DE2349186A1 - MEDICINAL PRODUCTS FOR IMPROVING CELL RESPIRATORY, CELLULAR PERFORMANCE AND BRAIN FUNCTION AND METHOD OF MANUFACTURING IT - Google Patents

Description

Dr. A. ULLRICH Dr. T. ULLRICH

PATENTANWÄLTE 9 "5 / QIQG

69 HEIDELBERG, Gaisbergstrasse 3 £ O 4 3 fOQ

Telephone: (06221) 25335 - Telegram address: ULLPATENT

Our reference: 8791

SOLCO Basel A.G., Basel

Medicines_for_improving_cellular respiration, _the heart muscle

The present invention relates to a medicament for improving cell respiration, cardiac muscle performance, and the brain function and is characterized by an unexpected and particularly intensified pharmacodynamic effect. The invention further relates to a method for producing the medicament.

The dialyzed extract from calf blood after having been freed from proteins and other high molecular weight components The method of German patent specification 1 076 888 promotes cell respiration, increases oxygen uptake in isolated Mitochondria and improves oxygen utilization too where the partial pressure has dropped: Jaeger et al, Arzneimittel-Forschung (Drug Research) 1 ^. 750-754 (1965). That Preparation increased according to Quadbeck - Austrian monthly books for medical port formation, Symposium Salzburg (1964), p. 49- den Glucose and phosphate transfer from the blood to the brain. It increases the maintenance, energy and reserve metabolism with Glycogen and potassium accumulation with a simultaneous decrease in 6-phosphogluconic acid dehydrogenase ^ K.H. Schwabe, Drug Research 16. ^ 64 (1966} /.

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It also brings about faster healing of homoisoplastic bone grafts: A. Lanzetta et al, Arch. Ortop. 72..488 (i960). Impressive therapeutic successes with this blood extract have also been seen in severe peripheral arterial circulatory disorders ^ A, Kappert, Medizin. Welt 752 (196517 * for arteriosclerotic and diabetic angiopathies / Meythaler, therapy week 15..57 0-965), Stemberger et al, Therapeutische Umschau 1 ^ .96 (1958} / and for arterial occlusive diseases.

In accordance with its main pharmacodynamic effect, the preparation was also used to improve metabolic function in the event of a risk of infarction / j. Bosse, country doctor ^ 6. 588 (1960} / and for the follow-up treatment of myocardial infarction ^ s "temberger et al, Wiener med. 508 (1958), Lubich et al, Il Policlinico 67, 1381 (1960} / used with good success.

It has now been found, surprisingly, that by adding heptaminol - 6-amino-2-methyl-heptan-2 ~ ol -, or a physiologically tolerable salt of the same to this blood extract, which is the pharmacodynamic described above Has spectrum of action, the effectiveness of the latter is considerable can be increased, far beyond the effects of the individual components; this is especially true also for otherwise pharmacologically inert doses of heptaminol.

The effect on the heart was measured, for example, by Professor J. La Barre, University of Brussels, using the following experimental set-up:

Isolated cardiac ears from rabbits were injected with the disodium salt of ethylenediaminetetraacetic acid Calcium ions are largely withdrawn and thus the ability of the organ to contract is suppressed after the addition of digitalis. In this way an artificial fatigue of the heart was created. The addition of 1/8 units of action of digitalis extract no longer produced an increase in contraction.

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a) If this arrangement is used, 1 ml of the standardized Blood extract with a dry content of 40/45 mg / ml, a very slight increase in contraction is measured of the organ.

b) 1 ml of a solution containing 2 mg of heptaminol hydrochloride is used to, one observes no measurable effect.

c) If, however, the medicament according to the invention is added to the arrangement from 1 ml blood extract and 2 mg heptaminol hydrochloride to, one observes a significant auricular response and an increase in the amplitude of contraction of 100 to 175 to 250 yrs.

The experiments were carried out on a large number of organs (around 80). Various salts of heptaminol various amounts of blood extract were added. The effect picture was always the same. The characteristic The increase in contraction was already achieved when adding 2 mg of heptaminol to just 0.5 ml of blood extract a dry content of 40/45 mg / ml is observed «If the preparation is made from 0.5 to 1 ml of blood extract and 2 mg of heptaminol -hydrochl or id for 1 to 2 hours on the isolated Acting on an organ, one measures contraction ^ of such strength, as it was by far never achieved on the same organ before the start of the experiment - i.e. before the artificial damage were · Through this observation, the heart-repairing effect of the combination preparation is particularly clearly visible.

Similar experiments were carried out on isolated frog hearts (Rana temporaria). Frog hearts are already showing after 60 to 120 minutes a strong fatigue, which can be recognized by a strong reduction in the contraction amplitudes which are accompanied by bradycardia. In these frog experiments, too, the preparation made from blood extract (1 ml) and heptaminol salt (2 mg) have a cardiotonic and cardioreparating effect, which is not only achieved by

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setting, strongly increased contraction amplitudes, but also through a long-lasting state of activity, i.e. the persistent Disappearance of cardiac fatigue, which is characterized by the blood extract alone or by heptaminol cannot be generated. The ability to contract is increased by about 40 ^ lasts for over ^ O minutes, for example.

Any undesirable toxic side effects, bradycardia, extracystoles, etc., were detected when using the inventive preparation never observed. Such symptoms disappeared with Appli. ation of the preparations according to the invention.

An amazing effect of the preparation made from blood extract and heptaminol was observed for learning ability in adult white rats. By administration of the blood extract, a standardized learning process was significantly accelerated. By administering the preparation from blood extract and heptaminol according to the invention, the learning process is again significantly potentiated.

Experimental set-up;

The method of JJ »Desmarez, Ann.Soc.Roy.Sc.med. et nat. Bruxelles 1960 , t 1J>, was used. Rats were placed in cages, which are equipped with irregularly arranged, labyrinth-like baffles that are changed according to a certain program. The permitted path to the food is marked with a yellow light. Taking the wrong path will result in a light electric shock. The experiments were carried out with white female rats weighing 230 to 250 g. For each measurement, 2 groups of 8 animals each in 4 cages were used.

Results:

The control animals (8 χ 2), which receive a daily intraperitoneal injection of 0.5 ml of physiological saline

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Solution took 20 to 22 days to learn their lesson.

The second group of test animals (8 χ 2), which were injected intraperitoneally with 0.5 ml of blood extract every day, required 13 days to achieve the same learning success.

The third group of 8x2 test animals received daily Containing 0.25 ml of blood extract with 0.25 ml of heptaminol 15 * 5 -ffit ^ heptaminol hydrochloride - administered intraperitoneally. It only took this third group of animals 8 days to master its lesson.

Through the combination with heptaminol, which is in itself ineffective with regard to the learning process, became the apprenticeship period is significantly shortened even with halved the dose of blood extract.

See Tables I and II.

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The improvement in learning is likely to be attributed to an increase in brain metabolism. This result is extremely surprising. So far, no substance has been found that accelerates learning. Neither that Neuroenergetic meclofenoxate, / p-chlorophenoxy-acetic acid-ßdiethylaminoethylester-hydroehlorid / ' nor the dynamizing neurotrophic pyritinol / bis (3-hydroxy-4-hydroxyinethyl-2-methyl-5-pyridylnjethyl) disulfide7 or mixtures of aminodicarboxylic acids or their salts recommended as neuroenergetics have an accelerating influence on the learning process.

The amazing effect of the preparation according to the invention from blood extract and heptaminol is most likely based on an improvement in the permeability of the active ingredients of the blood extract through the cell membranes through the heptaminol.

A preparation with such pronounced cardiovascular support and neuroenergetic positive effects is especially to strengthen the heart of old age as well as for regeneration age-related reduced neurocapacities. The claimed preparation is ideally suited as a Geriatric, tonic and reconstitute.

The surprising effect-enhancing effect of heptaminol to the blood extract has no direct parallels. While it is known that heptaminol has antihypertensive effects von Etifelmin / ^ - Ä ^ hyl-jJ ^ -diphenyl-prop ^ -enylamine / reinforced. Between the effect of the preparation according to the invention made from blood extract / heptaminol and from Etifelmin / However, there is no functional relationship to heptaminol.

Based on the pharmacodynamic results described above, a new drug for improvement has been made cell respiration, cardiac muscle performance and brain function, consisting of a blood extract from calf blood, which is gently freed from protein and then in a large dilution of a dialysis against water or diluted

A 0 9 8 2 1/1 1 1 7

th ethanol and finally gentle on one Concentration of 40/45 mg dry matter per 1 ml solution, which is characterized in that it a physiologically tolerable acid addition salt of 6-amino-2-methyl-heptan ~ 2-ol as a potentiating factor Heptaminol - contains.

The agent can be used as a solution for injection (possibly as Lyophilisate) or in capsules, tablets, globules and dragees, suppositories and syrups or in other galenicals Preparations are applied.

A single dose contains about 1 to 5 ml, preferably 2 ml, blood extract or the equivalent amount of dry extract, e.g. lyophilizate or adsorbate, and about 15 to ICX) mg, preferably 20 to 80 mg, of a heptaminol salt.

The method for producing the preparation according to the invention is characterized in that blood extract, Obtained from calf blood, gently freed from protein in a known manner, then in a large dilution of a Subjected to dialysis against water or dilute ethanol and finally gently to a concentration of 40/45 mg Concentrates dry matter per ml of solution, with an acid addition salt of heptaminol in a ratio of 1: 0.5 to 1: 1, based on the dry weight, added and added to injection solutions, syrups or lyophilisates or after adsorption the blood extract active ingredients to surface-active substances or lyophilization to tablets, dragees, globules or suppositories processed.

Dry preparations are prepared by adding an adsorbent to the preparation from blood extract and heptaminol salt, e.g. Aerosil, and then drying the thioxotropic gel obtained in vacuo or by lyophilization of solutions from blood extract and heptaminol salt »

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The solution of blood extract and heptaminol salt can but also as a liquid or lyophilizate by known methods in doses of up to 0.5 nil in gelatin capsules and administered orally in this form.

In the manufacture of the various dosage forms, care is taken to ensure that they are per dosage 1 to 5 ml, preferably 2 ml of blood extract or equivalent Lyophilizate or adsorbate and 15 to 100, preferably 20 to 80 mg of 6-amino-2-methyl-heptan-2-ol as the hydrochloride or contain sulfate.

The preparations obtained in this way are used after intravenous, intramuscular, oral or rectal administration achieves a strong increase in cell respiration, cardiac muscle performance and brain function.

The new preparations are particularly suitable as geriatrics.

Examples

1. Injection solution

1000 ml of blood extract, produced according to the method of German Patent 1,076,888, with a dry content of 40/45 mg / ml are mixed with 18 g of heptaminol hydrochloride added, sterile-filtered and filled into 500 ampoules.

Administration dose: 1/2 to 2 ampoules.

2. Tablets / dragees

a) 2000 ml of blood extract according to the method of German patent 1 0j6 888 are mixed with 90 g of heptaminol hydrochloride. The solution is mixed with 1000 g of Aerosil and the adsorbate paste is dried in vacuo at a maximum of 30.degree. The dried adsorbate is

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granulated after adding corn or wheat starch or dried red algae extracts (carrageenans) and then compressed into 4000 tablets. The tablets then usually become stomach-soluble coated.

b) 2000 ml of blood extract are mixed with 80 g of heptaminol hydrochloride offset. The solution is lyophilized, the lyophilizate is made with carrageenan, corn starch and a little Magnesium stearate and added to tablets or dragees processed.

c) The lyophilisate from 2000 ml of blood extract is 80 g Heptaminol hydrochloride mixed and then continued analogously to Example 2b) to tablets or dragees processed.

Dosage: 2 to 6 tablets or dragees per day.

3.) Capsules

a) 2000 ml of blood extract are mixed with 40 g of heptaminol sulfate and, according to known methods, in 8OOO gelatin capsules bottled or microencapsulated in a known manner. ,

Dosage: 4 to 8 capsules per day or equivalent amount of microcapsules.

b) The dried adsorbate produced according to Example 2a) is filled into 4000 capsules.

c) The lyophili- 'produced according to Example 2b) or 2e) sat is filled in 1000 capsules.

4. Syrup

ml blood extract according to the method of the German patent specification 1,076,888 are mixed with 2000 ml of syrupus simplex (Syrupus sacchari), in which 18 g of heptaminol hydrochloride were previously added were dissolved. The solution will be

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with flavor corrections (lemon or orange aroma) and filled in bottles of 50 ml.

Single dose: 1 teaspoon (5 ml).

Suppositories

The dried adsorbate produced according to Example 2a) is mixed with cocoa fat (3500 g) and the usual additives processed into a suppository mass and pressed into 2500 suppositories.

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Claims (8)

Claims 1.) Medicines to improve cellular respiration, cardiac muscle performance and brain function, consisting of a blood extract from calf blood, which gently removes protein and then subjected to dialysis against water or diluted ethanol and finally gently to a concentration of 40/45 mg dry substance per 1 ml solution, characterized in that it contains a physiologically tolerable acid addition salt of 6-amino-2-methyl-heptan ~ 2-ol - heptaminol - as a potentiating factor. 2.) Medicament according to claim 1, characterized in that it consists of solutions, capsules or tablets which contain about 1 to 5 ml, preferably 2 ml, blood extract or the equivalent amount of lyophilisate or adsorbate and 15 to 100 mg, preferably 20 to 80 mg, of a salt of 6-amino-2-methyl-heptan-2-ol per single dose. J.) Medicament according to claim 1 and 2, characterized in that it contains the hydrochloride or the sulfate of ö-amino-2-methyl-heptan-2-ol. 4.) Process for the preparation of the medicament according to claim 1 to 3, characterized in that blood extract obtained from calf blood is gently freed of protein in a manner known per se, then subjected to a large dilution of dialysis against water or dilute ethanol and finally gently to a concentration of 40/45 mg dry matter per 1 ml solution, mixed with an acid addition salt of 6 ~ amino-2-methyl-heptan-2-ol in a ratio of 1: 0.3 to 1: 1, based on the dry weights and for injection solutions, lyophilisates and syrups, or after adsorption of the blood extract 409821/1117 substances to surface-active substances or lyophilization processed into tablets, globules, coated tablets or suppositories. 5.) Process for the production of injectable dosage forms according to claim 4, characterized in that a salt of 6-amino-2-methyl-heptan-2-ol is added to the biologically active blood extract in the predetermined mixing ratio, the solution is lyophilized or after setting the desired concentration by adding double-distilled water under sterile conditions. 6.) Process for the production of solid dosage forms according to claim 4, characterized in that a salt of 6-amino-2-methyl-heptan-2 ~ ol in the specified mixing ratio a) is added with the biologically active blood extract and the resulting solution is lyophilized or adsorbed on solid carriers and dries or b) mixed with a lyophilizate or adsorbate of the biologically active blood extract and then the product obtained according to a) or b) is filled into capsules or mixed with a tablet base made of starch and a swelling agent or disintegrant, granulated and Tablets and, if necessary, sugar-coated in a stomach-soluble form or pressed into suppositories after mixing with cocoa fat. 7.) Process for the production of liquid oral dosage forms according to claim 4, characterized in that the biologically active blood extract is mixed with a salt of 6-amino-2-methyl-heptan-2-ol with sugar syrup and the resulting solution is optionally also flavored clogs. 8.) Geriatric drug, characterized in that it contains 1 to 5 ml (40 to 225 iqg) of blood extract and 15 to 100 mg of a salt of 6-amino-2-methyl-heptan-2-ol · 409821/1117