A method of obtaining a solution of dopamine for parenteral introduction
(57) Abstract:The method can be used in medicine, namely in pharmacology, for reconstitution for parenteral administration. Dopamine and sodium pyrosulfite is dissolved in water for injection at a temperature of 25-30oWith, bring the pH to 3.5-4 using 0.1 M hydrochloric acid, treated with bleaching with activated carbon, filtered through a membrane filter having a pore size of 0.2 μm under pressure of 0.8 kgf/cm2with the subsequent packing and sterilization of the solution at 100oC for 30 minutes Method allows to obtain stable during long-term storage solution, developing a minimum of side effects. The invention relates to the field of pharmaceutical industry and relates to a method of obtaining a solution of dopamine for parenteral injection.Dopamine (dopamine, intropin) - 2-(3,4-dioksifenil)-ethylamine, or oksitiramin. According to the chemical structure of dopamine is a catecholamine and has a number of pharmacological properties characteristic of adrenergic substances. He has specific effects on dopamine receptors, which is an endogenous ligand, but in large doses to expect norepinephrine from granular (presynaptic) depot, i.e., to provide indirect adrenomimeticescoe action. Under the influence of dopamine is an increase in peripheral vascular resistance (less severe than under the influence of noradrenaline) and systolic blood pressure (the result of stimulation of-adrenergic receptors), intensify heart contractions (the result of stimulation of-adrenergic receptors), increased cardiac output. Heart rate varies relatively little. The requirement of a myocardium for oxygen increases, but the increase in coronary blood flow is increased oxygen delivery. In the specific binding with dofaminovmi receptors renal dopamine reduces renal vascular resistance, increases in renal blood flow and filtration. Along with this increased natriuresis, is the expansion of the mesenteric vessels. This action on the renal and mesenteric vessels dopamine differs from other catecholamines (noradrenaline, adrenaline and others ). However, at doses greater than 15 mcg/kg per minute, dopamine can cause narrowing of the renal vessels. Dopamine inhibits the synthesis of aldosterone. Indications for use of dopamine are shock according to the ligature with a smaller effect on peripheral vascular resistance, the increase in renal blood flow and blood flow in other organs, less chronotropic effect and other features of the dopamine consider in these cases, more shows than norepinephrine and other catecholamines. Dopamine is also used to improve hemodynamics in acute cardiac and vascular disease, which develops in various pathological conditions.When introduced into the stomach dopamine poorly absorbed, its pharmacological effects when administered intravenously. Due to the fact that dopamine is rapidly degraded, the main way to use a slow drip infusion.Dopamine is administered intravenously; the initial speed is 1-5 mcg/kg per minute (2-11 drops of 0.05% solution). If necessary, a speed of up to 10 - 25 mg/kg per minute (average of 18 µg/kg per minute). Infusion produces a continuous period of 2-3 h to 1-4 days. Daily dose is 400-800 mg of the drug is quick and ends after 5-10 min after injection. The optimal dose must in each case be selected for continuous hemodynamic and ECG. Preparation before the introduction usually bred coenye funds. M.: Russian book, S. 169).As already noted, the dopamine belongs to the unstable drugs, which decays rapidly.It is known that the stability of drugs is influenced by various factors: the physical state of the substance, method of preparation, including selection of auxiliary substances, storage temperature, ambient atmosphere, light package.Of great importance in the development of new ways to obtain drugs in the form of solutions given to stability, and in the case of injection solutions, including stability during sterilization. Currently known two methods of stabilization - physical and chemical. The main importance is given to the selection of excipients, such as antioxidants, buferiruemoi or other agents that create a specific pH.A method of obtaining parenteral solutions of dopamine using 5% dextrose or its mixture with sodium chloride solution, or ringer's solution as a stabilizer (the Medline Database, Gardella L. A., Intropin (dopamine hydrochloride) intravenous admixture compatibility, Am.J. Hosp.Pharm., 1975; 32(6), 575-8).However, the solutions obtained by this method will have extemporal the thief of dopamine with the addition of one or several compounds of the type Proline, serine and acid-basic character (WO 84/01501, 26.04.1984).The drug may cause some side effects.The closest solution that can be specified as analogue, is a method of obtaining a solution of dopamine by dissolving in a solution containing glycerol, sodium bisulfate, bringing the pH with sodium hydroxide or hydrochloric acid to 3.5, dilution, packaging 300 ml and sterilized in the autoclave at a temperature of 1210o24 min with subsequent cooling (patent WO 85/03202 A2, 01.08.1985). The resulting preparation can be stored for 2 years.However, for infusion solutions are, as a rule, special requirements apirogennost, which, in this case, may be insufficient.The present invention is stable during prolonged storage of the solution, exhibiting a minimum of side effects.The problem is solved by a method of obtaining a solution of dopamine for parenteral introduction, which consists in the dissolution of dopamine or its hydrochloride and sodium pyrosulfite in water at 25-30oWith the addition of 0.1 M hydrochloric acid to pH 3.5-4, the processing of the obtained solution is not more than 0.8 kgf/cm2, packaging and additional sterilization at 100oC for 30 minutesSodium pyrosulfite, incorporated has antioxidant and antimicrobial effects, providing stability during storage. The specified pH is optimal for stabilization during sterilization. The use of alkaline solutions for adjustment of pH is very undesirable, because the stability is reduced. The stated modes of cleaning and sterilization allow you to get almost pyrogen-free solution and also help to increase the shelf.In the analysed level of technology not identified sources that describe the set of distinctive features, and the proposed solution is not obvious to a person skilled thus, it meets the criteria of the invention of "novelty" and "inventive step". The present invention can be used in the chemical-pharmaceutical industry, thus, it meets the criterion of "industrial applicability".Below are specific examples of carrying out the invention.Example 1.In svejeprokipachena cooled to a temperature of 25-30oWith water for injectability acid. The prepared solution is treated with bleaching with activated charcoal and pass on the thin filter. The filtering carried out on the installation with a membrane filter with a pore size of 0.2 μm under pressure of 0.8 kgf/cm2. The filtered solution is fed to the filling in capsules. Then the drug ampoules are sterilized at 100oC for 30 minutesExample 2.Carried out as in example 1, but take dopamine hydrochloride - 40 g/l, sodium pyrosulfite, 5 g/l, pH = 4.Get clean, almost pyrogen-free solutions with a lifespan of 3 years. The proposed method can be recommended for use in the pharmaceutical industry. A method of obtaining a solution of dopamine for parenteral introduction, characterized by the fact that dopamine and sodium pyrosulfite is dissolved in water for injection at a temperature of 25-30oWith, bring the solution pH to 3.5-4 using 0.1 M hydrochloric acid, treated with bleaching with activated carbon, filtered through a membrane filter having a pore size of 0.2 μm under pressure of 0.8 kgf/cm2with the subsequent packing and sterilization of the solution at 100oC for 30 minutes
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes compound of the formula (I):
as a free form or salt wherein Ar means group of the formula (II):
wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
13 cl, 3 tbl, 35 ex