RU2363475C2 - Antituberculous tablet - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to the agents possessing antituberculous action and used in phthisiology. The tablet contains 1-isonicotinyl-2-glucosylhydrazone dihydrate (isoglucosyl), hydroxypropylmethylcellulose or methylcellulose and calcium stearate. The tablet can be covered by a cover. The invention provides high therapeutic efficiency and hypotoxicity of the new agent in comparison with known antituberculous forms of Isoniaside and rifampicin.

EFFECT: provision of high therapeutic efficiency and hypotoxicity of the new agent in comparison with known antituberculous forms of Isoniaside and rifampicin.

2 cl, 1 tbl

Description

The invention relates to medicine, namely to drugs with anti-tuberculosis action and used in TB.

According to the World Health Organization, the number of cases of tuberculosis in the world is increasing every year, despite programs aimed at preventing tuberculosis. In our country, there is also an increase in cases of highly contagious open (pulmonary) tuberculosis. The treatment of tuberculosis is complicated by the ability of the causative agent of tuberculosis to change in the macroorganism and in this form to endure adverse conditions (the occurrence of L-forms), which leads to the development of drug resistance to anti-TB drugs, as well as to changes in virulence while maintaining the main quality - pathogenicity. To overcome this problem, it is necessary to use new anti-TB drugs in phthisiology, created by chemical modification of the most effective anti-TB drugs. The resulting substances have a higher chemotherapeutic index, which allows you to increase their therapeutic dose without fear of reactions from the macroorganism.

Currently, group I drugs in the treatment of tuberculosis are isoniazid and rifampicin, which have high bacteriostatic activity against tuberculosis mycobacteria. It should be noted that, despite the high activity of these drugs in relation to the causative agent of tuberculosis, they have a number of undesirable side effects of both allergic and non-allergic nature. So, isoniazid is characterized by such side effects as the effect on the central nervous system (convulsions, mental disorders, etc.), neuritis, allergic reactions.

For rifampicin, dyspeptic disorders, inhibition of liver function, allergic reactions, as well as the development of superinfection and the rapid development of resistance of mycobacterium tuberculosis to rifampicin can be distinguished. These side effects can be threatening and are an indication for drug withdrawal.

To improve the biopharmaceutical properties of isoniazid, prolong its action and reduce toxicity, it is proposed to use such polymers as ethyl cellulose, β-cyclodextrin, pectins, etc. [Ovcharenko L.P. The study of inclusion compounds of substances derived from isonicotinic acid with β-cyclodextrins: Abstract of thesis. Candidate of Pharmaceutical Science. - Pyatigorsk, 1991, p.21; Turkenbaeva K.A., Shipunova O.V., Krivtsova A.E. and others. On the possibility of treating tuberculosis with prolonged-acting polymer isoniazid. // Probl. tuberculosis, 1990, No. 3, S. 32-35].

Modified anti-tuberculosis drugs synthesized on polymer matrices and having a prolonged effect often lead to undesirable consequences - the formation of benign tumors. This is due to the fact that the polymers of synthesized preparations on polymer matrices significantly reduce the effect of other drugs used in combination with isoniazid derivatives [A.A. Priymak, G.B.Sokolova, A.M. Belkind, A.I. Slivkin and other Laboratory and experimental studies. // Probl. tuberculosis, 1987, No. 1, p. 53].

The active substance is isoglucosyl synthesized on a monomeric carbohydrate matrix with an isoniazid content of 46.5%. In vivo studies have shown that isoglucosyl exhibits high bacteriostatic activity against strains of mycobacterium tuberculosis and is characterized by low toxicity compared to isoniazid [Slivkin A.I., Lapenko V.L., Sirotkina G.G. et al. Polymeric form of isonicotinic acid hydrazide. // Man and medicine: Abstracts. IV Russian National Cong. (April 8-12, 2002). - M., 2002, p.698].

The objective of the invention is the creation of drugs based on isoglucosyl in the form of a solid dosage form, which will expand the range of anti-TB drugs.

The technical result consists in high therapeutic efficacy and low toxicity.

Isoglucosyl, an isoniazid derivative synthesized on the basis of the monomer matrix of the carbohydrate type, is an anti-tuberculosis compound; its in vitro activity is not inferior to that of isoniazid.

The toxicity of isoglucosyl is significantly lower than the toxicity of isoniazid (24 times in terms of LD ₅₀ ).

Isoglucosyl is able to remain at a bacteriostatic level 12 hours longer than isoniazid.

The breadth of the therapeutic effect of isoglucosyl is 15 times higher than isoniazid in the absence of negative phenomena, such as acute and chronic toxicity, embryotoxicity, teratoxicity, hepatotoxicity, characteristic of isoniazid. Iso-glucazyl has a prolonged property, in connection with which the frequency of its administration can be halved.

The technical result is solved in that the anti-tuberculosis tablet contains 1-isonicotyl-2-glucosyl hydrazone dihydrate (isoglucosyl), methyl cellulose and calcium stearate in the following ratio of components, g:

Isoglucosyl 0.285-0.315 Hydroxypropyl methylcellulose or cellulose 0.006 Calcium stearate 0.003

The tablet is additionally coated.

The composition of the shell includes film-forming substances in an amount of from 50 to 99% by weight of the shell, plasticizers in an amount of from 1 to 50% by weight of the shell, pigments (dyes) from 0 to 20% by weight of the shell, glossy substances from 0 to 10% by shell masses. The mass of the shell in this case is from 1 to 10% by weight of the tablet.

The film-forming substance can be selected from derivatives: cellulose, polymethacrylic acid, povidone, polyvinyl alcohol; enteric film-forming substances: acetylphthalyl cellulose, hydroxypropyl methyl cellulose phthalate.

Macrogol as a plasticizer, titanium dioxide as a pigment, and talc as a gloss substance.

Success in treating any disease and providing a drug to a population also depends on the choice of dosage form. We have proposed a solid dosage form - a tablet. Her choice is due to:

- the possibility of the proper level of mechanization of the main stages and operations of production, contributing to high productivity and hygiene;

- the accuracy of the dosage of drugs introduced into tablets;

- portability of tablets, convenient for dispensing, storage and transportation;

- long-term preservation of medicinal substances in a compressed state;

localization of the action of a drug substance in a certain section of the gastrointestinal tract (absorption occurs in the intestine, and not in the stomach, so there will be no irritating effect on the gastric mucosa);

- prolongation of the action of the drug substance.

ACTIVE TABLET SUBSTANCE

Isoglucosyl (1-isonicotyl-2-glucosylhydrazone dihydrate) is a powder, odorless, white with a cream tint, and is stable in air. Anti-tuberculosis drug.

C ₁₂ H ₁₇ N ₃ O ₆ · 2H ₂ O. mm. 335.3.

EXCIPIENTS

Methyl cellulose (MC) - a synthetic polymer is a powdery fibrous substance of a white or slightly yellowish color without sugar and taste. It is soluble in cold water, mixtures of lower alcohols with water. Unlike starch, dextrin and other similar products, it is more resistant to microflora. It is used as a binder, allowing to obtain granules with good compressibility.

Hydroxypropyl methylcellulose is a white powder without taste and odor, soluble in cold water and aqueous solutions of some organic solvents. The product has high chemical inertia and is relatively resistant to microbial degradation. It does not have an allergenic effect and is not digested in the gastrointestinal tract. Rapid hydration in the oral cavity facilitates easier swallowing of tablets. The formation of gels with high viscosity during dissolution of the tablets causes a slow (prolonged) release of the substance from the dosage form and helps to create a smoother concentration profile of the drug in the body.

Calcium stearate is a white powder with a slightly yellowish or grayish tint, insoluble in water. A low-toxic substance has an irritating effect on the mucous membranes of the eyes. As part of tablets, it is used as a lubricant to facilitate the ejection of tablets from the matrix to prevent tablets from sticking to punches. In addition, calcium stearate is a sliding and anti-adhesive substance.

Water data for preliminary work are presented in figure 1.

Taking into account the current requirements of OFS 42-0003-04 in terms of “dissolution”, at least 70% of isoglucosyl must pass into the solution in 45 minutes, the technology of works No. 2, 3, 4, in which tablets corresponding to specified requirements.

CHARACTERISTIC OF THE READY-FORMED MEDICINAL FORM

Pills in white or cream-white with a smooth surface of a flat-cylindrical shape. In appearance they must comply with the requirements of the Global Fund XI issue 2, p. 154. The diameter of the tablet (9 ± 0.1) mm, height (3.2 ± 0.4) mm.

Authenticity. According to the methodology of FSP 42-.

The average weight. 0.309 ± 5% (GF XI, issue 2, p. 154).

Deviations in the mass of individual tablets. Must comply with the requirements of the Global Fund XI, issue 2, p. 154.

Impurity content of isonicotinic acid hydrazide. According to the methodology of FSP 42 - (according to TCS, the stain of an isonicotinic acid hydrazide impurity should not exceed 0.4%).

Disintegration. No more than 15 minutes.

Dissolution. According to the methodology of FSP 42 - and the requirements of GF XI, issue 2, p. 154. Microbiological purity. Must withstand the requirements of the Global Fund XI, issue 2, p.193 and amendments No. 3 dated 06/01/1996 to the article of the Global Fund XI of the publication “Methods of microbiological control of medicines”, category 3

Quantitation. The content of isoglucosyl in one tablet should be from 0.285 to 0.315 g.

The technological process for industrial reproduction was determined by the results of experimental work.

A summary of the experimental work performed is presented in the table.

The suitability of the dosage form (tablets) created on the basis of 1-isonicotinyl-2-D-glucosylhydrazone is proved by the results of its preclinical study.

The preclinical study of 1-isonicotinyl-2-D-glucosylhydrazone was carried out in accordance with the Manual on the experimental (preclinical) study of new warmological substances, M., 2000. The results of the preclinical study of 1-isonicotinyl-2-D-glucosylhydrazone were presented in the form of an appropriate report. The report contains a report on the study of the general toxic effect of 1-isonicotinyl-2-D-glucosylhydrazone and a report on the study of the therapeutic effect of the new anti-tuberculosis drug 1-isonicotinyl-2-D-glucosylhydrazone.

Assessment of the general toxic effect of the drug was carried out according to the guidelines for the study of the general toxic effect of pharmacological substances ("Guide to the experimental (preclinical) study of new pharmacological substances", M., 2000, p.18-24).

The experiments were carried out on three types of animals: outbred mice of both sexes and linear mice of F1 hybrids (CBA × C57B1 / 6) of both sexes weighing 16-20 g; on outbred rats of both sexes weighing 100-150 g; on dogs of both sexes weighing 6-14 kg. The substance 1-isonicotinyl-2-D-glucosylhydrazone was used in the form of a tablet of a preparation with a methyl cellulose coating. Dogs on an empty stomach with a special probe were administered a tablet form. Then, the animals were not given food for 3.5 hours. After drug administration, animals were monitored for 2 weeks.

There were 2 dogs in the control group. In total, 11 dogs were in the experiment. The tablet form was administered orally in the following doses: - 55 mg / kg (corresponding to a dose of isoniazid 25 mg / kg) - one dog; 165 mg / kg to three dogs; 192 mg / kg to two dogs; 220 mg / kg to two dogs; 275 mg / kg per dog. At doses of 55 and 165 mg / kg, the drug was well tolerated by dogs. No changes in the behavior and general condition of the dogs were noted compared with the control. Increasing the dose to 192 mg / kg caused some excitement and motor activity for 3-4 hours. Subsequently, the dogs were oppressed. Normal state recovered after 6 days. In dogs that received the drug at a dose of 220 mg / kg, also after 3 hours, excitation was noted for 1.5 hours, turning into a depressive state (up to 3-5 days). On the remaining days, the dogs fully recovered. An increase in dose to 275 mg / kg caused the death of one dog after 6 hours from clonic-tonic seizures.

A study of the acute toxicity of 1-isonicotinyl-2-D-glucosylhydrazone in three types of laboratory animals showed that the drug is much better tolerated with oral and oral administration than isoniazid. The average lethal doses of 1-isonicotinyl-2-D-glucosylhydrazone for mice and rats with intraperitoneal administration were 6200 mg / kg and 6000 mg / kg, respectively. Thus, the average lethal dose of 1-isonicotinyl-2-D-glucosylhydrazone is 32 and 16 times higher for rats than isoniazid for rats. For dogs, the MPD of 1-isonicotinyl-2-D-glucosylhydrazone is 165 mg / kg and 6.6 times higher than that of isoniazid.

In the study of the anti-tuberculosis activity of 1-isonicotinyl-2-D-glucosylhydrazone, the appropriate guidelines were used ("Guide to the experimental (preclinical) study of new pharmacological substances", M., 2000, p. 287-292).

The effectiveness of the anti-TB drug 1-isonicotinyl-2-D-glucosylhydrazone was evaluated in an experiment on guinea pigs weighing 350-400 g. Animals (80 animals) were infected with a 2-week-old culture of MBT strain H37Ku, subcutaneously, in the right inguinal region at a dose of 0, 01 mg

After administration of the drug for 2 months at a dose of 50 mg / kg, pathogens are not detected in the internal organs and regional lymph nodes of guinea pigs infected with tuberculosis.

To justify the effectiveness of the therapeutic effect and the safety of the application, the determination of its concentrations in biological fluids and tissues of the body of guinea pigs was carried out. Parallel studies conducted with isoniazid.

The experiments were carried out on 24 intact female guinea pigs weighing 200-300 g. 1, 6, 14 and 24 hours after drug administration, the animals were killed and blood and organ tissues were taken for examination. The museum strain MBT N37Ku was used as a test culture. The data obtained indicate that 1-isonicotinyl-2-D-glucosylhydrazone is well absorbed. 24 hours after the administration of isoniazid, its blood level does not reach the MPC level, while the concentration of 1-isonicotinyl-2-D-glucosylhydrazone corresponds to 0.47 μg / ml, i.e. 1-isonicotinyl-2-D-glucosylhydrazone exceeds this level. In lung tissue 6, 14 and 24 hours after the administration of 1-isonicotinyl-2-D-glucosyl hydrazone, it is found in significantly higher concentrations than isoniazid. In the tissues of the liver and brain, the content of 1-isonicotinyl-2-D-glucosylhydrazone is lower than isoniazid. This explains the lower neuro- and hepatotoxicity of 1-isonicotinyl-2-D-glucosylhydrazone than isoniazid.

Anti-TB pill Name of components Amount, g Slave 1 Slave 2 Slave 3 Slave 4 Slave 5 Slave 6 1-isonicotyl-2-glucosylhydrazone dihydrate 150.0 150.0 150.0 150.0 150.0 150.0 Humidification: 10.0% MC solution 19.6 - - - - - 9.0% MC solution - - - - 23.0 19.0 7.0% MC solution - - 19.5 18.5 - - 5.0% MC solution - 23.0 - - - - Wet granulation through a mesh with a hole diameter, mm 2.0 2.0 2.0 2.0 2.0 2.0 Drying to residual moisture,% 1.8 1.86 2.0 2,4 2,4 2.2 Dry granulation through a mesh with a hole diameter, mm 1,0 1,0 1,0 1,0 1,0 1,0 Dusting: Calcium stearate 1,5 1,5 1,5 1,5 1,5 1,5 Tableting using a 9.0 mm flat cylinder press tool. Number of tablets received, pcs. 502 516 526 476 484 498 The quantitative content of the active substance in one tablet 0.299 0.291 0.285 0.315 0.310 0,301 The quantitative content of methyl cellulose in one tablet 0.006 0.006 0.006 0.006 0.006 0.006 The quantitative content of calcium stearate in one tablet, taking into account its residue after dusting 0.003 0.003 0.003 0.003 0.003 0.003 Average mechanical strength, cr 25.0 1 h - 7.0
2 h - 14.0 1 h - 2.0
2 h - 16.6 1 h - 10.0
2 h - 14.0 9.6 11.7 Dissolution: In 30 minutes 21.9 21.0 26.4 23.7 24.0 80.7 79.7 80.5 77.7 80.5 74.0 85.6 79.2 78.3 83.6 79.4 78.3 82.9 80.4 86.5 31.6 31.0 32.9 33.4 30.7 41.0 51.1 41.5 40.3 47.0 In 2 hours 45.6 48.3 45.8 46.2 47.8 - 100.0 100.0 71.8 76.8 71.2 80.5 70.5 87.6 84.8 88.6 86.9 90.5

Claims (2)

1. An anti-tuberculosis tablet containing 1-isonicotyl-2-glucosyl hydrazone dihydrate (isoglucosyl), hydroxypropyl methyl cellulose or methyl cellulose and calcium stearate in the following ratio, g:
Isoglucosyl 0.285-0.315 Hydroxypropyl methylcellulose or Cellulose 0.006 Calcium stearate 0.003 2. The tablet according to claim 1, characterized in that it is further coated.