DE2543004A1 - PHARMACEUTICAL PREPARATIONS WITH VACUUM-WIDTHENING EFFECT - Google Patents

Description

Patent attorneys Dipl.-Ing. E Wkickm \ nn, 2543004

Dipl.-Ing. H.Weickmann, Dipl.-Phys. Dr. K. Fincke Dipl.-Ing. RA-Weickmann, Dipl.-Chem. B. Huber

S MUNICH 16, DEN

PO Box 860 820

MÖHLSTRASSE 22, CALL NUMBER 98 39 21/22

HtM / th

SCIENCE UNION et Cie.,

14, rue du VaI d'Or, 92150 Suresnes / France

Pharmaceutical preparations with vasodilator
Effect.

The invention relates to pharmaceutical preparations or medicaments with a vasodilator or vasodilator effect. In particular, it relates to pharmaceutical preparations containing tetrahydroalstonine or a salt thereof with a
therapeutically acceptable acid as a mixture or in combination with an inert, non-toxic, pharmaceutically acceptable binder, carrier material and / or adjuvant.

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Tetrahydroalstonine corresponds to the following formula

CH ₃

CH ₃ OO

and can be in racemic form or in optically active form.

One can make this connection directly by leaching out the roots Rauwolfia or Vinca Minor plants or the bark of Alstonia or by catalytic hydrogenation of the quaternary bases isolated from the Rauwolfia alkaloids or by mild hydrogenation of alstonine or finally win by total synthesis.

Tetrahydroalstonine and its salts are described in FR-PS 1,397,537 has already been described as adrenolytic agents, but nothing beyond this pharmacological property Application can be found in this publication. Furthermore, G.H.Svoboda and KoIl. (Lloydia 27 (1964) 361) tetrahydroalstonine investigated to confirm that this substance has hypoglycemic properties at high doses.

It has now been found that the adrenolytic properties Are very weak and have only a slight change in cardiac blood pressure and arterial blood pressure in the anesthetized Effect of the dog.

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On the other hand, it has been found that tetrahydroalstonine and its salts provide a significant increase in femoral vein flow without any appreciable modification of cerebral blood flow cause.

It has also been shown that the oxygen consumption of the Brain and in parallel with it the glucose consumption increases after the administration of tetrahydroalstonine or a salt thereof.

The vasodilators on the cerebral vessels and / or peripheral vessels Acting properties were determined in particular with the help of pharmacological studies on groups of previously anesthetized Dogs examined. Despite its very low solubility in water and aqueous liquids, tetrahydroalstonine is evident -very effective when administered through the digestive tract.

The invention therefore relates to pharmaceutical preparations based on tetrahydroalstonine or a salt thereof. For therapeutic use, these preparations are in a for administration on parenteral, buccal, the perlingual or rectal route. In this context, one can particularly injectable solutions or Suspensions that are in ampoules, bottles, multi-dose bottles, self-injectable syringes etc. are tablets or coated tablets, sustained-release tablets, coated tablets, gel beads, granules, flavored or Name unflavored powders, sublingual tablets, and suppositories.

The pharmaceutical dosage forms are prepared using conventional pharmacotechnical methods. For the production the injectable solutions or suspensions, the active ingredient is mixed with a solvent such as distilled water, physiological serum, olive oil or benzyl alcohol, isotonic agents such as sodium chloride or sodium bicarbonate, preservatives, Buffers and / or antioxidants.

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25A3004

Obtains the forms suitable for administration by the buccal route one in particular by mixing the active ingredient with one or several inert carrier materials, such as calcium carbonate, magnesium phosphate, starch or kaolin, binders, such as Methyl cellulose or ethyl cellulose, lubricants such as talc or magnesium stearate, which delay the release of the active ingredient Agents such as varnishes that dissolve in the digestive tract, keratin, carnauba wax or modified and polymerized gelatins, agents that facilitate the release of active ingredients, such as lactose or casein treated with formalin, flavoring agents, fragrances and / or colorants.

The forms suitable for administration by the rectal route are obtained in particular by adding the active ingredient to cocoa butter, Polyethylene glycol stearate or synthetic carrier materials incorporated, the melting point of which for such Administration is suitable.

The pharmaceutical preparations can additionally contain one or more other active ingredients with similar, complementary or synergistic Effect included.

The pharmaceutical preparations according to the invention with cerebral vascular enlargement effect are for the treatment of • Suitable for cerebral circulatory disorders. They can also be used to treat peripheral circulatory disorders.

The nützliche.Dosierung extends between 30 mg and 6 g daily depending on the patient's age, the type of disease and the administration route.

In general, the pharmaceutical preparations according to the invention contain 10 to 500 mg of the active ingredient. The preparations can be administered one to four times a day and, if necessary, even more frequently.

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The pharmaceutical preparations according to the invention preferably contain 15 mg to 200 mg of tetrahydroalstonine or one Salt of it per unit, that is, one applies an active ingredient concentration between 5% and 75% of the total mass.

The following examples serve to further illustrate the invention.

example 1

Gel beads containing 20 mg of tetrahydroalstonine per unit

Mixing 20 kg of tetrahydroalstonine, 145 kg of lactose and 5 kg magnesium stearate and thus forms 100 000 capsules with a final weight of 0.17 g.

Tablets containing 20 mg of tetrahydroalstonine per unit

100,000 tablets with a final weight of 0.155 g are prepared using the following ingredients:

Tetrahydroalstonine 20 kg

Lactose 55 kg

Corn starch 10 kg

Calcium phosphate 54 kg

hydrolyzed starch (commercially available under

the name "PRIMOGEL" available) 5 kg

Talc 5 kg

Magnesium stearate 1 kg

Injectable solution filled into ampoules containing 50 mg of tetrahydroalstonine.

A solution is prepared using the following ingredients:

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Tetrahydroalstonine 50 g

Tartaric acid 11 g

Propylene glycol 20 g

methyl p-hydroxy-benzoate 0.1 g

Propyl p-hydroxy-benzoate 0.1 g

Sodium chloride 2 g

distilled water ad 2000 ml

The solution thus obtained is divided into 1000 ampoules with a capacity of 2 ml and sterilized. Each ampoule contains 50 mg tetrahydroalstonine.

Example 2

Effect of tetrahydroalstonine on the cerebral circulation.

The investigation of the vasodilating effect and the effect on the metabolism of tetrahydroalstonine is carried out in groups of 5 dogs given the active ingredient in increasing doses.

The dogs: are first given by intravenous injection Chloralose anesthetized. Then you determine:

a) After severing the inner left and right maxillary veins and after ligating the auricular veins Using a catheter pushed towards the upper cerebral veins, the volumetric cerebral blood flow is measured and

b) the mean diastolic and systolic arterial blood pressure.

To do this, cut through an artery in the arm and attach a catheter that is connected to an electromagnetic membrane is.

The various blood parameters are continuously recorded with the aid of a multiple recorder. Hemodynamic monitoring is additionally ensured with the help of two two-beam oscillographs.

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Tetrahydroalstonine is withdrawn every 15 minutes after the injection venous and arterial blood and determines the glucose content, the oxygen pressure, the carbon dioxide pressure and the arterial and venous quotients QO, of the cerebral circulation.

The studies illustrate the vasodilating effect on the femoral vein, which can be seen 45 minutes after administration of tetrahydroalstonine observed via the stomach and which lasts for at least 70 minutes. They also clarify the effect of tetrahydroalstonine on the cerebral circulation, on the cerebral metabolic effects (arterio-venous oxygen difference, increased oxygen consumption per minute) and on the Concentration of capillary oxygen, that is, on the oxygen amount that is delivered to the brain tissue.

The increase in oxygen consumption has a decrease in the venous oxygen partial pressure of the brain result (POve). This phenomenon is caused by an increase in glucose consumption of the brain accompanied so that the G / 0 index, that is, the percentage of oxidation of the consumed by the brain Glucose, did not vary in any significant way.

Furthermore, an increase in the ^ PCO ₂ and - ^ H ratio is observed in practically all cases
Oxygen difference of the brain.

the ^ PCO ₂ and - ^ H ratios on the gross arterio-venous

Tetrahydroalstonine has an increased dose of 100 mg / kg when administered via the in only one in five cases Gastrointestinal tract causes a noticeable decrease in arterial blood pressure as a function of time.

Results:

Under these experimental conditions and in normal animals anesthetized with chloralose, tetrahydroalstonine, when administered via the gastrointestinal tract, causes a noticeable and permanent increase in the thigh vein throughput and an irritation of the brain metabolism, which results in an increase in the acidity.

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Substance consumption and glucose consumption of the brain shows these phenomena appear quickly and persist for a long time.

Example 3

Effect of tetrahydroalstonine on memory and retention of experience.

This investigation determined the extent to which tetrahydroalstonine (compared to two widely used "Vascular" substances) can act on long-term memory disorders, that is, the recovery of already able to facilitate fixed experiences. A "room disorientation syndrome" is used, which is caused by a supra-maximal electric shock, which shows that the animal has difficulty after the convulsive crisis to run through a water labyrinth known from previous repeated learning processes without errors.

technology

This investigation is carried out with the help of 160 male rats of the Wistar AF-Han EOPS strain, which are 6 to 7 weeks old have and have a weight of about 160 g.

After leading the rats through the labyrinth to the exit under the guidance of the experimenter for the first time has, one first carries out four learning processes on the rats in the course of 2 days in a water maze, which is carried out by C.Giurgea and F.Mouravieff-Lesuisse (J. Pharmacol. Paris, 3 (1) (1972) 17-30). This device is 120 cm long, 50 cm wide and 40 cm deep and comprises an entrance from four rooms A, B-, C and D and an exit that leads to a comprises a metal grid covered wooden board, which is inclined at 45 ° and rests on the bottom of the labyrinth. A source of light (250 watts) is placed in such a way that the exit is in the darker part. Under these conditions, the rats are affected by the Attracted to light. The water level in the labyrinth is 24 cm.

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Observation of the rats does not exceed 5 minutes. On the third day, the rats are given according to their performance randomly divided into groups on the fourth test and then subjected to a supra-maximal electric shock with With the help of an electric shock device (Neurovar, from Alvar Electronic) and with the help of an oscilloscope (CRC OC 342) Is monitored. The electric shock (100 Hz, 0.5 ms, 1 second, 60 volts) is injected into the ear with the help of Electrodes impregnated with a saturated sodium chloride solution and effects in all Cases of a tonic crisis lasting about 10 seconds.

After going through the labyrinth once 20 minutes after the electric shock, the rats are treated with the aid of an esophageal tube. Then you do four exams, the 1 hour, 2 hours, 3 hours and 4 hours after the electric shock be effected.

The time it takes each animal to traverse the maze is measured and every mistake is recorded: Entering rooms A, B, C and D, turning back into the exit room, retreating and returning to the light source.

Mode of administration

Eighteen hours after traversing the labyrinth for the fourth time, the rats are placed on a water diet. The as comparison substances too Compounds used in tetrahydroalstonine papaverine and vincamine are administered in an aqueous solution containing the 0.25% carboxymethyl cellulose and 0.20% polyoxyethylene sorbitan raonooleate (Tween 80). The effects of papaverine and vincamine are in doses of 10 mg and 20 mg per kg while that of tetrahydroalstonine is being studied at doses of 0.6, 6.0 and 60.0 mg / kg. The control animals the same volume (0.5 ml) of solvent is administered per 100 g of body weight.

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Indication of the results:

The mean cumulative number of errors is determined in each series and the mean cycle time of the water maze, which is at 5 examinations occur that will be done after the electric shock. Then one determines in comparison to that "Control" series, the direction of the change in the number of errors (+ = deterioration; - = improvement) and the results statistical analysis of these values. This analysis is carried out with the help of the Fisher-Student test according to the "square root" transformation, to homogenize the variances.

In all cases a probability of 5% or more is considered significant.

A) Examination in the absence of the active substances

The accelerated learning process, which consists of 5 iterations of the Maze performed in 4 hours leads to an improvement in performance in the normal rat, which consists in that the mean number of errors from the first to the fifth examination drops from 4 to 1 and the processing time of the labyrinth is reduced by half.

Resulting from exposure to a supra-maximal electric shock there was a very strong deterioration in the two parameters examined. Indeed, in the case of the "control animals", the lead time of the maze tripled 20 minutes after the convulsive shock in terms of behavior during the last training run and for the examination carried out after 240 minutes, this running time is compared to that of Animals that have not gone through a convulsive crisis still doubled. Because of the relationship between the for achieving the time required to exit the maze and the number of errors made while going through the maze, in relation to the first test, the number of errors quadrupled.

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When examining the results, it can be seen that over the course of the five successive passes, one progressive Improvement of the behavior of the "disturbed" animals takes place.

The considerable disorientation found in all rats after 20 minutes is not the result of a motor impairment, since the rats otherwise behave normally when they have overcome their post-critical phase after about 10 minutes. Examination of the curves shows that the improvement is clear between 20 and 60 minutes and less clear during the first and third hours, and especially between the third and fourth hours, the ultimate recovery being slower as the number of errors has already been reduced . A certain number of the rats improved their behavior in the last two time intervals in question, but the corresponding percentages are not statistically significant.

B) effects of papaverine

It should first be noted that the first time it was passed through the Labyrinths no significant change in the groups that should receive 10 or 20 mg / kg of the active substances administered orally, occurs and that the animals forming these groups have the same population as the "control groups". It is determine that compared to the "control animals" the mean number of errors in oral administration of papaverine in is significantly reduced and that, depending on the dose, this improvement is more or less delayed. In fact, it is statistically significant when examined after 240 minutes of the group containing 10 mg / kg of the active ingredient received and during the examination after the third hour in the group who administered 20 mg / kg of the active ingredient became. In these two treated groups, the improvement begins to show with the examination at "120 minutes".

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C) Effect of Vincamine

Before treatment, there is no difference between the animals making up these two experimental groups and the animals making up the control group. When administered orally at a dose of 10 mg / kg, vincamine does not modify the mean number of errors in the four hours following the convulsive crisis, with only slightly superior behavior compared to the "control rats ^{11" being} observed after the second hour.

At a dose of 20 mg / kg, a significant reduction in the mean number of errors is observed compared to studies occurred 3 and 4 hours after the electric shock was administered. This beneficial effect begins with the Examination after 60 minutes, i.e. 40 minutes after the treatment.

D) Effect of Tetrahydroalstonxn

Before treatment, there is no significant difference between the 3 groups of animals to be treated and the "control group".

Tetrahydroalstonine exercises a beneficial proportional to the dosage Effect. In particular, the reduction in the number of errors is statistically significant and the more pronounced the higher the dose is:

After 180 minutes at 0.6 mg / kg After 120 minutes at 6.0 mg / kg After 60 minutes at 60.0 mg / kg

Furthermore, the investigations show that the effect sets in at a dose of 6 mg / kg after the 60th minute.

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discussion

The development found in the control group shows that the recovery of the animals depends on the time that has passed after the convulsive crisis, being without treatment with an active ingredient even after 2 and even after 3 hours there is a clear "spatial disorientation", with a behavior behavior in the control animals is achieved after 240 minutes prior to the electric shock. It can therefore be assumed that any early improvement in the syndrome, that is, any reduction in the number of errors made during iterating of the maze, illustrate the effect of a product. This beneficial effect of a compound is not one Improvement in motor skills can be attributed to the appearance and behavior of animals from the twentieth minute after shock on is normal and, on the other hand, the rats that have fallen into the water do not sink to the bottom, swim normally and their physical Efforts do not seem to be constrained by clinging to any wall that forms the obstacles of the maze cling, which extends the lead time without significant Modification of the number of errors would result.

One can remember that the neuronal hyperactivity of the convulsive crisis is an accumulation of acidic metabolic products caused. The action of a compound could then result in faster elimination of these metabolites be seen. It could be a result of the improvement in the cerebral cortical circulation, as under these experimental Conditions to determine the return to a previously learned behavior is »On the other hand, it should not be forgotten that the Reduction of cell acidosis, the resumption of the effective oxidative metabolism and thus a suitable neuron repolarization is equivalent to.

The results obtained suggest an effect of the three compounds in the brain area. Within the dose ranges, in which the two comparison products were examined, papaverine appears to act against the experimental syndrome

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to be more effective than vincamine. It is noted that the effects of these two products even after oral administration at a dose of 20 mg / kg, occurs only slowly (only after 180 minutes in a statistically significant manner), so that one can in particular infer a strengthening and consolidation of the spontaneous improvement.

Tetrahydroalstonine appears as a vascular active substance, the effect of which when administered orally at a dose of 6 mg / kg is comparable to the effects of papaverine or vincamine in doses of 20 mg / kg. The effect of this substance illustrates the fact that the recovery of long-term memory occurs faster the higher the dosage and that with a dosage of 60 mg / kg the behavior present before the electric shock already 2 hours after the convulsive crisis is reached again.

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Claims (4)

Claims fi \ Pharmaceutical preparations with a vasodilating effect, characterized in that they consist of
Tetrahydroalstonxn or a salt thereof as an active ingredient and
inert, non-toxic, pharmaceutically acceptable binders, carrier materials and / or auxiliaries. 2. Pharmaceutical preparations according to claim 1, characterized in that they eichnet the active ingredient in one Amount contained between 10 and 500 mg per dose unit. 3. Pharmaceutical preparations according to claim 1 and 2,
characterized in that they Contain 15 to 200 mg tetrahydroalstonxn per dose unit. 4. Pharmaceutical preparations according to claim 1, characterized in that they are used in one for
Administration by the parenteral, buccal, perlingual or rectal routes. 'I. 609817/1071