on the epidermis, freed from keratinized cells and the mucous membrane. In addition, the ointment does not have an anti-inflammatory effect and therefore has a low therapeutic effect.

Turunda with nitrofungin, intramuscular antibiotics, and desensitizing therapy were used to treat diffuse otitis externa.

The disadvantage of nitrofungin is its irritating effect on tissues, and antibiotics have various side effects (10).

The invention is based on the task of creating a highly effective nonsteroidal drug for the treatment of regressive and stationary stages of psoriasis, lichen planus, and diffuse otitis externa, to speed up the recovery period of patients, to avoid the side effects of drugs used nowadays, and to extend the remission period.

The set task is achieved by the fact that the original compound of the non-steroidal series M-/4-difluoromethylmercaptophenyl/anthranilic acid is used as a physiologically active substance (Author's certificate

USSR Me931058) on a lanolin-vaseline base with the following ratios of components, wt. 9o: -/4-difluoromethylmercaptophenyl/anthranilic 5- acid 10

Lanolin 20. to

Vaseline 100

The compound is a fine crystalline powder of yellow color, bitter taste, odorless, insoluble in water, easily soluble in alcohol, ether, acetone, oils. According to chemical tests, the substance is stable when stored both in its native form and in medicinal form (ointment).

We came to the use of this substance as a medicinal product as a result of studying its anti-inflammatory effect, biochemical mechanism of action and pathogenesis of the inflammatory process. At the same time, it was established that the substance has anti-inflammatory, anti-protease, anti-bradykinin, angioprotective and membrane-stabilizing effects.

The anti-inflammatory effect of M-/4-difluoromethylmercaptophenyl/anthranilic acid was studied in comparison with flufenamic acid, which, like our substance, belongs to derivatives of M-phenylanthranilic acid and is a highly active anti-inflammatory drug. As a model, inflammation was chosen mainly with the phenomena of alteration, exudation and proliferation. The substance was studied in a conditionally therapeutic dose - 19mg/kg (1095 LDvzo) when administered intraperitoneally.

The antiexudative effect was established on the model of edema of the rear limb of rats caused by subplantar injection of 0.1 ml of phlogogenic agents - 290 formalin solution, 0.2595 trypsin solution, 695 dextran solution, 0.590 serotonin solution, iodine. kallikrein (the active ingredient of the drug Dilminal), 1:10 "bg/ml of bradykinin solution. The substance under investigation was administered intraperitoneally according to ZOkhv. before the injection of phlogistics. The antiexudative effect was recorded using a plethysmometer.

The protective effect of the substance on alternative inflammatory processes was studied on rats weighing 180-200 g.

Inflammation was induced by intravenous injection of 0.590 of serotonin-creatinine-sulfate solution at a dose of 10 mg/kg with simultaneous intradermal injection of 0.2 ml of urea solution.

The effect of the substance on the proliferative processes in the focus of inflammation (formation of granulation-fibrous tissue and the content of leukocytes in the exudate) was studied using the "pocket" granuloma method according to H. Selye, modified by V.B. Rosena (12). Inflammation was induced in rats weighing 210-240g by injecting 20cm3 of air into the back area under ether anesthesia and injecting 0.5ml of 5095 oil solution of turpentine into the air sac. The substance was injected into the stomach once in a dose of ZOmg/kg. Animals were studied on the 7th and 14th day.

The obtained data (Table 1) show that M-/difluoromethylmercaptophenyl/anthranilic acid was superior to fluphenamic acid in the degree of inhibition of formalin, trypsin and dextran edema.

Table 1

Anti-inflammatory activity of M-/difluoromethylmercaptophenyl/anthranilic acid and flufenamic acid on rat limb edema models with subplantar injection of formalin, trypsin, dextran /MeEt/

PZhuvvn r

M-/difluoromethylmercaptophenyl/anthranilic 41.912.8 41.5132 40.013.0 acid, n--7 35.53, 39.053.6 23.5-2.2

The development of edema of the limbs of rats with serotonin, kallikrein and bradykinin "inflammation" in control experiments was characterized by a moderate increase with a maximum 3-4 hours after subplantar injection of phlogogenic agents. Previous, according to ZOkhv before the injection of the latter, intraperitoneal administration of M-/4-difluoromethylmercaptophenyl/anthranilic acid, respectively, in doses of 19 mg/kg and 18 mg/kg (equimolar to the first) leads to a decrease in the development of the above-mentioned edemas (Table 2).

A noticeable advantage of M-/4-difluoromethylmercaptophenyl/anthranilic acid over flufenamic acid in the degree of inhibition of kallikrein edema was observed throughout the experiment, less noticeable in inhibition of serotonin edema. As for the inhibition of bradykinin edema, the studied substance was 1.3 times more active than flufenamic acid at the 4th hour (P<0.05).

Table 2

The influence of M-/4-difluoromethylmercaptophenyl/anthranilic acid (19 mg/kg) and flufenamic acid (18 mg/kg) during intraperitoneal administration on the development of serotonin, bradykinin, and kallikrein edema /MeEt/ -| Rat limb volume (relative units) and magnitude

Series of experiments Phlogogenic inhibition of edema (9o before control) by: agent 374017 | 39015 | 430.22 | 410.25

M-a 2.9 0287 290 2.6 50.07 2.3 50.06 difluoromethylmercaptophenyl/anthranilic acid 257 39.6 440 acid, p-6 Serotonin pR«ebo5 Re«0.05 Re«0.05 Re0, 05 yr Ri»0.05 Ri»0.05 Ri»0.05 Ri»0.05

Evil from every year 2001 2.65 0.08

Flufenamic acid, p-6 16.3 23 34.9 36.6

Re0.05 Re0.05 Re0.05 Re0.05 480.46 | 535043 | 58-04 | 4,250.33

M-a 435035 46032 4.6 0.25 21-02 difluoromethylmercaptophenyl/anthranilic 10.4 132 20.6 500 acid, p-6 Bradykinin P»0.05 Re«0.05 Re«0.05 Re0.05 rad Ri»0.05 Ri»0.05 Ri»0.05 Ri»0.05 4255037 400.25 37 08 23021

Flufenamic acid, n--7 10.6 245 344 36.5

Р»0.05 Ре0.05 Ре0.05 Ре0.05 4210.44 | 7.3:0.58 | 7.8-0.78 | 6,940.6

Ma 35017 5.3 50.33 4.703 38033 difluoromethylmercaptophenyl/anthranilic 166 273 39.7 449 acid, n-6 Kallikrein Re0.05 Re«0.05 Re«0.05 Re0.05 r Ri«0.05 Ri«0 .05 Ri«0.05 Ri«0.05 520.42 600-027 65024 577-028

Flufenamic acid, p-6b (9) 178 16.6 17.3

Р»0.05 Р»0.05 Р»0.05 Р»0.05 x Numerator - relative units, denominator - 95 inhibitions;

P - in relation to the control; P1 - in relation to flufenamic acid

In experiments with "pocket" granuloma M/4-difluoromethylmercaptophenyl/anthranilic acid and fluphenamic acid reliably inhibited the formation of granulation-fibrous tissue. The substance M-/4-difluoromethylmercaptophenyl/anthranilic acid proved to be more effective, which not only suppressed the formation of granulation tissue, but also suppressed exudative processes on the 7th and 14th day, as evidenced by a significant decrease in the mass of wet granuloma (Table 3).

Table C

The effect of M/4-difluoromethylmercaptophenyl/anthranilic acid and flufenamic acid when administered intragastrically to rats on the formation of granulation-fibrous tissue and the content of leukocytes in exudate (Met) and g. Mass of granulation-fibrous tissue, mg | The number of leukocytes in

Series of experiments of 1 ml of exudate

11111111 | wet | dry | wet | dry | 7 days l4doba

M/4- 2846:2101,1| 6242541 11900:95,11250522,4| 9510-5876 | 62235543 Difluoromethylmercaptophenyl/anthranilic Re«eО0.05 R«0.05 R«e0.05 R«0.05 R«0.05 R«0.05 acid, p-6 R«0.05 R«0.05 | Ri«0.05 | Ri«0.05| Ри«0.05 Ри«0.05 ' Ре0.05 Р«0.05 Р«0.05 | Р«0.05 Ре«0.05 Ре0.05

Both substances created a barrier for the penetration of leukocytes into the center of inflammation: their migration on the 7th day under the influence of M/4-difluoromethylmercaptophenyl/anthranilic acid and flufenamic acid decreased by 45.4905 and 26.495, respectively, and continued to decrease to 57.3905 and 44.495 on 14 a day In these terms, a weakening of the intensity of proliferative processes was also observed, as evidenced by a decrease in the mass of dry granuloma by 43.295 under the influence of M/4-difluoromethylmercaptophenyl/anthranilic acid and by 20.595 under the influence of fluphenamic acid, i.e. the effectiveness of /M/4-difluoromethylmercaptophenyl/anthranilic acid exceeded that of flufenamic acid in 2.1 times (Р«0.05).

Study of preliminary intraperitoneal administration of M/4-difluoromethylmercaptophenyl/anthranilic acid and flufenamic acid, respectively, in equimolar conditionally therapeutic doses of 19 mg/kg and 18 mg/kg for 30 min. before causing inflammation showed that with alterative inflammation /M/4-difluoromethylmercaptophenyl/anthranilic acid effectively prevented the development of widespread necrosis with destruction of the skin and subcutaneous tissue, while reducing the size of necrotic areas. Flufenamic acid had a similar, but less pronounced effect (Table 4).

Table 4

The effect of M/4-difluoromethylmercaptophenyl/anthranilic acid and flufenamic acid on the alterative processes in the focus of inflammation caused by the introduction of serotonin-creatinine-sulfate and simultaneous intradermal introduction of urea 3-15 ЯИ 5 | nu | Jan

CONTROL. n-!0 d/h |101 | 1 | 3 | with | z acid, p-10 (Flufenamic acid p-10 -/-: | 0 | z | z | 2 | 2 - no changes t point necrosis z- necrosis size 100mm2 z--ja- necrosis size 290mm2 z-n- widespread necrosis with loss of skin and subcutaneous tissue

The obtained data show that M/4-difluoromethylmercaptophenyl/anthranilic acid is more effective than flufenamic acid in delaying the development of alterative processes, stimulating the scarring of skin defects.

The above-mentioned properties (antiprotease, antibradykinin, angioprotective, and membrane-stabilizing) of m/4-difluoromethylmercaptophenyl/anthranilic acid are presented in the dissertation (13) and materials reviewed by the Pharmacological Committee of the Ministry of Health of Ukraine (Meb protocol dated October 29, 1992), and the obtained permission for clinical use the latter in the form of 590 Difluorant ointment for the treatment of stationary and regressive forms of psoriasis, lichen planus, and diffuse otitis externa.

Thus, the data obtained by us indicate that M/4-difluoromethylmercaptophenyl/anthranilic acid suppresses the alterative, exudative and proliferative phases of inflammation, reduces the content of bradykinin in the blood, which takes part in the development of inflammation, stabilizes cell membranes, and is a good angioprotector. In addition, M/4-difluoromethylmercaptophenyl/anthranilic acid has an analgesic and antipyretic effect.

Method of obtaining. To obtain the medicinal product in laboratory conditions (595 and 1095 ointment

Difluorant) take 5g and 10g of crystalline powder of the physiologically active substance, respectively, place in a porcelain mortar and grind thoroughly with the addition of 5-10 drops of petroleum jelly. Then, in portions, add 95g for 590 ointment and 90g for 10905 ointment of lanolin-vaseline base in a ratio of 1:5 and mix it all to a homogeneous mass.

The declared composition in the form of 595 and 1095 Difluorant ointment on a lanolin-vaseline basis in a ratio of 1:5 is used in the traditional way.

Example 1. Patient N., 35 years old, complained of a rash that covered different parts of the body, periodic itching. Diagnosis - exacerbation of psoriasis. He has been suffering from psoriasis for 9 years. He was treated on an outpatient basis and in a hospital with various ointments, general strengthening therapy, UFO. There was a temporary effect.

Objectively: the skin process is widespread, localized on the upper and lower limbs, on the trunk. Papules of pink color with silvery-white scales on the surface of the center of the element measuring from 2 to 4 cm in diameter. Exacerbation in the stationary stage.

The patient was prescribed 595 ointment, which includes M-/4-difluoromethylmercaptophenyl/anthranilic acid. Lubricated the affected areas of the skin twice a day for 16 days. After the course of treatment, a significant improvement of the skin process was noted: psoriatic elements on the trunk were absorbed, and regressed on the limbs. The patient has no complaints. He was discharged in a state of clinical remission.

5 patients who were diagnosed with psoriasis in the inpatient stage of treatment served as controls. The site of skin damage - upper and lower limbs, trunk.

Treatment in the hospital was carried out with 295 salicylic ointment by applying a thin layer twice a day for 25 days.

The results of treatment showed that clinical recovery was observed in 2 patients, significant improvement in 1 patient, treatment was not effective in 2 patients.

Example 2. Patient A., 41 years old. Diagnosis: red lichen planus. He has been sick for 5 years. The disease was discovered for the first time when the patient turned to a dermatologist with a complaint of a profuse rash of nodular elements in the form of a ring at the site of former scratches on the flexor surfaces of the upper limbs, which was accompanied by itching. Relapses were repeated in the spring in the form of papules covered with horny scales. Place of localization - flexural surfaces of the upper limbs and lower legs, subjectively - itching that worsened at night.

The patient was treated in a hospital with 595 Difluorant ointment, which was applied in a thin layer to the affected areas of the skin 2 times a day for 10 days. The therapeutic effect began to manifest itself on the 2nd day after applying the ointment. The itching is gone. As a result of resorption, papules began to decrease in size. The skin on the papules had a pale pink color. The patient was discharged from the hospital in satisfactory condition.

When using 295 salicylic ointment in patients with a diagnosis of lichen planus, the improvement of skin processes was observed within 15-16 days, that is, a little later than when treated with the above-mentioned ointment.

Example 3. Patient H.G. went to the polyclinic with complaints of pain in the external auditory canal of the right ear, swelling, itching, hyperemia of the skin. Diagnosis: external diffuse otitis. Got sick for the first time. He was sent to a hospital for treatment.

The patient was treated with 595 Difluorant ointment. The ointment was applied to the skin of the external auditory canal every day, 2 times a day. On the 3rd day of treatment, a significant improvement in the general condition was noted - normalization of body temperature. On the 7th day of the disease, inflammatory phenomena in the external auditory canal were removed, the pain completely disappeared. The patient was discharged from the hospital in satisfactory condition.

Table 5 shows the results of treatment of diffuse otitis externa in 30 patients with 595 ointments

Difluorant and 10 patients who received a traditional course of treatment: intramuscular antibiotics, desensitizing agents, physical therapy. methods and local treatment (turunda in the ear with nitrofungin).

As can be seen from the data in the table, treatment of patients with Difluorant ointment according to the presented indicators is superior to treatment with traditional methods.

Table 5

Indicators of treatment of patients with diffuse otitis externa

The period of complete recovery of patients with diffuse otitis externa when treated with Difluorant ointment was 7-8 days, when treated with traditional methods - 10-12 days.

The effectiveness of Difluorant ointment 5905 and 1095 was studied in the clinical conditions of the Central Research Institute of Dermatology and Venereology of the Ministry of Health of the USSR, TsOLIUL and the Kharkiv Research Institute of Dermatology and Venereology of the Ministry of Health

of Ukraine.

The results of the treatment of patients indicate that 5956 Difluorant ointment was effective in stationary and regressive stages of psoriasis. Thus, out of 96 patients in the inpatient stage of the disease, 18 patients were fully recovered within 7 to 21 days; significant improvement - in 53 patients, improvement - in 2 patients. Ineffective treatment was observed in 21 patients. In the regressive stage of the disease (10 patients), all patients recovered within 7 days.

It should be noted that in comparison with the treatment times of patients in the control group, in 6,290 patients whose treatment complex included Difluorant, a reduction in recovery times was observed by an average of 1,795.

Treatment of patients with red lichen planus (14 people) showed that in 12 patients when applied

Difluorant improved on the 6-9th day of treatment. Clinical recovery was observed in 3 patients, significant improvement in 3 patients, improvement in 3 patients. Treatment was ineffective in 5 patients.

The use of the proposed remedy for the treatment of psoriasis in stationary and regressive stages, lichen planus, and diffuse otitis externa gives a high therapeutic effect and does not have a harmful effect on the body.

References 1. Vedernikov V.A., Zvyagina G.A. Treatment of psoriasis with ascorbic acid. - In the book Labor Day

Arkhangelsk med. in-ta, vpp. 15. Arkhangelsk, 1957, p.197. 2. Hluhenkyi T.T., Huda 3.Zh. The use of vitamin B and C in the complex treatment of patients with scaly lichen. // Medical case. - 1969. Meo7 - P.145-146. 3. Zheltakov M.M., Sharapova G.Ya. Hormone; and skin - West. dermatol. and venereal - 1967. - MoI - p. 3-12. 4. Akoeva I.D. Treatment of psoriasis with zmbykhinovy ointment. // Healthcare of Tajikistan. - 1956. - Mo3Z -

P. 40-42. 5. Berlin S.I. Treatment of lichen planus with anthrasulfonic and anthramine ointments. // Vest. dermatol. and venereal - 1964. - Me7 - Sat. 72-73.

6. Ivanov N.A. Corticosteroid treatment of some dermatoses. - M.: Medgiz, 1963. 7. Kartamyishev A.I. Treatment of skin diseases with corticosteroid drugs. - M., 1963. 8. Mashkilleyson L.N. Private dermatology. - M.: Medicine, 1965. 9. Zadorozhnyi B.A. Psoriasis. - K.: Health. - 1973. - 1770. 10. Mashkovsky M.D. Medicines. - M.; Medicine, 1993. 11. Yablenyk B.S. Scaly lichen. L.: Medicine, 1964. 12. Rosen V.B. Methods of reproduction of standard aseptic inflammation. - Pat. physiol. and zxper. therapy, 1961. - 5, Mob - P.72-73. 13. Chernoshtan K.A. Pharmacological studies of fluoride-derived M/-phenylanthranilic acids. -

Diss... candidate. medical sciences Kyiv, 1982.

Claims (1)

Means for the treatment of psoriasis in stationary and regressive stages, lichen planus 1 and diffuse otitis externa, which includes a non-steroidal anti-inflammatory substance and a base, which is distinguished by the fact that as a non-steroidal anti-inflammatory substance it contains M-(4-difluoromethylmercaptophenyl|anthranilic acid on lanolin- petroleum jelly base with the following ratio of components in mass.9o: M-I4-difluoromethylmercaptophenyl|anthranilic acid 5-10 lanolin 20 petroleum jelly to 100.