JPS649963B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pharmaceutical compositions for treating diseases caused by viruses of the herpes group (HV). Viral infections are widespread among populations around the world. most widely spread,
Among the dangerous viral infections, there are diseases caused by viruses of the herpes group, such as herpes zoster, herpetic keratitis, keratoconjunctivitis, viral hepatitis, and encephalitis. Intrinsic features that substantially impede control of herpestic infections reside in the long persistence of herpesviruses in the organism, frequent recurrences, and multiple clinical manifestations. Common herpes (herpes simplex)
simplex)) is characterized primarily by a vesicular rash. The intensity of the infection varies, but the common symptoms are moderate and include herpetic fever with hyperthermia, depression, headache, and joint pain. Symptoms of the disease also include stomatitis, glossitis, keratitis and keratoconjunctivitis, laryngitis, and a vesicular rash on the mucous membranes and skin. Additionally, the face, around the mouth, nose, eyelids, and genitals are often injured. In the case of herpes zoster, skin lesions are preceded by inflammatory phenomena and changes in the ganglionic roots and dorsal columns of the spinal cord, which are accompanied by intense and often irresistible pain along the nerves and localized skin signs, i.e. Accompanied by edema, itching, and vesicular rash. In herpetic diseases, herpetic hepatitis is often seen in both children and adults. Although research is relatively insufficient, meningitis,
There are disorders of the central nervous system in the form of encephalitis and encephalomyelitis. This is a common form of herpes with fatal consequences. Despite extensive research into drugs with antiviral activity, the problem of researching viral diseases caused by viruses of the herpes group remains an urgent problem. Existing antiviral drugs do not meet all the demands placed on them, and their application does not result in complete recovery or prevent recurrence. Attempts have been made to treat herpetic diseases using antibiotics, certain chemical compositions, corticoids, and specific and nonspecific vaccine therapy.
It has been found that the use of sulfanilamide and antibiotics has no effect on the progression of herpetic diseases and is only able to prevent or eliminate bacterial infections. Chemical agents used to treat these diseases include analogues of pyrimidine bases, JDU (5-iodine-2-desoxyuridine), and 5-fluorouracil, which are antimetabolites and are effective against viruses; It also affects living organisms. Furthermore, these are rather toxic substances. As a result, the known antiviral drugs do not meet all the necessary requirements (do not prevent recurrence, do not cause complete recovery) and therefore treat viral diseases caused by viruses related to the herpes group. The problem still remains to be solved. The present invention provides a treatment for diseases caused by viruses of the herpes group that has highly selective activity against infected individuals, provides a high degree of therapeutic efficacy, is non-toxic, and can be manufactured. The object of the present invention is to provide a pharmaceutical composition that will do the following. For this purpose, 2-c-β-D-glucopyranosyl-1, represented by the following formula as an active ingredient,
3,6,7-tetraoxyxanthone This can be achieved by a pharmaceutical composition comprising a combination of a pharmaceutical carrier and a pharmaceutical carrier. The active ingredient of the present invention is one of the xanthonic substances (mangiferin euxantogen) of the formula C ₁₉ H ₁₈ O ₁₁ . Its appearance is a yellow crystalline substance with a melting point of 258-261°C, poorly soluble in ethanol, insoluble in water, chloroform and ethyl ether, this compound has never been used in medicine before. As mentioned above, the active ingredients of the invention are used in combination with a pharmaceutical carrier. For external application in case of viral diseases of the skin and mucous membranes (herpes simplex, herpes zoster, lichen planus, genital herpes, aphthous vesicular stomatitis, laryngitis, rhinitis and other diseases of viral etiology) It is advantageous to use a pharmaceutical composition containing the active ingredient in combination with a pharmaceutical excipient for an ointment consisting of a mixture of petrolatum oil and petrolatum. Such pharmaceutical compositions are preferably used in proportions by weight of 2-5% active ingredient, 4-10% petrolatum oil and 85-96% petrolatum. For oral administration, the pharmaceutical composition is preferably used in tablet form. Lactose, starch, talc and calcium stearate are used as pharmaceutical excipients for this purpose. Preferably, the pharmaceutical composition uses 40% by weight of active ingredient, 40% by weight of lactose, 17% by weight of starch, 2% by weight of talc and 1% by weight of calcium stearate. This drug can be administered in cases of the above-mentioned diseases as well as in cases of viral hepatitis, encephalitis, meningitis, etc. The drug according to the invention was named "Alpizarin". The study of the antiviral properties of the active ingredients of the invention
In vitro experiments in chicken lung fibroblast cell cultures were performed according to the procedures commonly used for primary screening of antiviral drugs. Cells were grown in flasks or tubes on nutrient medium 199 supplemented with 5-10% bovine serum by volume. Virus-containing material was then added in doses of 1, 10, 100 and 1000 TCD ₅₀ into the flask to bring the virus into contact with the cells. Adsorption of the virus onto the cells was carried out for 1 hour at room temperature, after which the virus-containing medium was removed and the medium 199
was introduced into a flask or test tube. This medium contains the active ingredient at the maximum tolerated concentration for the cells (the substance at this concentration has no cytotoxic effect). The flask or test tube is then 37
The temperature was kept constant at ℃. Viral suppression efficacy was determined by comparing the presence of cytopathogenic effects in 5-day control and test flasks and tubes. As controls, a monolayer of cells, active ingredient without virus and virus without active ingredient were used. As a result, the active ingredient at a concentration of 10 μg/ml is
It was found that 100TCD ₅₀ HV had a high degree of virus suppression effect. The chemotherapeutic efficacy of the active ingredient and the entire pharmaceutical composition was performed on an experimental viral model of herpetic encephalitis in white mice. Over 1,500 animals were used in the experiment. To obtain experimental encephalitis, white mice weighing 8-10 g were infected intracerebrally. Prior to infection, the scalp of the animal is coated with iodine and then a 10-fold dilution of virus-containing solution is applied to 0.03
ml volume was injected directly into the brain with a tuberculin needle into the supraorbital area near the frontal midline to a depth of 1-2 mm. After 3 to 7 days, signs of disease were observed in the animals (excitement, loss of coordination, muscle weakness, paresis and paralysis), which gradually intensified and led to death. Experiments were evaluated by percent animal survival and mean lifespan of test animals compared to controls. For therapeutic purposes, the active ingredient or pharmaceutical composition in tablet form can be administered orally to infected animals by means of a gavage as an aqueous suspension in a volume of 0.5 ml per kg of body weight.
Doses ranging from 20 to 500 mg were administered once or twice a day. This test was conducted in three different formats. In the first mode, the active ingredients or tablets were given to the animals 1-2 days before infection in order to saturate their bodies beforehand (prophylactic study). In the second mode, in order to demonstrate the therapeutic effect of active ingredients or pharmaceutical compositions, these were introduced on the day of infection or 1-2 days after infection. In the third mode (therapeutic-prophylactic) the active ingredient or pharmaceutical composition was administered the day before or on the day of infection, and in each case treatment of the animals continued for 5 to 7 days after infection. When the active ingredient or pharmaceutical composition was administered by the first two modes, death of the animal occurred within the same time period as the subject animal, so it is statistically certain that the chemotherapeutic effect of the pharmaceutical composition or active ingredient is It was impossible to produce any effect. The most advantageous chemotherapeutic effects of active ingredients or pharmaceutical compositions have been demonstrated under conditions of therapeutic-prophylactic application (tertiary mode). The test results are shown in Tables 1 and 2 below.

[Table] The data presented in Table 1 demonstrate that the highest degree of statistically reliable chemotherapeutic efficacy is achieved when the active ingredient or pharmaceutical composition is administered twice daily. Recognize.

[Table] It can be seen from Table 2 that the chemotherapeutic effect of the active ingredient or pharmaceutical composition is highest when administered at the shortest possible time from the time of infection. The pharmacological characterization of the active ingredients of the invention was performed using two methods. In other words, regarding the effects on heart defects and the central nervous system, due to the cardiac rhythm effect,
Blood aggregation morphology was investigated for anti-inflammatory, anti-ulcer and anti-diabetic effects. A study of the effects of this compound on hemodynamic and respiratory properties was carried out in an acute experiment in which 50 mg/Kg of the active ingredient was administered intragastrically to 6 paralyzed cats (urethane 1.0 g/Kg, chloralose 60 mg/Kg). I went. Respiration frequency, cardiac contraction frequency, systemic arterial blood pressure, magnitude of blood flow in the abdominal aorta, cerebral rheogram, and thigh muscle rheogram magnitude were simultaneously recorded in each cat. Test results showed that the active ingredient slightly lowers systemic arterial blood pressure. Other hemodynamic properties remained virtually unchanged. Breathing frequency is 21
% decreased (10 min, P less than 0.05) and 32% decreased (30 min, P less than 0.01). Arterial blood pressure and respiratory frequency and decrease values at 60 and 90 minutes after administration of this compound were not different from controls. The cardiological effects of the active ingredients were studied in experiments on isolated cat hearts, the effects on electrocardiographic properties were studied in experiments on rabbits, and the vasodilatory effects on isolated rabbit ear vessels. The antispasmodic effect was studied on acetylcholine and barium spasms in the smooth muscle of isolated parts of the small intestine of rats. Studies have shown that intravenous administration of the active ingredient to rabbits at a dose of 20 mg/Kg reduced cardiac contraction by 34% (P=
0.05) and 41% (P=
0.05) increases and dilutes the rabbit heart contraction rhythm by an average of 10-18% and peak P voltage by 32%
increased. Intragastric administration of the active ingredient at doses of 50 and 150 mg/Kg had no substantial effect on the rhythm of cardiac contractions and the length of the interval between cardiac cycles. A slight 20% increase in peak P voltage on average was observed. Therefore, this active ingredient does not have vasodilatory and antispasmodic effects;
Also, the slight cardiac stimulant effect of this active ingredient has no practical significance. The cardiac rhythmic effects of the active ingredient were studied in a rat aconitine model of arrhythmia by intravenous administration of 10 and 50 mg/Kg. Electrocardiogram analysis showed that the active ingredient at the doses studied had no cardiac rhythm effect. The neurotropic activity of the active ingredient is assessed by its influence on the hypnotic effects of hexenal or chloral hydrate. The substance is administered orally at 1, 10 and 100
It is introduced in an amount of mg/Kg. At these doses, the compound has no substantial effect on the length of sleep induced by chloral hydrate or hexenal. Rat caffeine with anti-ulcer effect as an active ingredient
A model of arsenic ulcer was studied. The substance is 1,
It was administered orally for 9 days at doses of 10 and 20 mg/Kg. This compound was found to give a weak anti-ulcer effect at a dose of 20 mg/Kg. The effect of the active ingredient on the intensity of bile secretion was studied in an acute study on cats. 20 and 50
At doses of mg/Kg, this compound did not increase bile secretion intensity. The effect of the active ingredient on the acute exudative and chronic proliferative phases of inflammation at doses of 10 and 50 mg/Kg was studied for oral administration to mice. According to research results, this compound has only a slight anti-inflammatory effect. Formalin 12.7 inhibited the spread of the exudative phase of inflammation at a dose of 50 mg/Kg.
(P less than 0.005) and Dextran 16.5 (P less than 0.05)
It has anti-inflammatory activity against edema and reduces cutaneous blood vessel invasion by 15% (P less than 0.05). For models of chronic proliferative inflammation, this compound somewhat inhibits the exudative phase and delays the formation of granulated-fibrous tissue during the proliferative phase of chronic inflammation. A study of the effect of the active ingredient on certain properties of blood coagulation was carried out on five rabbits. The compound was administered orally as a suspension in 2% starch paste at a dose of 50 mg/Kg. Blood tests were performed before administration and within 4 hours after a single dose of suspension. What was measured was plasma recalcification;
Trocybin time, elastogram properties and platelet concentration. According to the analysis of the results obtained, the active ingredient at the doses studied practically does not affect the blood coagulation process. To determine the active ingredients and anti-diabetic effects, the effects on glucose content in rabbits under nutritional carbohydrate loading conditions were studied. The active ingredient is passed through the tube as a 1% starch paste at 50% and 100%
It was administered orally at a dose of mg/Kg. The experimental procedure was as follows. The glucose content of the rabbit's blood during fasting was measured, and the glucose content in the blood was measured again 40 minutes later. Then add glucose to the rabbit 1.5
Administer at the rate of g/Kg to control the glucose content in the blood.
Measurements were taken after 15, 30, 45, 60, 90 and 120 minutes. The results obtained indicate that the active ingredient does not influence the characteristics of the changes in the glycemic curve under carbohydrate loading conditions at a dose of 50 mg/Kg. At a dose of 100 mg/Kg, glucose tolerance in rabbits is uncertainly 14%
It increased. Therefore, the results of the study of the pharmacological properties of the active ingredient showed no substantial activity in the above points. Studies on the acute toxicity and tolerability of the active ingredient and the pharmaceutical composition in tablet form were carried out in white mice, rats, guinea pigs and dogs using various dosage forms. Tablets of the active ingredient and pharmaceutical composition were administered in the form of an aqueous suspension by subcutaneous injection, intraperitoneal injection and into the stomach. For intraperitoneal administration of active ingredients and pharmaceutical compositions the LD ₅₀ is 3000-4000 mg/Kg, for subcutaneous administration more than 5000 mg/Kg and for intragastric administration.
It is 10000mg/Kg. The pharmaceutical composition according to the invention also shows good tolerability in the form of an ointment and has no irritating effect on the skin. That is, when a 10% ointment was applied to the skin of a white rat for 2 months, when a 1% ointment was applied to the mucous membrane of a rabbit's eye for 10 days, and when a 10% ointment was applied to the mucous membrane of a rabbit's eye for 10 days,
When applied to the vagina of white rats for 1.5 months, no decrease in the stimulating effect was observed in the applied area, and no changes in pathological morphology were observed. A study of the teratogenic activity of the active ingredient was carried out on 15 pairs of adult rats weighing 350 g divided into three groups of 5 capsules each. Females in the first group were administered 10 mg/Kg of the active ingredient orally daily for 30 days until rat pups were born. Females in the second group received 100 mg/Kg of active ingredient for the same period. Females in the third group are controls. The active ingredient was found to have no teratogenic properties. That is, the offspring of rats in the test group were born on time and were adequate in number and health status compared to the control group. Also, this active ingredient does not have mutagenic activity. Therefore, the active ingredients and pharmaceutical compositions based thereon have low toxicity. Dermatological, oral chemical and otolaryngological clinical studies have been carried out on pharmaceutical compositions in the form of ointments. The study was conducted on 981 patients. Ointments containing 1%, 2%, 5% and 10% active ingredient were used. Ointments were administered by rubbing or painting 1 to 3 times a day. Data from the clinical study is shown in Table 3 below.

[Table] In the case of treatment of herpes simplex, on the second day the edematous properties and strength of the sac decrease, on the third day a thin scab is formed in the center of the sac, the rash of new elements stops, and from 5 to Recovery was observed on the seventh day. A positive treatment effect was seen in children suffering from flat warts. Within 7-10 days the appearance of warts was completely removed. After removing the molluscum contagiosum rash, children were given a 2% ointment to prevent recurrence of the disease and complications from pyogenes infection, with positive effects. The therapeutic effects of ointment in cases of lichen planus were as follows. On the first day, the patient's itching phenomenon disappeared, followed by partial regression. No new rash was observed during treatment with ointment.
However, complete resolution of the papular rash was not observed. For this purpose, 15 mg of prednisolone was prescribed orally daily with the administration of an ointment, the dose was subsequently reduced, and after 21 to 25 days, the administration was discontinued, which allowed complete clinical recovery. Ta. In the case of psoriasis, neurodermatitis, common warts, and other diseases, the effects of the ointment form were not so obvious. Therefore, the greatest efficiency in dermatology was seen in various localized herpes simplex, lichen planus and flat warts. For stomatitis, the ointment form was applied 1 to 4 times daily for acute and chronic stomatitis, erythema multiforme, herpes, and other diseases. Efficiency of ointment forms containing 2% and 5% by weight of active ingredient was observed in the following cases. Cold sores on the lips - resolution of the process within 5-7 days (usually 10-7 days)
Acute aphthous stomatitis - epithelial formation of erosions was seen within 3 to 5 days (normal progression - within 7 to 14 days). In patients suffering from multiform exudative erythema and chronic recurrent aphthous stomatitis, the ointment form used showed less efficacy. In otolaryngology, the ointment form was used in cases of acute respiratory diseases, acute bullous otitis, exacerbations of vasomotor rhinitis with herpetic rash on the skin of the lips and nose, and acute otitis externa. High efficiency of the ointment form was observed in cases of acute respiratory system diseases. Use of the ointment halts virtually all disease progression within the first two days. In the case of herpetic eruptions and exanthematous otitis, administration in ointment form hastened the disappearance of the process by an average of 2-3 days, and early administration completely prevented the spread of the vesicular elements. In all cases of the above diseases, 2-5% by weight
A good medical effect is achieved with the use of ointments containing the active ingredients. Increasing the active ingredient by up to 10% does not improve the therapeutic effect.
By lowering the active ingredient to 1%, the therapeutic efficacy of such ointments is slightly reduced. The drug is administered as a 2% or 5% ointment, with an average dosage of 0.2 to 1.0 g per day, depending on the nature of the disease, 3 to 4 times a day.
Preferably, it is administered in multiple doses. Viral skin diseases can thus be treated by stretching and rubbing or applying a 2% to 5% ointment 1 to 3 times daily. The drug is deposited by stretching, smearing, or embolizing rods 1 to 3 times daily. For the treatment of rhinitis caused by a virus, apply 2 doses to the nasal mucosa 1 to 3 times daily.
It is better to apply % ointment. For the treatment of otitis of viral etiology, it is better to inject 2% ointment with a plug 1-3 times daily. 2-5% ointment once daily in case of viral diseases of the genitals and anus
It is best to treat by applying ~3 times. The therapeutic regimen is determined in each case depending on the type of disease and the individual tolerance of the drug (ie for a period of several days to three months). In cases of chronic, recurrent, or progressive disease, the above treatment regimen may be followed by repeated treatments. 10~ per patient per treatment course
It is best to use 50g of ointment. In this way, in the case of herpes simplex on the lips and wings of the nose, viral otitis, and rhinitis, use a 2% ointment during the treatment process.
10 g, 10-20 g of 2-5% ointment for viral stomatitis and genital herpes, and 20-50 g of 5% ointment for more extensive skin lesions, e.g. herpes zoster. It is sufficient. The pharmaceutical composition according to the invention expands the therapeutic opportunities of drugs with similar effects. It is also
Since it has no side effects, it can be used under both stationary and ambulatory conditions. No contraindications were found to the administration of the drug. The medicament according to the invention should be stored in a cool, dark place. Active ingredient 2-c-β-D-glucopyranosyl-
1,3,6,7-tetraoxyxanthone (mangiferin) is present in Hedysarum alpinum, Hedysarum flavescens sp.
It can be prepared from a medicinal herb called flavescenes sp.Fabaceae). The ground parts of medicinal herbs are mixed with 80% ethanol.
Extract for 4 hours at a temperature of 60-70°C. The volume ratio of vegetable matter to extractant is equal to 1:10. The extraction is carried out four times. Combine the extracts, evaporate, and add warm water (90%
~95℃) and the resulting mixture was heated for 12 to 14 hours.
Let stand at a temperature of ~10°C. The residue (accompanying product) is filtered off and the solution containing mangiferin is purified with chloroform. The purified solution is treated repeatedly with butanol saturated with water. The butanol extract is vacuum distilled, cooled for 14-16 hours at a temperature of 5-10 DEG C., the precipitate is filtered off and then recrystallized from a dioxane-water (1:1) mixture. The pharmaceutical composition of the present invention in ointment form has, for example, the following preferred composition. Composition Active ingredient (mangifuerin) 2 g Petrolatum oil 4 g Vaseline Added up to 100 g Composition Active ingredient (mangifuerin) 5 g Petrolatum oil 10 g Petrolatum added up to 100 g An ointment of the above composition can be prepared as follows. Mangiferin is broken down into a fine powder by thoroughly grinding it in a porcelain mortar. Add the required amount of petrolatum oil to the resulting powder and grind the whole mixture again. Vaseline is then added in portions with continuous stirring. A pharmaceutical composition in tablet form can have the following composition. Active ingredient (mangiferin) 0.1g Lactose 0.1g Starch 0.0425g Talc 0.005g Calcium stearate 0.0025g Total weight of tablet 0.25g A tabletted pharmaceutical composition having the above composition can be prepared as follows. Pre-sieve all ingredients of the tablet. Then mix together the mangifuerin, lactose and starch powder.
Stir the resulting mixture thoroughly and add 5% starch paste. The resulting mixture is then
Scrape through a 1.5-2 mm mesh sieve.
The obtained fruit grains are dried at room temperature for one day.
The resulting granules are pulverized with predried starch, talc, and calcium stearate, scraped through a sieve again, and then tableted.

Claims (1)

[Claims] 1. General formula 2-c-β-D-glucopyranosyl-1,3,6,7-tetraoxysanthone expressed as an active ingredient, which is combined with a pharmaceutical carrier, is used for viruses of the herpes group. A pharmaceutical composition for treating an infected disease. 2. Claim 1, wherein the pharmaceutical carrier for ointment use is made of petrolatum oil and petrolatum.
The pharmaceutical composition described in Section 1. 3. When the active ingredient is combined with the pharmaceutical carrier for the ointment, the pharmaceutical composition contains 2-5% by weight of the active ingredient, 4-5% by weight of the active ingredient;
Pharmaceutical composition according to claim 1 or 2, containing 10% by weight of petrolatum oil and 85-96% by weight of petrolatum. 4. The pharmaceutical composition according to claim 1, wherein lactose, starch, talc, and calcium stearate are used as pharmaceutical carriers for tablets. 5. When the active ingredient is combined with a pharmaceutical carrier for tablets, the drug contains 40% by weight of active ingredient, 40% by weight of lactose, 17% by weight of starch, 2% by weight of talc and 1% by weight of calcium stearate. ,
A pharmaceutical composition according to claim 1 or 4.