A method of obtaining a bronchodilator drug composition of the prolonged action on the basis of theophylline
(57) Abstract:The invention relates to medicine, in particular to the pharmacy. The purpose of the invention is the increase in the duration of maintaining an effective concentration of a drug in the blood. This objective is achieved in that the original mix theophylline with interpolymer complexes (IPC) polymethacrylic acid and polyethylene glycol, the mixture is then moistened with a solution of FDI in phosphate buffer, alcohol or in an aqueous-alkaline solution of pH 4.5 and 7.5, the resulting mass is subjected to wet granulation, then dried and conduct follow-on operations for the manufacture of finished dosage forms. Alternatively, the tablets can be obtained by the method of briquetting. Tablet cover film-forming solution based on the same IPC. The product obtained by the proposed method, is effective in a dose of 450 - 600 mg/day, maintains therapeutic concentrations of theophylline in plasma with 2 - fold admission, the mean absorption time 12 noon, 2 C.p. f-crystals, 3 tables. The invention relates to medicine, more specifically to a method for producing tablets of theophylline prolonged action, which are used in medicine as a bronchodilator in all FEMA and others.Currently, a large variety of bronchodilator drug compositions prolonged action on the basis of theophylline containing various polymeric carriers of natural and synthetic origin, obtained by different technological methods: microencapsulation, microgranuloma, pressed into pellets and others. It is known drugs manufactured by the leading companies of different countries, such as Quibron", "Slophillin", "Teostat", "Bronchoretard". "Teo-24". "Teo-Dur".A method of obtaining a bronchodilator drug composition with a prolonged action, containing encapsulated theophylline, polyvinylpyrrolidone, sugar, ethylcellulose. Medication in pill form is obtained by applying the solution of theophylline with polyvinylpyrrolidone on sugar granules with a diameter of 0.71-0.84 mm, with subsequent evaporation of the solvent. Received theophileescargot granules coated with ethyl cellulose solution in ethyl alcohol. The granules are mixed with the lactose and tabletirujut, as a lipid coating applied gidrirovannoe vegetable oil. By changing the ratio of polyvinylpyrrolidone and cellulose, achieve different dissolution rate. Patients the past 12 o'clock The specified drug is characterized by a large mass used auxiliary substances and complexity of the technological process of its receipt.Also known is a method of obtaining pharmaceutical compositions on the basis of theophylline following composition (tablets), mg: Theophylline monohydrate 330
Oxypropylated - allysa (100 SP) 92
Oxypropylated - cellulose (15000 SP) 25 Lactose 80 magnesium Stearate 5 the silicon Dioxide 3
This method consists in mixing the source of the ingredients, followed by pelletizing, and the composition is characterized by complexity and the large number of auxiliary substances.A method of obtaining pharmaceutical compositions on the basis of theophylline, of the following composition (tablets), mg: Theophylline 300
Disubstituted calcium phosphate 300
Acetylphenyl - cellulose 30 Ethylcellulose 30 Stearate 4,6
This method consists in mixing theophylline disubstituted with calcium phosphate. The resulting mixture is moistened with a solution of acetylcellulose and ethyl cellulose in a mixture of organic solvents (50 ml of isopropyl alcohol and 150 ml of methylene chloride) and get a granulate which is dried, optivault (stearate) and the table is cherished the complexity and high content of auxiliary substances (55% by weight of the tablet). In addition, the method of obtaining this song toxic, flammable and explosive organic solvents complicates the process requires additional equipment.Closest to the proposed to the technical essence and the achieved effect are the tablets of theophylline prolonged action on the basis of polyvinyl chloride and the way they are received. Tablets consist of a polymer matrix, allowing a controlled release of single therapeutic doses of theophylline for about 8 hours Tablets contain a therapeutically effective amount, about 100-1000 mg of anhydrous theophylline, 5-15 wt. polyvinyl chloride (PVC), counting on a lot of tablets, and 0-2 wt. hydrophobic moving.The method consists in the wet granulation of theophylline with a solvent containing ethanol, drying the granules at 110aboutC for 20-30 min, Blagoi granulation PVC with solvent containing ethyl alcohol and methylene chloride in an equal volume ratio, drying the granules PVC at temperatures below 90aboutWith the mixing of theophylline granules and PVC, optional addition of moving, such as stearate, again requiring protect personnel from harmful fumes, and equipment fire and explosion measures.The aim of the invention is to remedy these disadvantages.This goal is achieved by using a method of receiving bronchodilators composition of prolonged action, including a mixture of theophylline with the polymer matrix, the introduction of a moisturizing agent, granulation, drying the mixture and then get the dosage form, characterized in that the polymer matrix used interpolymer complex polymethacrylic acid and polyethylene glycol, wetting agent is water or 5-15 wt. the solution of interpolymer complex pH 4.5 and 7.5 in aqueous-alkaline solution, phosphate buffer or ethanol.It was found that if the wetting agent to use a solution of interpolymer complex in phosphate buffer, in aqueous-alkaline medium or in ethanol, improving such technological parameters of granules as bulk density and flowability, and also improves the quality of the finished tablets. This goal, as it turns out, can be accomplished by using another variant of the method, which is that mixed in a dry state theophylline out grinding, optivault obtained granules with magnesium stearate or calcium and tabletirujut.In both cases, to mask the bitter taste of the dosage form in the form of tablets and increase the duration of action of the drug in the body can be applied to these forms of protective polymeric membranes from solutions 5-15 wt. the same interpolymer complex, 0-4,5 wt. caustic soda or sodium bicarbonate, 1-5 wt. Tween-80 with the addition of 0-2 wt. diocese titanium in distilled water or ethyl alcohol.In table. 1 shows the technological characteristics of the granules obtained in the first embodiment of the proposed method, which prove the efficiency of the solutions of the CPN as a moisturizing agent. Indicators release of theophylline are shown in table. 2.The inventive method allows for simplified technology to obtain the target product of high quality. The method is simple to implement, does not require special equipment. Get a bronchodilator drug composition has pharmacological properties typical of theophylline. Bronchodilatory effect of the proposed drug develops slowly over 3-6 h after administration. Theophylline desire in the blood within 12-24 hours Persistent clinical effect is achieved after a few days of treatment.Studies of chronic toxicity of the composition prepared by the proposed method, carried out in experiments on dogs have shown that the drug with the introduction of an oral dose of 100 mg/kg for 6 months. does not cause any changes on the part of animal behavior, weight gain, peripheral blood, as well as indicators of the morbid morphological studies of organs and tissues in experimental dogs.In the clinic, the drug is tested in comparison with a known drug Teodor. Special attention was paid to pharmacokinetic studies. Using strictly selected according to age, weight, severity of the disease group of patients, determined the concentration of theophylline in blood by high performance liquid chromatography after 1, 2, 6, 9, 12, and 24 h after administration of a dose of 300 mg of the compound prepared by the present method, and also collected urine at intervals 0-6, 6-12 and 12-24 hoursThe results of calculations of pharmacokinetic parameters are presented in table. 3.Slow absorption of theophylline from prolonged forms is clearly seen when comparing independent of the parameter "average time of suction". For drugs the niche 8,2 h, for conventional tablets of theophylline this parameter is only 1.4 hours, a Similar ratio is obtained by comparing the time of the suction 75% dose. The result is full, but slow suction, there is a significant increase in the duration of circulation of theophylline when receiving prolonged forms. Integral parameter that characterizes the "average lifetime" medicinal substance in the body for compositions prepared by the present method, is equal to an average of 21 hours for tablets Teodora 16,8 PMAt clinical examination in 95% of patients already on day 4-5 reception compositions noted improvement in overall health, decreased quantity and intensity of asthma attacks during the day, there was an increase of physical activity, lower intensity, and loss of nocturnal asthma attacks.In the long-term clinical study of the composition revealed that the drug has a high efficiency at a dose of 450-600 mg/day, is capable of maintaining therapeutic concentrations of theophylline in plasma with 2-fold receiving long-term control of bronchial patency and reduce the need for in other groups of drugs used in T with improvement of the clinical status of patients that is reflected in increased physical activity, reduction in the frequency and intensity of asthma attacks, the disappearance of night attacks of dyspnea, and decrease the needs of patients in inhalation sympathomimetics and systemic corticosteroids.P R I m e R 1. In the mixer load 3.0 kg of theophylline and 1.0 kg of interpolymer complex mix. To the mixture was added 500 ml of 10% aqueous solution of interpolymer complex in phosphate buffer pH 7.5, with stirring. This is followed by wet granulation and drying the granulated mixture at a temperature of 50-60aboutC to a residual moisture content of the granules 1-2% Yield is 97 wt. Dried granulated mixture optivault the calcium stearate and tabletirujut.P R I m m e R 2. The process is carried out analogously to example 1, using as a moisturizing agent 5% solution of interpolymer complex 1.5% aqueous solution of sodium bicarbonate, the pH of the resulting solution of the complex is equal to 4.5. Dried granulated mixture optivault the calcium stearate and tabletirujut.P R I m e R 3. The process is carried out analogously to example 1, using as a moisturizing agent 15% solution of interpolymer complexness polymethacrylic acid and polyethylene glycol, mix. The resulting mixture bitteroot followed by granulation grinding, receiving granules in the size range of 0.05-1.5 mm Granulated mixture optivault the calcium stearate and tabletirujut. Get tablets containing of 0.1; 0.2; 0.3 g each of theophylline.P R I m e R 5. In the mixer load 3.0 kg of granulate of theophylline and 0.98 kg interpolymer complex polymethacrylic acid and polyethylene glycol, mix. The resulting mixture bitteroot followed by granulation grinding, receiving granules in the size range of 0.05-1.5 mm Granulated mixture optivault the calcium stearate and tabletirujut. Get tablets containing of 0.1; 0.2; 0.3 g each of theophylline.P R I m e R 6. In the mixer load 3.0 kg of theophylline and 1.0 kg of interpolymer complex mix. To the mixture was added 500 ml of 10% aqueous solution of interpolymer complex pH 7.5 in the sodium hydroxide solution with stirring. This is followed by wet granulation and drying the granulated mixture at a temperature of 50-60aboutC to a residual moisture content of the granules 1-2% Yield is 97 wt. Dried granulated mixture optivault the calcium stearate and tabletirujut. The obtained tablet cover film-forming solution, after which To 1 liter
500 g of tablets are loaded into the hopper installation for coating in the fluidized bed. The coating is carried out at a temperature of the air flow at the entrance 40-50aboutWith, the exhaust temperature 20-30aboutWith the flow of the film-forming coating 10-20 ml/min or coated tablets is performed with the use of film-forming solution of the following composition, g/l:
Specified interpoly - dimensional complex 100 tween-80 20 Ethyl alcohol To 1 l 1. A method of OBTAINING a BRONCHODILATOR DRUG COMPOSITION of the PROLONGED ACTION ON the BASIS of THEOPHYLLINE, including the mixing of theophylline with polymer matrix, moisturizing, granulation, drying, pelleting, characterized in that the polymer matrix used interpolymer complex (IPC) polymethacrylic acid and polyethylene glycol, and hydration are 5 to 15% solution of the same IPC with a pH of 4.5 to 7.5 in phosphate buffer or in an aqueous-alkaline solution, or in ethanol.2. A method of obtaining a bronchodilator drug composition of the prolonged action on the basis of theophylline, including the mixing of theophylline with polymer matrix, granulation and tableting, characterized in that the polymer matrix ptx2">3. The method according to PP. 1 and 2, characterized in that the tablets are covered with film forming solution on the basis of the specified IPC.
Known medicinal composition of antimicrobial action, contains similar in structure with the connection 1 substance: 1-(-oxyethyl)-2-methyl-5-nitroimidazol formula:
O2N(A) called metronidazole (2)
SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.
EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.
5 cl, 9 ex
FIELD: organic chemistry, heterocyclic compounds, biochemistry.
SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.
EFFECT: valuable biochemical properties of compounds.
11 cl, 4 tbl, 221 ex
FIELD: organic chemistry, biochemistry, biology.
SUBSTANCE: invention relates to a pharmaceutical composition eliciting the inhibitory effect on activity of serine protease (caspase-3) in the form of tablet, capsule or injections placed into acceptable package, to a method for its preparing and a method for treatment of diseases associated with enhanced activation of apoptosis. The composition comprises compound 2,3-dihydro-1H-benzo[g]pteridine-4-one of the general formula (1) (1)
or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.
EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.
7 cl, 1 dwg, 2 tbl, 5 ex
SUBSTANCE: the present innovation deals with antiviral preparations that contain aliphatic alcohol C21-C28 in combination with either nucleoside or nucleotide analog or phosphoformic acid in pharmaceutically acceptable carrier. It is necessary to mention that n-docosanol is considered to be a preferable aliphatic alcohol. Concentration of aliphatic alcohol C21-C28 corresponds to 0.05% to 40% by weight. Concentration of either nucleoside or nucleotide analog or phosphoformic acid corresponds to 0.1% to 10% by weight. The innovation, also, deals with the ways to treat viral infections due to applying such compositions. Aliphatic alcohols C21-C28 synergistically intensify antiviral activity of nucleoside analogs directed against replication of several herpetic viruses and that of cow's pox.
EFFECT: higher efficiency of inhibition.
28 cl, 13 dwg, 21 ex, 6 tbl
FIELD: veterinary science.
SUBSTANCE: about 20-25 d before calving one should introduce intramuscularly 0.5%-sodium selenite solution for cows at the dosage of 10 ml. Twice before and twice after calving at 10-d-long interval - tetravit at the dosage of 10 ml at the content of 50000 IU vitamin A, 25000 IU vitamin D, 20 mg vitamin E and 5 mg vitamin F per 1 ml. Succinic acid should be introduced 20-25 d both before and after calving at the dosage of 1.0 g. The method provides efficient correction of the main values of homeostasis in cows after calving.
EFFECT: higher efficiency of normalization.
2 ex, 4 tbl
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:
wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.
EFFECT: improved preparing method and treatment, valuable properties of compounds.
20 cl, 5 tbl, 149 ex
FIELD: veterinary science.
SUBSTANCE: one should introduce endovit complex preparation once daily for dogs. Moreover, during the first 5 d endovit should be introduced at the dosage of 30 mg/kg, during the next 10 d - 25 mg/kg and during the last 5 d 20 mg/kg body weight. The suggested innovation provides normalization of myocardial trophic nature, interrupts dystrophic processes in it, improves functional state of cardiac conductory system and, thus, provides the chance to treat both the main and secondary disease by the mentioned scheme without applying any additional cardiological remedies.
EFFECT: higher efficiency of therapy.
FIELD: obstetrics and gynecology.
SUBSTANCE: over a 2-5 day period, 2.0 ml of Ginipral is administered once a day intravenously in a drop-by-drop manner followed by intravenously drop-by-drop administered 30-40 min later 2.0 ml of Instenone and, in the evening, 1 dragee Instenone orally. Afterwards, Instenone and Ginipral are administered orally: the former in dose of 1 dragee thrice a day with meal and the latter in dose of 1 pellet four times a day after meal until symptoms of the risk of prevention of pregnancy disappear.
EFFECT: prolonged pregnancy and prevented premature birth, which favors reduced irritation, normalized tonus, contractive activity of uterus, and improved psychic and emotional state of women.