RU2309731C1 - Emetine hydrochloride granulate, method for its preparing and medicinal formulation based on thereof - Google Patents

Abstract

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a novel granulated formulaton of emetine hydrochloride used in prophylaxis and treatment of alcoholism. The formulation comprises 70-90% of emetine hydrochloride, polyvinylpyrrolidone and eudragite, a tabletted or capsulated medicinal formulation based on thereof. Also, invention relates to a method for preparing the indicated granulate. Invention provides delivery of emetine hydrochloride in intestine and suppression of the emetic effect.

EFFECT: improved preparing method, valuable medicinal properties of granulate.

4 cl, 6 tbl, 32 ex

Description

The invention relates to the field of pharmaceuticals and medicine and relates to agents affecting metabolic processes in the human body, in particular, the rate of enzymatic oxidation of alcohol (in particular ethyl alcohol), and the rate of enzymatic oxidation of aldehydes (in particular acetaldehyde).

There is a method of treating alcoholism by medication with the use of various drugs that cause a predominantly conditioned reflex reaction (aversion) to alcohol [1].

For example, the drug teturam is known, which is taken orally for the treatment of chronic alcoholism [2]. The effect of the drug is based on its ability to specifically affect the metabolism of alcohol in the body. Alcohol undergoes oxidative transformations, passing through the phase of acetaldehyde and acetic acid. With the participation of acetaldehydroxidase, acetaldehyde usually oxidizes rapidly. Teturam blocks the enzymatic biotransformation of alcohol at the stage of oxidation of acetaldehyde, which leads to an increase in the concentration of acetaldehyde in the blood after alcohol intake. The accumulation after alcohol intake under the influence of teturam acetaldehyde leads to severe changes in the body for the patient: redness of the skin, feeling of heat in the face and upper body, tightness in the chest, shortness of breath, noise in the head, palpitations, a sense of fear, sometimes chills, etc. .

A known method of treating alcoholism by the simultaneous use of teturam and apomorphine hydrochloride for 15-45 days [3]. The simultaneous administration of teturam and apomorphine often causes adverse side effects: asthenic reaction, nausea, vomiting, allergies.

It is known to use emethine hydrochloride, which is an isoquinoline alkaloid, in the creation of various drugs. In this case, mainly injectable or powdery forms of emitin hydrochloride are used [4]. So in the method developed by I.F.Sluchevsky and A.A. Friken, injectable forms of apomorphine or emethine are used against the background of small doses of alcohol [5]. After several combinations, a persistent conditioned vomiting reflex forms in appearance, taste and smell of alcohol. However, like all constantly conditioned reflexes that are not reinforced, it fades in the future and therefore the treatment effect is unstable.

There is a method of treating alcoholism using emetin hydrochloride as an emetic to form a stable reflex of fear of drinking alcohol [6]. The disadvantage of this method is its low efficiency, associated with the presence of a vomiting effect, which does not suppress the pathological attraction to alcohol and remission is based only on a conditioned reflex of fear of drinking alcohol, which tends to weaken and fade.

There is also known a method of treating alcoholism by acting on ethanol-oxidizing enzymes, in particular alcohol dehydrogenases, with inhibitors such as emethine hydrochloride, doses that inhibit enzyme activity but do not induce vomiting, and the frequency and daily dose are determined depending on the patient’s clinical condition [7].

There is also known a method of treating alcoholism by administering to a patient sub-emetic doses of emetin, which is supplemented by the administration of piracetamai and choriogonic gonadotropin. In this case, emetin is administered in the form of powders [8].

All these known known methods of administering anti-alcohol drugs, in particular emethine hydrochloride, involve injectable or oral powder dosage forms of emethine, the use of which has its drawbacks. So injection forms of administration are quite difficult to use in practice and in everyday life. When using powder forms of emethine hydrochloride, the release of the active substance occurs in the stomach, which causes a gag reflex, and effective absorption of the drug does not occur. In addition, powder forms have negative ethical and practical aspects.

An object of the present invention is to provide an effective oral dosage form of emetin hydrochloride that does not interact with gastric receptors and does not induce an emetic effect, which increases the bioavailability of the drug and reduces the patient's dependence on alcohol.

The problem is solved by creating granules of emethine hydrochloride for the treatment and prevention of alcoholism containing 70-90 wt.% Emethine hydrochloride, polyvinylpyrrolidone and eudragit, by developing a method for its preparation and a tablet or encapsulated dosage form of emethine hydrochloride for targeted delivery to the intestines for the treatment or prevention of alcoholism.

In accordance with the invention, a granulate of emetin hydrochloride for the treatment and prevention of alcoholism is described, containing 70-90 wt.% Emetin hydrochloride, polyvinylpyrrolidone and eudragit.

Also described is a method for producing granules of emethine hydrochloride by granulation of emethine hydrochloride by irrigation of crushed emethine hydrochloride with an aqueous solution of polyvinylpyrrolidone at elevated temperature, followed by irrigation of the obtained granules with a 10-30% aqueous suspension of eudragit.

A tablet or capsule dosage form of emethine hydrochloride is also described for targeted delivery to the intestines for the treatment or prevention of alcoholism, including the above granules of emethine hydrochloride and excipients, which are used microcrystalline cellulose, starch, sugar, calcium or magnesium stearate and talc with the content of emethine hydrochloride 2-15 wt.%.

The described dosage form provides the release of emtin hydrochloride in the intestine, which allows the effective use of emetin hydrochloride, eliminate the gag reflex and avoid the negative aspects of its use.

The invention is illustrated by the following examples.

The manufacture of granules of emetin hydrochloride

Example 1

10 grams of powdered to the size of a powder (single crystal size does not exceed 100 μm) emethine hydrochloride is placed in a pelletizing boiler heated to 50 ° C, and with constant rotation, 6 ml of a 5 wt.% Aqueous solution of polyvinylpyrrolidone is irrigated from the sprayer based on the total amount of polyvinylpyrrolidone PVP) 3% (of emethine hydrochloride). Blowing the pelleting boiler is made with air heated to 60 ° C with an intensity not higher than the entrainment of the substance from the pelleting boiler. Then, with constant rotation, 10 ml of a 30% aqueous suspension of eudragit are irrigated from a spray bottle; the amount of suspension sufficient to create a complete coating of the surface of emethine hydrochloride is 30% by weight of the amount of emethine hydrochloride. After final drying, the granulate is discharged from the pelletizing boiler. The weight of the obtained granulate is 12.5 g, the content of emetine hydrochloride is 75%.

The following table 1 shows the remaining examples of the manufacture of granulate emethine hydrochloride.

Table 1 Example No. T-ra drage. boiler, ° С T-ra Blowing, ° C Concentrate suspension of eudragit,% The amount of suspension of eudragit,% Concentrate PVP solution,% The number of PVP,% The content of emetine hydrochloride,% 2 40 60 thirty twenty - - 83 3 fifty 60 twenty thirty - - 75 four 40 70 10 thirty - - 75 5 40 40 thirty 10 5 3 88 6 fifty 60 10 twenty 10 3 81 7 fifty fifty thirty twenty 5 one 82 8 fifty fifty twenty thirty 10 one 76 9 40 70 10 thirty 10 3 75 10 40 70 thirty twenty 5 2 82 eleven 40 70 twenty thirty 5 5 74 12 60 60 thirty 40 - - 71

The manufacture of the finished dosage form.

Example 14

10 g of the granulate obtained in Example 1 are placed in a planetary mixer, 1.5 g of calcium stearate, 3 g of talc, 135.5 g of microcrystalline cellulose (MCC) are added. The total amount of auxiliary is 140 g. Stirred for 60 minutes. From the finished mixture pressed tablets weighing 100 mg with the content of emetin hydrochloride in a tablet of 5 mg, which is 5% by weight of the tablet.

Example 15

10 g of the granulate obtained in example 2, is placed in a planetary mixer, add 1.5 g of calcium stearate, 3 g of talc, 151.5 g of MCC. The total amount of auxiliary is 156 g. Stirred for 60 minutes. 100 mg tablets are compressed from the finished mixture. The content of emethine hydrochloride in the tablet is 5 mg, which is 5% by weight of the tablet.

Examples 16-24 are made in a similar manner and are shown in table 2

table 2 Example No. The amount of calcium stearate, g The amount of talc, g The number of MCC, g Granulate from Example No. 16 1.5 3 134.5 3 17 1.5 3 134.5 four eighteen 1.5 3 161.5 5 19 1.5 3 147.5 6 twenty 1.5 3 159.5 7 21 1.5 3 137.5 8 22 1.5 3 134.5 9 23 1.5 3 159.5 10 24 1.5 3 133.5 eleven

Example 25

4 g of the granulate obtained in Example 2 are placed in a planetary mixer, 1.5 g of calcium stearate, 3 g of talc, 151.5 g of MCC are added. The total number of auxiliary 156 g. Stirred for 60 minutes. 200 mg tablets are pressed from the finished mixture.

The content of emethine hydrochloride in the tablet is 4 mg, which is 2% by weight of the tablet.

Example 26

30 g of the granulate obtained in example 2, is placed in a planetary mixer, add 1.5 g of calcium stearate, 3 g of talc, 151.5 g of MCC. The total amount of auxiliary is 156 g. Stirred for 60 minutes. 100 mg tablets are compressed from the finished mixture.

The content of emethine hydrochloride in the tablet is 15 mg, which is 15% by weight of the tablet.

Example 27

Production of starch sugar granulate

10 kg of powdered sugar and 5 kg of dry starch are placed in a fluidized bed dryer. The air temperature is set at 45 ° C, the flow rate is 500 m ³ / hr and irrigated through the nozzle with five liters of 2% starch paste. After final drying, the granulate is sieved through a sieve.

10 g of the granulate obtained in example 2, is placed in a planetary mixer, add 156 g of starch-sugar granules. Stirred for 60 minutes. The finished mixture in an amount of 100 mg is placed in a hard gelatin capsule No. 3. The content of emethine hydrochloride in the capsule is 15 mg. The finished mixture in an amount of 200 mg is placed in a hard gelatin capsule No. 2. The content of emethine hydrochloride in the capsule is 10 mg. The finished mixture in an amount of 300 mg is placed in a No. 1 hard gelatin capsule. The content of emethine hydrochloride in the capsule is 15 mg.

Examples 28-31 carried out similarly to example No. 27 and are shown in table No. 3

Table 3 Example No. The amount of starch-sugar granulate, g Granulate from Example No. 28 138 3 29th 138 four thirty 166 5 31 151 6

Example 32

Determination of the rate of release of emethine hydrochloride from the obtained tablets or capsules

A capsule or tablet containing 5 mg emetin hydrochloride is placed in a container with a standard buffer solution with a pH of 1.5-2. The release rate is 1 mg / hour. The data obtained indicate that in the stomach, the release of emethine hydrochloride does not occur, since the average residence time in the stomach is approximately 30 minutes. At pH 5.5, the release rate is 10 mg / hour, which indicates a complete release in the intestine.

The determination of the therapeutic effect was carried out as follows.

Two groups of subjects were compared, 20 people each. For the study, 2 groups of patients were selected.

1 group (main) - patients receiving the drug - 20 people,

2 group (control) - patients who did not receive the drug - 20 people.

The distribution of patients by sex was as follows: in the first (main) group of men - 15 people (75%) of women - 5 (25%), in the second (control) group of men - 14 (70%), women - 6 (thirty%)

Distribution of patients by age: in the first group of patients aged 18-25 years old there were 3 people (15%), from 26-35 years old 6 people (30%) and over 36 years old 11 people (55%); in the second group, between the ages of 18–25 years old there were 4 people (20%), from 26–35 years old, 8 people (40%) and over 36 years old, 8 people (40%).

The distribution of patients according to the stages of the disease: in the first group (main) of patients with stage I disease, 5 people were taken (25%); with stage II 10 people (50.0%); with stage III 5 people (25%). In the second (control) group, with stage I disease, 6 people were selected (30%), with stage II people (10.0%) and stage III patients 4 (20%).

The type of primary psychological attraction to alcohol in the 1st (main) group was constant in 5 patients (25%), periodic in 6 (30%), mixed in 196 people (45%). In the 2nd (control) group, respectively, 4 (20%), 6 (30%), 10 (50%).

Thus, the clinical characteristics of the patients selected for the study in the 1st (main) and 2nd (control) groups were approximately the same and quite suitable for comparative observation.

The subjects were asked to take orally three tablets (capsules) of emethine hydrochloride containing 5 mg emethine hydrochloride prepared in accordance with the invention. As criteria, the magnitude of the activity of alcohol dehydrogenase (ADH) was considered. The observation duration was 60 days. Table 4 shows the data on the measurement of ADH activity in the control and main groups

Table 4 Observation day one 10 fifteen twenty thirty 40 60 Activity
The main column
ADH, units / l 4,5 ± 1,2 3.5 ± 1.1 3.0 ± 1.0 4,5 ± 1,2 4,5 ± 1,2 4,5 ± 1,2 0.5 ± 0.3 Activity
Control gr
ADH, units / l 4.4 ± 1.3 4.7 ± 1.6 4.1 ± 1.3 4.2 ± 1.3 4.4 ± 1.4 4.0 ± 1.5 4.3 ± 1.3

The above data show a gradual steady decrease in ADH activity against the background of the control group. As observations of the dynamics of stopping the mental component of subdepression have shown (table 5), the use of the described dosage forms of emetin hydrochloride leads to a sustainable therapeutic effect.

The dynamics of stopping the mental component of subdepression is shown in table No. 5.

Table number 5 Symptoms Main group (1) 1 day 14 day 28 day 60 day abs. % abs. % abs. % abs. % Dissatisfaction with oneself 17 85 19 47.5 12 30,0 8 40 Dissatisfaction with others 16 80 17 85 9 45 6 thirty Craving for alcohol twenty one hundred 17 85 fifteen 75 8 40 Indecision eleven 55 10 fifty 8 40 6 thirty Irritability 19 95 fourteen 70 10 fifty 6 thirty

Symptoms Control Group (2) 1 day 14 day 28 day 60 day abs. % abs. % abs. % abs. % Dissatisfaction with oneself 17 85 16 80 17 85 fifteen 75 Dissatisfaction with others 16 80 17 85 16 80 fifteen 75 Craving for alcohol twenty one hundred 19 95 twenty one hundred eighteen 90 Indecision eleven 55 12 60 fourteen 70 eleven 55 Irritability eighteen 90 19 95 17 85 eighteen 90

Bibliography

1. "Alcoholism", A manual for doctors, edited by G.V. Morozov and others, M., Medicine, 1983, pp. 321-328.

2. Strelchuk I.V. Antabuse treatment of alcoholics, "Neurology and Psychiatry", 1952, No. 4, pp. 43-50.

3. SU, 1806743, A61K 31/485, 04/07/1993.

4. Mashkovsky M.D. Medicines, 2001, Moscow, edition, volume 2, p. 351.

5. Korkina M.V. and other Psychiatry, M., Medicine, 1995, p. 211.

6. Lakusta V.N. "Methodology for the treatment of alcoholism", Chisinau, 1987, p. 87.

7. RU 2153336, A61K 31/445, 07.27.2000.

8. SU 1734752, A61K 31/00, 05.23.1992.

Claims (3)

1. Granulate emethine hydrochloride for the treatment and prevention of alcoholism, containing 70-90 wt.% Emethine hydrochloride, polyvinylpyrrolidone and eudragit. 2. A method of producing granules of emethine hydrochloride, characterized in that granulate emethine hydrochloride by irrigation of crushed emethine hydrochloride with an aqueous solution of polyvinylpyrrolidone at elevated temperature, followed by irrigation of the obtained granules with a 10-30% aqueous suspension of eudragit. 3. A tabletted or encapsulated dosage form of emethine hydrochloride for targeted delivery to the intestines for the treatment or prevention of alcoholism, including granules of emethine hydrochloride according to claim 1 and excipients, which use microcrystalline cellulose, starch, sugar, calcium or magnesium stearate and talc with the content of emetin hydrochloride 2-15 wt.%.