BG61991B1 - Form for the treatment of viral diseases - Google Patents

Abstract

The form is used for the treatment of viral disease caused byDNA-containing viruses such as the viruses herpes simplex - 1type, herpes simplex - 2 type, varicella-zoster viruses,adenoviruses and diseases of mixed infections of the indicatedviruses with gram(+) bacteria, with macosis and other similar. Theactive component is ionophoric antibiotic Monezine produced fromStreptomyces cinnamonesis in quanties from 0.001-0.4 wt.pt. andrelevant components of the medicamentous form. It is administeredin the form of solution, gel or cream for specific local treatmentof labial, genital and skin herpes, for herpes stomatites andkeratitis, keratoconjunctivitis, adenoviral diseases, varicellaand herpes-zoster and for diseases of mixed etiology - bacterial,mucose, conditional.

Description

Technical field

The invention relates to a treatment for viral diseases caused by DNA-containing viruses such as herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster viruses, adenoviruses, and diseases of mixed infections of these viruses with gram (+ ) bacteria, with mycoses and similar microorganisms. The agent is preferably intended for human medicine.

BACKGROUND OF THE INVENTION

GB 1024156 is known for the treatment of herpes, adenoviral and other DNA viral diseases with the active ingredient idoxirin (2'-deoxy-5-iodouridine), which is a purine synthetic halogen-containing analogue. DE 2539963 discloses another agent for the treatment of these diseases, acyclovir, which is a purine nucleoside analogue and is (2-amino-1,9-dihydro (2-hydroxyethoxy) methyl) -6H-purin-6-one. It is known to be used in eye diseases as eye drops in 0.1 or 0.15% solution or 1% ointment. Topically applied in the form of 3% ointment or 5% cream 4 to 6 times a day for 5 to 10 days. Acyclovir is also given in 200 mg tablets.

BG 45570 is known for the treatment of viral diseases caused by DNA-containing viruses, which contains as an active ingredient the ionophore antibiotic nigericin produced by Streptomyces hydroscorpicus in an amount up to 3.0 parts by weight. by the total amount of the dosage form. The treatment of labile, facial, genital and gluteal herpes, shingles, herpes and adenoviral keratins, keratoconjunctivitis and herpes stomatitis is preferably performed locally. The active ingredient is administered by a collar at a dose of 1 drop every hour: by ointment, which is rubbed 4-6 times daily for 3 to 10 days. The agent is also administered in the form of globules.

The use of gammaglobulin and auto-chemotherapy for the treatment of the aforementioned diseases is also known, as well as the use of physico-chemical agents that represent abrasion, i. correction of pores of tissues by tissue viruses, in addition tincture with iodine tincture is applied as well as combination of these agents. Cryotherapy by low temperature burning is also applied.

SUMMARY OF THE INVENTION

The effectiveness of treatment with known agents is hampered by the development of resistant mutants, including cross-over several drugs. Difficult solubility, development of toxicity, and undesirable side effects such as 3Q soreness and corneal opacity are problems that limit the use of known agents. These problems are solved by the present invention, which relates to a treatment for viral 35 diseases caused by DNA-containing viruses such as herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster viruses, and diseases of mixed infections of these viruses with gram (+) bacteria, with mycoses and other similar microorganisms, characteristic of the agent is that the active ingredient is the ionophore antibiotic monensin produced by Streptomyces cinnamonesis and having the formula

in an amount of from 0.001 to 0.4 parts by weight. and up to 100 relevant components of the dosage form.

The ionophore antibiotic monensin is known as an antibacterial antibiotic with low antiviral activity (Calbiochem catalog. Contents, 1990-1991. Lucern, p. 313315). It is produced and applied in veterinary medicine as a prophylactic supplement to animal and bird feed.

It is known that the ionophore antibiotic monensin applied to viral diseases caused by DNA-containing viruses exerts a specific antiviral effect by the following possible mechanism. Selectively inhibits viral DNA synthesis at doses that do not affect cellular DNA synthesis; the synthesis of the viral enzyme thymidine kinase is inhibited; the glycosidation of viral proteins is impaired. As a result, extremely defective virions with very weak infectious properties are formed in the infected cells. It has also been found that at concentrations much lower than therapeutic monensin becomes a strong interferon inducer (BG 51387).

This multifaceted effect makes it possible to create a treatment for viral diseases caused by DNA-containing viruses with the active ingredient ionophore antibiotic monensin of formula I in an amount of from 0.001 to 0.4 parts by weight. and the rest are the relevant components of the dosage form.

The agent can be administered in the form of a solution, wherein the ionophore antibiotic monensin is in an amount of 0.05 to 0.15 parts by weight, the rest are the components corresponding to the dosage form: alcohol from 30 to 50 parts by weight. polyol from 2.5 to 40 parts by weight and distilled water to 100.

The term "alcohol" encompasses ethanol, propanol, isopropanol, etc., which are known for the purpose, and combinations thereof.

The term "polyol" encompasses glycerol, 1,2-propanediol, sorbitol, liquid polyethylene glycols and the like. known to the target as well as their combinations.

The preparation of the agent in the form of a lotion is by the technology for liquid dosage forms - molecular solutions.

The agent of the invention can be administered in the form of a transparent oleogel, wherein the ionophore antibiotic monensin is in an amount of 0.05 to 0.15 parts by weight, remaining up to 100 parts by weight. is a hydrophobic oleogel. The active ingredient is dissolved in the liquid triglyceride phase. Various liquid vegetable, animal and synthetic oils, such as sunflower, rapeseed, can be used as the liquid phase of the hydrophobic oleogel. fish, olive, almond, isopropyl myristate, isopropyl stearate, butyl stearate and more. similar individually or in combination. It is appropriate to use magnesium, aluminum and zinc stearates as well as various types of highly dispersed silica individually or in combination as a gelling agent.

The transparent oleogel was prepared by dissolving the active ingredient monensin in the liquid phase, after which the solution was gelled, limiting the amount of gelling agent to the need to obtain a transparent gel without syneresis.

The agent according to the invention can be administered in the form of a hydrophilic, water-washable osmotic gel in which the active ingredient is in an amount of 0.05 to 0.15% by weight. is dissolved in polyols of 80 to 96% by weight. and a gelling agent of from 4 to 20% by weight. The polyols used are described in more detail above in solution. The gelling agent is selected from those known for the purpose suitable for the preparation of a syneresis-free gel. The active ingredient is dissolved in the polyol or polyol mixture. The resulting solution was gelled with the gelling agent to obtain a gel without syneresis.

The agent can also be administered in the form of an alcohol-aqueous hydrogel, wherein the ionophore antibiotic monensin is in an amount of 0.05 to 0.4 parts by weight and the rest are alcohols from 1 to 30 parts by weight, polyols from 5 to 40 parts by weight, gelling agent from 0.1 to 10 parts by weight and water up to 100 parts by weight The alcohols and polyols used according to the invention are disclosed above in the lotion. Polysaccharides, proteins, cellulose derivatives, acrylic acid derivatives, alginates, and the like, known gelling agents, and combinations thereof, may be used as gelling agents.

The liquid alcohol-aqueous phase is gelled with a gelling agent in known manner for the preparation of hydrogens. The active ingredient solution is incorporated into the finished gel. A clear, washable gel was obtained.

The agent according to the invention can also be administered in the form of a hydrophilic, water-washable cream in which the active ingredient ionophore antibiotic monensin is in an amount of 0.05 to 0.15 parts by weight, remaining up to 100 parts by weight. is an emulsion base consisting of an oil phase of 5 to 35 parts by weight, polyols of 5 to 40 parts by weight, an emulsifier complex of 5 to 15 parts by weight. and water up to 100 parts by weight Hydrophobic components of vegetable and mineral origin, for example liquid vegetable and mineral oils, as described in the preparation of oleogels, saturated hydrocarbons - paraffins: liquid and solid, petroleum jelly, alone or in combination, may be used as the oil phase. As the polyols, the components mentioned in the solution can be used. A mixture of water-oil (B / M) type emulsifiers can be used as an emulsifier complex, for example: lanolin, lanolin alcohols, styrene, glycerin oleates and the like. like and oil-water (M / B) type emulsifiers, for example: polyoxyethylene sorbitan - esters of higher fatty acids, alkyl-, aryl-, ether sulfates or sulfonates of higher fatty acids, polyoxyethylene-ethers of higher fatty alcohols and the like known for the purpose. The emulsion vehicle is prepared by known methods for preparing M / B emulsions. The solution of the active ingredient monensin, which dissolves in the outer hydrophilic part of the emulsion, is included in the finished emulsion after cooling.

The agent according to the invention in a different form is intended for specific local treatment of viral diseases such as labial, genital and skin herpes with different localization, for herpes stomatitis, for adenovirus and herpes keratitis and kerat conjunctivitis, for varicella and herpes zoster, as well as for herpes zoster and zoster disease. with a mixed etiology - bacterial, mycosis, con- ditional. The treatment is carried out locally by repeatedly smearing the lesions on the skin and mucous membranes, through eye drops for 3 to 5 days.

Due to its multifaceted antiviral effect and its wide therapeutic potential, as it inhibits viral reproduction, the concentration of the active ingredient in the agent of the invention is over 100 times lower than the cell toxicity. Another advantage of the agent is the 10-fold lower dose for inhibition of viruses and viral mutants that are resistant to other antiviral agents. It also has a better effect on the cause of genital and neonatal herpes. The broad antimicrobial spectrum of the agent according to the invention allows for good therapeutic effect in mixed infections. This effect is also compounded by the induction of interferon by the agent in low concentrations.

Embodiments of the invention

The embodiments illustrate it in more detail without limiting it.

Example 1.

Toxicological and pharmacological studies of monensin.

1.1. Acute toxicity. To determine the acute toxicity of the agent, monensin 10% was introduced into a food probe in various biological models. The results are shown in Table 1.

Table 1

Acute toxicity of monensin 10% 8 me / ke.

Type Tealo (age) Number ^l To ^Λ * 50 ^L ^ 1OO ICR Mouse Trouble 18-20 is. 42 50 70 + 24.6 22B White Wister rats 1B0-200f. 72 70 140+ 41 190 Chicken broilers 2Days 108 BO 200+ 81 460 Chicken broilers BB-days B5 B0 155 + 38 300

In dead animals, pathological changes are in the blood vessels, the kidney cortex, in the liver and rarely in the brain.

1.2. Subchronic toxicity. The experiments included 40 white Wister rats weighing 150-200 g and 50 broiler chickens.

45-day age, divided into 4, respectively 5 groups of 10 each. The experiment in rats lasted 60 days with studies on days 15, 30 and 60, and on chickens for 30 days with studies on days 15, 30 and 30. Part of the results obtained are shown in Table 2.

Table 2. Subchronic toxicity of monensin -10% as ppm.

Type Monensin 10 doses per ppm INDICATORS gain In ar. erythrocytes ucf leukocytes 1.K? chemovlubin vr% White rats 120 100,3 7.7 7.0 16.4 type Wister 360 59,1 7.3 8.7 16.7 1B0-200 ·. 600 25.7 5.5 9.3 7.9 control 95,5 7.1 8.6 15.4 Chickens 120 1084 2.4 55 10.9 broilers 240 73B 2.1 59 10.9 4-day days 360 667 2.3 49 9,8 600 B91 2.2 53 9, B. control 1289 2.3 56 9.9

The table data shows that monensin - 10% at higher doses of 360 and 600 ppm has a negative effect on growth and some blood counts. At the same time, in the same experiments, no deviations were found in the high concentrations of monensin of the other parameters studied, such as: blood sugar, urea, liver samples (GOT and GPG), differential blood count and plasma and potassium content.

1.3. Tolerance. When monensin was administered internally - 10% in different birds, it was found to be well tolerated for chickens at 4-5 ED _5o , for turkeys - less than 1 ED ₅₀ , for geese

- up to 1 ED ₅₀ and for ducks - up to 2 ED ₅₀ .

When applied locally to rabbit eyes at doses in excess of 15 times the therapeutic concentration, it does not cause inflammatory reactions or other abnormalities. The experiment was carried out on 20 rabbits weighing 2.5-3 kg, the aqueous solution was added 5 times over 7 days. No pathological abnormalities were observed with 3 times rubbing 0.1% aqueous solution for 5 days in the oral mucosa of 30 guinea pigs weighing 250-300 g. In the form of 0.1% aqueous-alcohol solution, 0.1% cream and 0.1% ointment, it was tested with 6 times rubbing for 7 days in the skin of 25 rabbits, 40 guinea pigs and 35 volunteers. In all tested forms, monensin showed very good tolerability for topical treatment.

1.4. Embryotoxicity and teratogenicity. The experiments were performed on 242 7-day-old hen embryos (white lung). Are determined LD _50-3 mg / kg (± 1 mg) and N, _100-18 mg / kg (± 2,2 mg) . To study the embryotoxicity, different doses of monensin emulsion in a volume of 0.1 ml were injected into the yolk bladder. Up to 1/5 of LD ₅₀ monensin has been found to be toxic to embryos. At doses lower than 1/10 LD ₅₀ does not show embryotoxic and teratogenic action.

1.5. Distribution in the body. The experiments used 45 broilers, 12 piglets and 12 shillings. They are fed with feed mixes containing monensin - 10% for 30 days for chickens and piglets and 90 days for shillets. The daily dose of monensin for the different groups of chickens was 120, 240 and 360 ppm, for the piglets 60, 120 and 240 ppm and 10, 20 and 30 ppm, respectively. The amount of residual monensin in organs and body fluids was examined at various intervals after discontinuation of monensin. In chickens, monensin was detected in all organs and fluids tested at 18 hours after stopping power, with the highest amount in bile juice. At 42 hours, monensin is found in small quantities only in the kidneys. The 72nd hour is nowhere to be found. In 18-hour piglets, monensin is only found in bile, liver and kidney. At the 42nd and the 66th hour no one was detected in any of the samples tested. In Schillets, monensin is detected in all samples after 1 hour, at 25 hours only in the kidneys, and at 49 hours is missing in all samples. The experiments of the three types of biological objects show that monensin is completely excreted by the organisms on the 3rd day after discontinuation of its application.

Example 2.

Preclinical trials for the therapeutic effect of the agent of the invention monensin for topical treatment of various herpes diseases.

The grounds for the preclinical trial are: (a) the proven therapeutic effect in these diseases of the ionophore antibiotic nigericin (BG 45570); (b) the antiviral activity of the two antibiotics in in vitro cell culture experiments and their similar mechanism of antiviral action; (c) positive results from experiments with monensin for the treatment of experimental rabbit herpes keratitis and experimental guinea pig herpes stomatitis.

The preparation was administered to volunteers as a 0.1% water-alcohol solution or as a 0.1% cream. The preparations were rubbed at the site of herpes lesions 6 times for 3 days. The data obtained are presented in Table 3.

Table 3.

Drug Illness, causative agent number of volunteers The effect of treatment very good good no effect number % number % number % Monensin 0,1% water-alcohol solution Labial herpes (VHS-1) 42 22 52,4 18 42,8 2 4,8 Skin Herpes (VHS-1) 12 7 58.3 4 33,4 1 8.3 Genital herpes (VHS-2) 82 42 51,2 37 45,1 3 3.7 Skin Herpes (VHS-2) 14 8 57,2 5 35,7 1 7.1 Herpes / Zoster (VZV) 38 24 63,2 11 29.0 3 7.8 TOTAL 188 103 54,8 75 39.9 10 5,3 Monensin 0.1% cream Labial herpes (VHS-1) 14 8 57.1 5 35,8 1 7.1 Skin Herpes (VHS-1) 8 5 62.5 2 25,0 1 12.5 Genital herpes (VHS-2) 26 14 53,8 10 38.5 2 7.7 Skin Herpes (VHS-2) 6 3 50.0 2 33,4 1 16.6 Xepnec'socmep (VZV) 21 13 61.0 6 28.6 2 0.5 TOTAL 75 43 57,3 25 33,4 7 9.3 TOTALLY 263 146 55.5 100 38 17 8.5

Legend: VHS-1 (herpes simplex virus - type 1), VHS-2 (herpes simplex virus - type 2), VZV (varicella zoster virus).

A very good curative effect is the cases where the period of subjective complaints (pain, burning, tingling) is shortened by 3-4 days and the time of complete healing by more than 3 days. Good effect is accepted in patients where the duration of complaints and recovery is reduced by 1-2 days. Patients suffering from frequently recurrent herpes (at least 6 times a year) for the duration of the complaints and for the healing period were used for comparison in patients with HCV-1 and HCV-2. In patients with shingles, the effect of treatment is compared with data from patients treated with symptomatic agents only and with literature data.

As can be seen from the data in the table, monensin 0.1%, both as a water-alcohol solution and as a cream, has a beneficial effect in all major herpes diseases. This effect is superior to the results obtained in a broad clinical trial conducted in 1981-83 with nigericin (pandavir) in 8 university clinics.

Treatment for all volunteers begins within the first three days of the onset of the disease. It is well known that effective specific treatment for herpes disease should start as early as possible. When analyzing some of the patient data, this was fully confirmed, as can be seen in Table 4.

Differences 8 clinical effect with monensin 8 depending on the start of treatment

Table 4.

Viral Causes * Tel Starting treatment Number of volunteers Therapeutic effect very good good no effect number % number % number % One day 16 14 87.5 2 12.5 0 0 VHS-1 2 day 24 12 50 10 41,7 n 9.3 3-4 days 10 2 20 4 40 4 40 One day 14 12 85.7 2 14.3 0 0 VHS-2 2 day 20 9 45 9 45 2 10 3-4 days 6 1 16, c 2 33,4 3 60 One day 2 2 100 0 0 0 0 VZV 2 day 22 16 72.7 4 18,2 2 9.1 3-4 days 6 3 50 2 33,4 1 16.6

In the later phase, patients with shingles are relatively better affected, which is associated with its slower, but more severe and 30 long-term development.

The preliminary clinical trial of monensin preparations shows their undoubtedly good therapeutic capabilities, which warrant a clinical trial in hospitals.

Example 3.

Anticoncessional activity.

The example used 120 12-day-old chicks in groups of 20 each. Infected with 130,000 E.Tekela units. 10% monensin (production of Biovet JSC - Cave) and others was applied. anticoccidials such as Avatec La Roche, Salinomycin Hochst. 45 The preparations were administered in the food mixtures 2 days before infection and up to 7 days thereafter at daily doses of 75 ppm for selicomycin and 100 ppm for the others. The results obtained for the anticoccidial effect are very similar. A production experiment of 18500 and 17025 chickens showed similar results, with the mortality of coccidin-infected chickens being 0.7% when administered with a monensin preparation and 1% to 1.7% with preparations with other ionophore antibiotics.

Monensin shows good effect on gram (+) bacteria and fungal diseases. Applied according to the invention, for skin lesions with mixed etiologic agents, very good results are obtained.

Example 4.

The agent of the invention is administered in the form of a solution containing, by weight,%: monensin 0.1; polyethylene glycol 5.0 and ethanol to 100.0. It is prepared by the technology of molecular solutions. The application is according to example 2.

Example 5.

The agent of the invention is administered in the form of a hydrophobic oleogel with a composition by weight of: monensin - 0.1; fine silica - 15.0; petroleum jelly up to 100.0. The monensin and the petrolatum are mixed, followed by gelation with silica gel. The application is according to example 2.

Example 6

The agent of the invention is administered in the form of a hydrophilic water-washable gel containing, by weight,%: monensin 0.1; polyethylene glycol 4000 - 20.0 and up to 100.0 polyethylene glycol 400. The thick viscous gel is obtained by dissolving monensin in the glycol mixture and gelling to a gel without syneresis if necessary. It is applied as described in Example 2.

Example 7.

The agent of the invention is administered in the form of an alcohol-aqueous hydrogel containing by weight. %: monensin - 0.2; methylcellulose. 5,0; sorbitol 70% - 10.0 and distilled water to 100.0. The alcohol-water mixture was gelled in a known manner to give a hydrogel, then a solution of monensin was added. The gel was applied as described in Example 2.

Example 8.

The agent of the invention is administered in the form of a hydrophilic water-washable cream containing by weight. %: monensin -0.1; emulsion waxes - 15,0; petroleum jelly - 25.0 and distilled water to 100.0. The emulsion vehicle is prepared by known methods for M / B emulsions. To this was added the monensin solution. It is applied as described in Example 2.

Claims (6)

A remedy for the treatment of viral diseases caused by DNA-containing viruses. characterized in that it contains as an active ingredient the ionophore antibiotic monensin produced by Streptomyces cinnamonesis in an amount of from 0.001 to 0.4 parts by weight. and $ corresponding form components up to 100.0. An agent according to claim 1, characterized in that it contains the ionophore antibiotic monensin in an amount of from 0.05 to 0.15 parts by weight. and the corresponding components, comprising an alcohol of from 30 to 50 parts by weight. polyol from 2.5 to 40 parts by weight and distilled water up to 100 parts by weight. An agent according to claim 1, characterized in that it contains in addition to the ion- 15 formic antibiotic monensin in an amount of 0.05 to 0.15 parts by weight. and up to 100 parts by weight triglyceride oleogel consisting of liquid oil and gelling agent with additives. The agent according to claim 1, characterized in that it contains the ionophore antibiotic monensin in an amount of from 0.05 to 0.15 parts by weight. with the corresponding components being polyols of 80 to 96 parts by weight. and a gelling agent of from 4 to 20 parts by weight. The agent according to claim 1, characterized in that it contains the ionophore antibiotic monensin in an amount of from 0.05 to 0.4 parts by weight, the other components being alcohol from 1 to 30 parts by weight, polyols from 5 to 40 parts by weight, gelling agent from 0.1 to 10 parts by weight the rest up to 100 parts by weight is distilled water. An agent according to claim 1, characterized in that it contains 35 form antibiotic monensin in an amount of from 0.05 to 0.15 parts by weight, oil phase from 5 to 35 parts by weight, polyols from 5 to 40 parts by weight, emulsifier complex from 5 to 15 parts by weight and up to 100 parts by weight distilled water.