CZ281348B6 - Therapeutical preparations exhibiting reversible anti-cholinesterase activity - Google Patents

Abstract

This therapeutic preparation consists of pharmaceutical auxiliary substances, which are mainly disintegrants, fillers and sliding substances for producing tablets, and mainly water, isotonizing agents and antifreeze agents for producing injections, and these auxiliary substances are mixed with the active component consisting of a salt of 9-amino-7-methoxy-1, 2, 3, 4-tetrahydroacridine of the general formula, where X<-> is an anion, mainly Cl<->, Br<->, I<->, SO4<2->, NO3<->, lactate, acetate, citrate, tartrate. The effective dose of the active substance is from 0.1 to 2 mg.kg<-1> and the content of the active substance in relation to pharmaceutical auxiliary substances is 0.25 to 90% by weight.

Description

The invention relates to a medicament useful in the field of internal medicine, surgery, anesthesia, psychiatry and veterinary medicine. In particular, the medicament is intended for the treatment of intoxications caused by disabling poisoning agents such as anticholergic hallucinogens, for the elimination of side effects of treatment or poisoning by anticholinergics, tricyclic atidepressants, benzodiazepines, barbiturates, antipakinsonics, antihistamines and neuroleptics. It is also intended to increase the duration of succinylcholine-induced myorelaxation and reduce its dosage, to reduce unwanted manifestations after general anesthesia and to shorten the time to wake from anesthesia, to stimulate the respiratory center during intoxication with respiratory depressants, to enhance the analgesic effect of morphine gravis pseudoparalytica, for the treatment of paraphytic ileus, for the treatment of symptoms in tardive dyskinesias and for the treatment of Alzheimer's type dementia.

Up to now, physostigmine has been used in the vast majority of physiostigmine, in some indications pyridostigmine, neostigmine, synthostigmine and in some literature, for the treatment of side-effects and symptoms of poisoning induced by anticholinergic agents, myasthenia gravis, glaucoma, alcohol poisoning and dementia. uses tacrine. Disadvantages of these substances and especially of physostigmine are their relatively high toxicity (maximum single dose according to CSL 3 = 1 mg), small therapeutic index, short duration of action, low stability in aqueous solutions and a number of undesirable symptoms in overdose (salivation, miosis, pulse rate decrease) , increase in blood pressure, feelings of vomiting to vomiting, muscle twitching).

These drawbacks are overcome by the medicament according to the invention, which consists of pharmaceutical auxiliaries such as disintegrating agents, fillers and glidants for the manufacture of tablets or water, isotonizing agents, antifreeze agents for the production of injections and an active ingredient consisting of a salt 9-amino-7-methsy-1,2,3,4-tetrahydrosridine

wherein x ^- represents anion I ", CL, Br, SO ² " ₄ , NO ₃ , lactate, citrate, tartrate, acetate at an effective single dose of 0.1 mg to 2 mg.kg ^-1 , wherein the content of active ingredient relative to the excipients are from 0.25 to 90% by weight.

The advantages of the newly resolved medical device are lower toxicity of the active ingredient used, long-term effect and advantage of the therapeutic efficacy index. Another advantage is that dosing of 0.1 to 0.3 mg.kg im ^_1 respectively 0.5 - 1 mg.kg ^-1 after, the minimum incidence of side effects. In addition, the incidence of side-by-side administration of atropine by im or a potentiating effect induces an increase in peristalsis inotropic and negative and potentiates the symptoms can be eliminated at doses of 1-3 mg. Therapeutic cholinomimetics such as acetylcholine, smooth intestinal muscle, has a positive chronotropic effect on the heart muscle and potentiates the size of the diaphragm contractions. The medicament according to the invention induces reversible inhibition of cholinesterases (both adetylcholinesterase and butyrylcholinesterase) in the central and peripheral nervous system, blood and a number of body tissues. Tests for mutagenic concerogenic effects and fertility have shown that the substance is harmless even when administered chronically. The results of subacute (one-week) and chronic (three-month) administration of the substance over a wide dose range (0.5 to 50 mg.kg ^-1 im, iv and po) demonstrated harmlessness of the substance at useful doses in animal growth monitoring, haematological parameters, examination of blood, urine, liver and kidney functions, morphological, histological and enzymological examination. The medicament can be used in all kinds of dosage forms, for example as a lectate in injectable form or as a hydrochloride in tablets.

The use of the medicament of the invention will be explained and described in more detail in the following examples.

Example 1

Dogs treated with 3-quinuclidyl benzilate (anticholinergic hallucinogen) at doses of 0.05-0.5 mg.kg im developed severe symptoms of intoxication within 30 minutes. These symptoms persisted without treatment for several hours, some to two days. Administration of the medicament of the invention wherein the active ingredient, 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine lactate, was at an effective concentration of 0.1 to 5 mg.kg ^-1 im, intoxicated animals at the maximum development of symptoms of poisoning was a rapid adjustment of altered autonomic, motor and central functions, depending on the dose used, within 2 to 4 hours. In no case did the symptoms of intoxication return within 24 hours after treatment. In the case of preventive drug administration followed by administration of noxy, the symptoms of intoxication were significantly less, of short duration, or were completely suppressed.

Example 2

In experiments on dogs administered with the medicament according to the invention, with the active ingredient 9-amino-7-methoxy-1,2,3,4-tetrahydroacridinium lactate, at an effective concentration of 0.3 mg.kg ^-1 im 15 minutes before iv administration 0.4 mg.kg ^{-1 of} succinylcholine, it was found that the duration of skeletal muscle relaxation lasted 12 to 15 minutes, as opposed to the 2 to 3 minutes duration of myorelaxation after administration of succinylcholine alone at the same dose.

-2GB 281348 B6

Example 3

In rat experiments, the active ingredient of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridinium lactate was found to be active at doses ranging from 0.1 to 5 mg.kg- ¹ -im significantly improves memory recall and learning processes, followed by food and pain stimulation methodologies in animals whose learning ability and memory itself have been affected by depressant drugs.

Examples of manufacture of a medicament according to the invention are as follows:

Example 4

An injection solution containing 5 mg of 9-amino-7-methoxy-1,2,3,4-tetrahydroacridinium lactate in 1 ml of an aqueous solution is prepared by dissolving 5 g of 9-amino-7-methoxy-1,2,3,4- tetrahydroacridinium lactate and 44.8 g mannitol in 900 ml of water for injection, under nitrogen bubbling and protected from light. The volume of the solution is made up to 1000 ml with water for injection, filtered and filled into ampoules under nitrogen. The ampoules are further sterilized by autoclaving. The injections thus prepared, stored at 25 ° C and protected from light, are stable for at least two years.

Example 5

Solution for injection containing 5 to 25 mg of 9-amino-7-methosy-1,2,3,4-tetrahydroacridinium lactate in 1 ml of aqueous solution with polyethylene glycol, using the following substances:

9-amino-7-methoxy-1,2,3,4-tetrahydroacridinium lactate (0.5 to 9%)

2.5%).

mannitol (2.5 to 4.5%) polyethylene glycol 400 (5 to 10%) water for injection (ad 1.0 cm ³ ) is prepared by dissolving the individual substances, filtering, filling and sterilizing as well as in Example 4. The injections thus prepared, stored at 25 ° C and protected from light, are stable for at least two years.

Example 6

Lyophilized injections of the same composition as in Example 4 may also be prepared. Their stability at 25 ° C is at least three years. The composition of these injections is as follows:

9-amino-7-methosy-tetrahydroacridinium lactate 25 mg mannitol 25 mb

Dissolve the indicated quantity of the substance in 1 ml of water for injection, filter through a 0,2 μπι bacteriological membrane filter and fill in aseptic medium into a vial.

-3GB 281348 B6 new vials. The solution is then frozen at -30 ° C for four hours. Freezing is followed by lyophilization, which results in drying at 35 ° C. The vials are sealed with rubber cloths and sealed with aluminum caps. The lyophilisate in vials is stable for at least three years, protected from light and at 25 ºC.

Example 7

Tablets containing 100 mg of 9-amino-7-methoxy-1,2,3,4 tetrahydroacridine chloride per tablet are prepared by mixing the appropriate amount of active ingredient sequentially with lactose and corn meal and homogenizing the resulting dust mixture. A starch-gelatinous aqueous solution is added to the homogeneous mixture and granulated and dried. The dried granulate is treated by sieving through a 1 mm sieve, and corn starch, microcrystalline cellulose, calcium stearate and sodium starch glycolate are added. Tablets are prepared from the resulting tablet and are encapsulated with a cellulose derivative-type film-forming agent, e.g., hydroxypropylmethylcellulose or a sugar syrup suspension.

Example 8

Tablets containing 50 mg of 9-amino-7-methosy-1,2,3,4-tetrahydroacridine sulphate per tablet are prepared by successive mixing with microcrystalline cellulose, lactose, corn starch, calcium stearate and sodium starch carbosymethyl starch. The resulting mixture is homogenized and tableted into tablets having a weight of 300 mg and a diameter of 9 mm. The tablets were prepared in the same manner as in Example 4.

Claims (1)

PATENT CLAIMS A medicament with a reversible anticholinesterase effect, characterized in that it consists of the active ingredient consisting of a 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine salt of the general formula -4CZ 281348 B6 wherein X ^- represents an anion, especially Cl ", Br ~, I, ² S0 _4, N0 _3>, lactate, acetate, citrate, tartrate, an effective dose of from 0.1 to 2 mg.kg ^-1 and pharmaceutical excipients which are, in particular, disintegrants, fillers and glidants for the manufacture of tablets and water, isotonizing and anti-freezing agents for the manufacture of injections, the active ingredient content being from 0.25 to 90% by weight with respect to the pharmaceutical excipients.