Combined anti-tuberculosis drug and method thereof

 

(57) Abstract:

The invention relates to the field of medicine and relates to a combined anti-tuberculosis drugs, containing as active substances isoniazid and pyrazinamide or ethambutol hydrochloride, and as auxiliary substances - calcium phosphate dihydrate and/or starch, polyvinylpyrrolidone and/or talc, stearic acid or its salts, and method of its production by mixing the active ingredients with calcium phosphate dihydrate and/or starch, moistening the mixture with an aqueous solution of starch or polyvinylpyrrolidone with subsequent granulation, drying and dusting. The tool reduces the risk of resistance of Mycobacterium tuberculosis to antibiotics. 2 S. and 3 C.p. f-crystals, 3 ill., 3 table.

The invention relates to medicine and can be used to treat various forms of tuberculosis.

Most high bacteriostatic activity possesses isonicotinic acid hydrazide, isoniazid, which is the main anti-TB drugs, especially in the treatment of new TB cases [M. D. Mashkovsky, Medicines, Kharkov, Torching, 1997, so 2, page 331] . Yes - the main antibacterial;

drugs II series is back.

Drugs number I, which is the main chemotherapeutics for the treatment of tuberculosis of various types, include isoniazid and its derivatives, para-aminosalicylic acid and its derivatives, the group antibiotics streptomycin. Antibiotics other groups highly effective anti-TB drug rifampicin is.

The second-order drugs include ethionamide, protionamide, ethambutol, cycloserine, pyrazinamide, thioacetazone, kanamycin.

Anti-TB drugs I stimulants are highly effective, but their use is rapidly developing resistance to tuberculosis bacteria. When alone sustainable forms of mycobacteria may appear in 2-4 months. At the time of treatment of TB from 8 to 18 months or more it becomes evident the need for multiple medications.

The second-order drugs less active effect on Mycobacterium tuberculosis than isoniazid, however, they act on the bacilli become resistant to the drugs I series.

In recent years, in the Arsenal of TB there were drugs, possessing, along with pricin).

Development of resistance in mycobacteria is much slower in case of simultaneous use of several drugs. Therefore, modern antibiotic therapy of tuberculosis is combined. In 1987, at a conference of the International Union against tuberculosis and lung diseases was expressed for the idea of use in the treatment of tuberculosis combined preparations with fixed doses. At the present time is actually 25% of patients use a combination of anti-TB drugs to fixed-dose combinations. Who recommends their use not less than 95% of patients with tuberculosis. Apply 2-3-component and 4-component drugs (rifater, isoptin, myrin-P and others).

An attempt was made to combine isoniazid and ethambutol in the single chemical compound [U.S. Pat. Germany 2026935, 1971 and U.S. Pat. USA 4450274, 1984]. To this end was synthesized by Sol isoniazidresistant acid and ethambutol, which has not only a much stronger effect compared to a single source substances, but surpasses the combined effect of both the original substances. However, the literature contains no information on the toxicity obtained soedineniya.

In U.S. patent 5104875, 1992, describes pharmaceutical combined preparation containing rifampicin, Thiacetazone and optional isoniazid or ethambutol (see tab. 1).

In EP 0650728, 1995 (prototype) the TB pharmaceutical compositions in which to enhance therapeutic activity of combinations of known anti-TB drugs is proposed to use the piperine in an amount of from 0.4 to 0.9% of the total mass. The composition includes two or more drugs selected from:

Ethambutol - 8-15 mg/kg body weight

Rifampicin - 100-300 mg

Isoniazid - 100-300 mg

Pyrazinamide is 500-1000 mg

Conducted a pharmacokinetic study of the combination (see table. 2).

It is shown that the concentration of drugs in blood in the presence of piperine significantly higher than in its absence (see tab. 3).

However, in the patent specifies only the number of active substances, but do not specify the composition of the dosage form and quantity of auxiliary ingredients.

The objective of the invention is to expand the Arsenal of anti-TB drugs by the creation of a combined anti-tuberculosis drugs that reduce the ability voznikshego to conduct controlled treatment and reduce medication burden on the patient.

The technical result is obtained when implementing the present invention is that the resulting dosage form new combination TB drugs satisfies all the requirements of Gosfarmakapei pharmaceutical agent, namely: it is stable during storage, has desired raspadaemost, provides a high clinical effect, convenient dosage and high bioavailability of its components.

This technical result is achieved by the fact that the claimed combination anti-tuberculosis drug contains isoniazid, and pyrazinamide or ethambutol hydrochloride and pharmaceutically acceptable additives target, which are to create a solid dosage form using calcium phosphate dihydrate and/or starch, polyvinylpyrrolidone and/or talc, stearic acid and/or its salts in the following ratio, wt.%:

Isoniazid - 10,0-35,0

Pyrazinamide or ethambutol hydrochloride - 50,0-85,0

Calcium phosphate dihydrate and/or starch - 2,0-15,0

Polyvinylpyrrolidone and/or talc - 0,1-6,0

Stearic acid and/or its salts - 0,5-3,0

On the model of the generalized tuberculosis mice was shown tselesoobraznom level. Infected with Mycobacterium tuberculosis (MBT) animals were treated with pyrazinamide (P) or ethambutol hydrochloride (e) alone or in combination with isoniazid (S) within 1 month. Then take into account the inoculation of colonies of the office of the lung tissue and expressed in percentage in relation to Visavuori from the lungs of mice in the control group (). The results of the experiment shown in Fig. 1.

Inoculation of colonies from the lungs of mice treated with the combination And+P, amounted to 10.3%, which is 3.8 times lower compared to the one of P. Differences in performance between And+P, and one minor, but the value of this combination is due to the special properties of pyrazinamide: to act on the inside macrophages office and to influence the pharmacokinetics of isoniazid (Fig. 2).

As follows from Fig. 1, the inoculation of colonies of the office of mice treated with e+And almost 7 times lower than one e and 2 times compared to one, which indicates a pronounced synergistic effect of interaction on the microbial level.

In the study of TB patients the pharmacokinetics of ethambutol hydrochloride during simultaneous administration with isoniazid statistically significant increase in maximum concentration and a lengthening of the lie is in ethambutol hydrochloride indication of slowing its excretion in the presence of isoniazid.

When creating solid dosage forms such as tablets claimed combined anti-tuberculosis drugs to give the best technological properties, namely, the flowability and pressuemosti, mixtures of TB substances as diluents were used starch and/or calcium phosphate dihydrate in an amount of from 1.0 to 15.0 wt. %. Starch can be used in a variety of: potato and/or corn and/or rice and/or modified starch.

To ensure the strength of the granules and tablets as a binder used aqueous solutions of polyvinylpyrrolidone and/or starch, or gelatin in an amount of from 0.1 to 3.0 mass. %.

To improve fluidity tableting mass, prevent sticking them on the plungers and the walls of the holes of the matrix as a lubricating and sliding substances used stearic acid and/or its salts, and/or talc, and/or polyvinylpyrrolidone. They provide good flowability and uniform supply tableting mass from the hopper into the matrix, which ensures the accuracy and consistency of dosage of medicinal substances. The number of substances that promote the slip, is 0.1 to 3.0% of the total mass.

Composition is Tate receive a mixture of substances, having good processing properties in the process of granulation and tableting, and the resulting tablets have properties that satisfy the requirements of the pharmaceutical agent, i.e., have a saleable condition without chips and cracks, have sufficient strength and raspadaemost, are stored for at least 2 years, we provide high clinical effect, convenient dosage and high bioavailability of its components.

One way of getting of pills is a method of wet granulation, comprising the following steps: mixing powders, hydrating, mixing, granulation, drying, dusting, pressing ("Technology of medicinal forms", so 2, edited by L. Ivanova A., M.: Medicine, 1991, S. 142).

The method of obtaining the claimed combined anti-tuberculosis drugs is that mixed isoniazid, pyrazinamide or ethambutol hydrochloride, calcium phosphate dihydrate and/or starch, the mixture components hydrate aqueous solution of starch or polyvinylpyrrolidone and passed through a granulator, wet granulate is dried at a temperature of 30-50oWith up to a moisture content of 0.5 to 3.0 wt.%, the dried granules are passed cher what pirrolidone and tabletirujut.

The invention is illustrated by the following examples:

Example 1. Carefully mix 100.0 g pyrazinamide, 30.0 g of isoniazid, and 2.2 g of starch. The mixture is moistened 27.3 g 3% starch paste. The resulting mass granularit through the perforated grid hole diameter 3.5 mm Granulate is dried at a temperature of 35-40oTo the moisture content of 1.4-2.0%. The granulate is milled and passed through a sieve with the hole diameter of 1.25 mm Get 121.8 g of dry milled granulate, which optivault 2.5 g of starch, 1.3 g of talc and 1.3 g of stearic acid. The prepared mixture is tabletirujut on dropwinsonde tablet press. Control the weight, strength and raspadaemost received tablets. Get 126.0 g or 180 tablets with an average weight of 0.7 g (norm 0.665 g - 0.735 g); strength 11-15 kg; raspadaemost 4-8 min (normal: less than 15 min); dissolution: 101% pyrazinamide (norm: not less than 75%) and 99% of isoniazid (norm: not less than 75%); the content of pyrazinamide 0.504 g (norm 0.475 - 0.525 g), isoniazid, 0.154 g (norm-0.143 - 0.158 g).

Example 2. Mix 80.0 g of ethambutol hydrochloride, 30.0 g of isoniazid, 9.0 g of calcium phosphate dihydrate and 3.5 g of potato starch. The mixture was mixed thoroughly and moisturize 13.8 g of a 20% aqueous solution of p the Granulate is dried at a temperature of 30-40oWith a moisture content of 1.0-1.5%. The dry granulate is passed through a granulator hole diameter 2.5 mm Get dry milled granulate 115.8 g, which optivault 2.4 g of polyvinylpyrrolidone and 1.9 g of magnesium stearate. All are thoroughly mixed to obtain a homogeneous mass. Flowability tabletas mixture of 6.0-7.0 g/C. Ready weight tabletirujut on dropwinsonde laboratory tabletting machine. Get 117.0 g or 180 tablets with an average weight of 0.65 g (norm-0.618-0.683 g); strength 8-11 kg; raspadaemost 5-6 min (norm: not less than 15 min); dissolution: ethambutol 90.1% (normal: not less than 75%), isoniazid 100,0% (normal: not less than 75%); the content of ethambutol: 0,411 g (norm-0.380-0.420 g), the content of isoniazid: 0.153 g (norm-0.143-0.158 g).

Example 3. Carried out analogously to example 1 or 2. For dusting using 5.0 g of a mixture containing sodium starch glycolate (primogel), talc and stearic acid in a ratio of 2: 1:1. Get tablets strength 15-18 kgs and raspadaemost 3 minutes Other quality indicators comply with the normative documentation (see examples 1 or 2).

The results of clinical trials.

Combined anti-tuberculosis drug in example 1, 3.

(Any combination of isoniazid 0 is x with a predominance of infiltrative form (15). In 10 patients the process was bilateral in 5 celebrated the defeat of the entire lung. All patients were allocated to the office, and two with resistance to isoniazid and streptomycin, and had a cavity decay. In 95% of patients had symptoms of tuberculosis intoxication.

Combined antituberculosis drug was dosed out on isoniazid 10 mg/kg and was administered 1-2 times per day after meals. At the same time in the treatment regimen consisted of rifampicin, streptomycin, vitamin b6and multivitamins in normal dosages. The duration of treatment is 3 months.

Already after 2 months. treatment by 68.4% of patients had no symptoms of tuberculosis intoxication. According to the criterion of sputum conversion efficiency of treatment was high (90%). Only patients with sustainability office bazillionaire was achieved within 3 months., given the large prevalence of lung tissue destruction percentage of closing cavities (45%) can be considered quite high.

Combined anti-tuberculosis drug according to example 2, 3.

(Any combination of isoniazid 0.15 g of ethambutol hydrochloride 0.4 g)

Clinical trials of combination anti-TB drugs isoniazid and ethambutol hydrochloride carried out at 20 ill is persistent (rifampicin and isoniazid) office. All patients were determined by the cavity decay. Of clinical forms prevailed infiltrative tuberculosis of the lungs (85%). In 8 patients the process was bilateral in 7 celebrated the defeat of the entire lung. In 85% of patients were expressed symptoms of tuberculosis intoxication.

The treatment was performed within 3 months. The drug was dosed out on isoniazid 10 mg/kg and was administered 1 time per day before meals. At the same time patients received rifampicin and streptomycin in normal dosages.

The symptoms of tuberculosis intoxication disappeared in most patients (88%) after 2 months. treatment at all - by the end of treatment. Sputum smear conversion at the end of treatment was achieved in 90% of patients with initially sensitive to drugs mycobacteria. In patients with sustainability office and a generous smear-positive sputum smear conversion came at a later date.

Given the high prevalence of process in the lungs, closing cavernous 40% after 3 months. proof enough for effective treatment of the claimed drug.

Thus, the advantage of the claimed combined anti-TB drugs is scientifically grounded selection of effective and well-Perrin especially at the stage of aftercare on an outpatient basis.

1. Combined anti-tuberculosis drug containing isoniazid and pyrazinamide or ethambutol hydrochloride and pharmaceutically acceptable additives target, wherein the target additives it contains calcium phosphate dihydrate and/or starch, polyvinylpyrrolidone and/or talc, stearic acid and/or its salts in the following ratio, wt. %:

Isoniazid - 10,0-35,0

Pyrazinamide or ethambutol hydrochloride - 50,0-85,0

Calcium phosphate dihydrate and/or starch - 2,0-15,0

Polyvinylpyrrolidone and/or talc - 0,1-6,0

Stearic acid and/or its salts - 0,5-3,0

2. Combined anti-tuberculosis drug under item 1, characterized in that it is made in the form of solid dosage forms.

3. Combined anti-tuberculosis drug on PP. 1 and 2, characterized in that it is made in the form of tablets.

4. The method of obtaining a combined anti-tuberculosis drugs on PP. 1-3, namely, that mix isoniazid, pyrazinamide or ethambutol hydrochloride, calcium phosphate dihydrate and/or starch, the mixture components hydrate aqueous solution of starch or polyvinylpyrrolidone and passed through a granulator, wet grain is or talc, and/or starch and/or polyvinylpyrrolidone and tabletirujut.

5. The method according to p. 4, characterized in that the drying of the granulate lead to a moisture content of 0.5 to 3.0 mass. %.

 

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