Drug for the treatment of atherosclerosis and its complications

 

(57) Abstract:

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-(D-glyukopiranozil)ammonium-2(acridin-9-one-10-yl)acetate]cycloferon, and can be used for the treatment of atherosclerosis and its complications. The objective of the invention is the provision of quality and effective low-toxicity universal tool for the treatment of atherosclerosis and its complications. The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substances included the compound N-methyl-N-(a, D-glyukopiranozil)ammonium-2-(acridin-9-one-10-yl)acetate, and the solvent is water in the following ratio, wt.%: active substance 18,0-22,5; water - the rest. 3 table.

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-(D-glyukopiranozil)ammonium-2(acridin-9-one-10-yl)acetate] cycloferon (application trademark N 93006831/50 from 24.03.93), and can be used for the treatment of atherosclerosis and its complications.

Known parenteral form of the medicinal product based on the chemical analogue of cycloferon salmenniemi composition:

as active substances substituted acridine sodium salt of 10-carboxymethyl-8-acridine structural formula

< / BR>
surfactant;

sodium hydroxide;

water is the solvent.

The tool was not used for the treatment of atherosclerosis.

Known means at the specified prototype has the following disadvantages:

expressed irritating and painful action, due to the high pH value (9,0);

the risk of necrosis and gemokoagulyatsii;

insufficient concentration of the active substance (50 mg/ml 5%), which requires an increase in the volume of injectate for the manifestation of therapeutic effect (up to 10 ml or more).

In order to reduce pain effect with the drug we were trying stabilization specified in the prototype dosage forms allowed in the Pharmacopoeia by means of, for example, buffer solutions and complexing agents. During the experiment, we tried to reduce the pH of the dosage form below to 8.0, but this did not lead to any positive result. At pH below 8.0 a gradual precipitation of acridan-acetic acid, which testifies to the impossibility of creating a qualitatively is documentatie means, eliminating or reducing risk factors, and medications, such as various hypolipidemic (cholestyramine, polysporin, linecol, heparin, chondroitin sulfate, etc.) (Mashkovsky M. D. Medicines, including 1 and 2. M. Medicine, 1987, T. 2, S. 89, 92, 73, 156).

None of the existing lipid is not universal, and almost all have side effects. The search for new anti-sclerotic funds are among the various classes of chemical compounds:

derivatives of urea and thiourea (U.S. patent N 4397868, 4387105, 4623662);

derivatives of aminobenzoic acid (EPO application 0170361, CBL. application Japan 59-24135, 63-26729);

benzothiazine (EPO, 0174458);

derivatives of indole (UK application N 2190587);

derivatives hexahydronaphthalen (U.S. patent N 4444784).

The most common medication used for the treatment of atherosclerosis, is clofibrate (mickleton, lipomed, atromid) isobutyrate (Mashkovsky M. D. Medicines, including 1 and 2. M. Medicine 1987, H. 2, S. 90) prototype treatment. It reduces blood levels of lipoproteins that are rich in cholesterol and triglycerides. It is used for atherosclerosis with increased blood levels of these substances., syvaet some side effects. It can cause intrahepatic cholestasis, accompanied by the formation of stones in the gall bladder and biliary tract.

The task of the invention is the provision of quality and effective low-toxicity universal tool for the treatment of atherosclerosis and its complications.

The problem is solved in that the medicinal product containing the active substance and the solvent, as the active substances included the compound N-methyl-N - (D-glyukopiranozil)ammonium-2-(acridin-9-one-10-yl)acetate formula

,

and as a solvent water in the following ratio, wt. active substance 18,0-22,5; water the rest.

Currently, medical-biological tests have proved that the effective daily therapeutic dose of cycloferon is 360-450 mg per person in a single dose. In accordance with the proposed therapeutic dose of the applicant has been a lot of work to create effective and high-quality pharmaceutical form. The development of the dosage form was carried out for vials with a volume of 1.2 and 5 ml applied to obtain a standard dosage forms.

To receive parenteral Lek who ranks number allowed in the Pharmacopoeia of the N-methylglucamine.

Dosage form obtained according to the method described below.

The results of the studies are given in table. 1.

From table. 1 shows that when using N-methylglucamine less of 96.5 g dosage form is not stable: formed turbidity or precipitation during storage. When using N-methylglucamine more of 96.5 g of the solution has a pH above 9.0 and has a strong local irritant effect. Thus, the optimal ratio of components is of 96.5 g of N-methylglucamine 125 g greenexpo acid in aqueous solution.

Taking into account the optimal ratio of components of the dosage form, the optimal therapeutic daily dose of 360-450 mg per person, single administration, as well as manufactured standard vials (1, 2 and 5 ml) was obtained the optimal concentration of active substance in the dosage form - 18,0-22.5 wt.

The results of the studies are given in table. 2.

As follows from the table. 2, when use vials with a volume of 5 ml with a concentration of active substance of 7.2-9.0% of the volume of solution is too large for a single injection. When using vials in 1 ml with a concentration of active substance 45,0% dosage form is not techno table. 3 shows the comparative characteristics of qualitative indicators of the claimed dosage forms and prototype structural entity.

As follows from the table. 3, the claimed medicinal product has the following advantages:

the complete absence of irritating and painful steps in injecting drug due to close to physiological pH (blood pH 7,3);

in 5-20 times higher concentration of the active substance in solution, allowing to obtain a pronounced therapeutic effect with minimal amounts of administered drug;

the absence of biogenic particles (chelating agents, components, buffer);

upon receipt of the dosage form does not require special equipment for sealing ampoules under inert gas.

A formulation was prepared as follows. In chemical beaker with a capacity of 2 litres pour 1 liter of water for injection, load 193 g N methylglucamine, stir until dissolved and add 250 g greenexpo acid and again stirred until dissolution. Control of pH potentiometric, bring the solution volume to 2 l with water for injection, filtered through Millipore and poured into ampoules and vials. The ampoule is carlavirus.

As a result of biomedical research has been proved to be highly effective drugs in the treatment of atherosclerosis and its complications.

Example 1. Patient B. 54 years, locksmith, was admitted to the Department 2.08.91, with complaints about squeezing pain in the heart and behind the sternum, in the left hand, periodic bouts of increased frequency of breathing with episodes of transient loss of consciousness. Delivered by ambulance after 6 hours from the onset of the disease. A serious condition. The pulse rate of 108 beats in 1 min, arrhythmic. AD - 130/100, BH 18 minutes ECG acute phase of focal lesions in the posterior wall of the left ventricle. Ventricular extrasystoles. AV block II degree (2: 1). D-C: IHD. Acute transmural myocardial infarction posterior wall of the left ventricle from 01.08.91, Ventricular extrasystoles. Introduced fibrinolitiki, lidocaine.

At 9 o'clock 2.08 started a course of treatment of the claimed medicinal preparation. Just made 3 injections of the drug (2, 4, 6.08.91,) intramuscularly with 2 ml of 22.5% solution.

The condition and the patient's health improved immediately after injection and remained satisfactory during the whole observation time, rhythm and conductivity normalizada is 156 g/l and erythrocyte from 4.5 to 5,21012l, and white blood cells (lymphocytes increased in 4 times), the repeated clinical, biochemical and instrumental investigations (ECG, EchoCG) showed a clear positive trend (in particular, 10.08 have no data for the transmural nature of the lesion of the myocardium). Discharged 1.09 in satisfactory condition.

Thus, this example demonstrates the positive effect of the drug in complicated transmural myocardial infarction caused by severe atherosclerosis of the coronary arteries in a patient with middle age.

Example 2. Patient F. 70 years, was admitted to the Department 7.08.91 with complaints of pain in the heart area and pressing nature, interruption of cardiac activity, shortness of breath, weakness. Delivered by ambulance. A serious condition. Pale skin, cyanosis of the lips. The apical thrust is spilled, heart expanded to the left, rough systolic murmur at all points. I tone weakened, the accent of II tone on the pulmonary artery. Congestive rales in the lungs. Liver +2,5 see ECG deterioration of coronary circulation in the area of the scar, the rise of T2-U5.

D-C: IHD. Re myocardial infarction from 07.08. The paroxysm of atrial fibrillation.

Amid the usual treatment of conduct).

In the treatment of arrhythmia stopped and never resumed, the health and condition has improved significantly. Positive changes from red and white blood cells, similar to that shown in example 1, ECG normalization of the ST segment on the 2nd day after receipt, the positive dynamics of clinical, ECG, echocardiography and biochemical parameters. Discharged 6.09 in satisfactory condition. This example demonstrates the positive effect of the drug on the course of recurrent myocardial infarction in a patient of advanced age caused by atherosclerosis of the coronary vessels.

Example 3. Patient S. 70 years, was admitted to the Department 12.08.91 with complaints dramatically increased shortness of breath, arrhythmia. A serious condition. Swelling in the legs, ascites, and right-sided hydrothorax. ECG from 12.08. atrial fibrillation. The modified form of the ventricular complex in left chest leads. Amid the usual treatment is a course of injections of the drug 13, 15 and 17.08.91, similar to those described in examples 1 and 2.

D-C: IHD. Acute re-myocardial infarction from 12.08. Postinfarction cardiosclerosis. Atrial fibrillation tachysystolic form NC II B III Art.

On treatment immediately stopped shortness of breath, became gradually the part to go. Positive developments in instrumental (ECG, echocardiography, clinical and biochemical studies (in particular, from the red and white blood cells) is similar to the above.

This example demonstrates the positive effect of the drug in the patient with severe heart failure on the background of recurrent myocardial infarction caused by atherosclerosis.

This drug belongs to a new class of drugs that have immunomodulatory effects and showed a definite positive effect in the treatment of atherosclerosis and its complications such as myocardial infarction.

Drug for the treatment of atherosclerosis and its complications, containing the active substance and a solvent, characterized in that the active substance it contains the compound N-methyl-N (D-glyukopiranozil)ammonium-2-(acridin-9-one-10-yl)acetate formula

< / BR>
and as a solvent water in the following ratio, wt.

Active substance 18,0 -22,5

Water Ostalnoe

 

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