RU2247561C1 - Composite pharmaceutical composition with antituberculous activity - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antituberculous formulation made in the form of solid dosage form containing as active principle combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries: starch, lubricant, and optionally microcrystalline cellulose. Composition is characterized by storage stability and high therapeutical efficiency.

EFFECT: increased assortment of antituberculous drugs.

6 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, specifically to combination anti-TB drugs, and can be used to treat various forms of tuberculosis.

Despite the significant successes achieved in recent decades in many areas of medicine, including tuberculosis therapy, the incidence rates of tuberculosis are still quite high. The main problems of treating tuberculosis include the limited arsenal of antituberculosis drugs and the rapid development of resistant forms of mycobacterium tuberculosis to the drugs used and, as a result, the increase in the number of patients infected with mycobacterium tuberculosis initially resistant to the main antituberculosis drugs.

The development of resistance of mycobacteria is much slower with the simultaneous use of several drugs. However, with combined therapy, patients with tuberculosis, due to the difficulties and the length of the selection of effective drugs, as well as the course of therapy, either carry it out irregularly or do not finish it, which causes a return of the disease and the emergence of secondary drug resistance. Therefore, the World Health Organization (WHO) recommends the abandonment of mono- and combination therapy and indicates the need for the use of combined anti-tuberculosis drugs with fixed doses in one tablet, providing an optimal therapeutic effect.

In the patent of the Russian Federation No. 2182483, 2002, a combined anti-tuberculosis drug is proposed that contains isoniazid and pyrazinamide or ethambutol hydrochloride. However, the presence in its composition of only two active components slightly reduces the ability of the drug to inhibit the development of resistance of tuberculosis mycobacteria during treatment and, accordingly, its effectiveness and requires the appointment of additional other anti-TB drugs.

The preferred course of treatment for tuberculosis is to prescribe isoniazid, rifampicin and pyrazinamide, to which the fourth drug, ethambutol, is usually added. Therefore, a combination agent containing isoniazid, rifampicin, pyrazinamide and ethambutol in one tablet can completely replace the course of combined therapy in the intensive phase of treatment for tuberculosis. But in combined preparations containing rifampicin, its bioavailability is significantly reduced due to the influence of other active substances, which worsens the therapeutic activity of the drug.

In European patent No. 0650728, 1995, pharmaceutical anti-tuberculosis compositions are described comprising two or more active ingredients selected from isoniazid, rifampicin, pyrazinamide and ethambutol. To improve the bioavailability and, accordingly, enhance the therapeutic activity of the combination of anti-TB drugs, it is proposed to use piperine in an amount of from 0.4 to 0.9% of the total weight of the composition.

International application WO 02/11728, 2002, gives examples of an oral composition containing isoniazid, rifampicin and additionally pyrazinamide and ethambutol. The composition has satisfactory rifampicin bioavailability due to the separate release of rifampicin and other active ingredients. This is achieved either by a barrier shell of pH-dependent polymers for different active substances, or by introducing the latter into the composition in various crystalline forms, such that significant differences in the release rate for different substances are ensured.

International application WO 02/87547, 2002, describes a composition of isoniazid, rifampicin, pyrazinamide and ethambutol obtained by the method of three- or four-stage granulation. This composition is characterized by a satisfactory bioavailability of rifampicin without the introduction of a sufractant, such as, for example, sodium lauryl sulfate.

However, with the course application of the above four-component preparations, a pronounced toxic effect and the occurrence of side effects are observed.

In the patent of the Russian Federation No. 2195937, 2003, a combined anti-tuberculosis drug is proposed containing, as an active principle, a combination of isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine, and methocell, methyl cellulose ethers containing 14-30% methoxy groups as a excipient (prototype ) This composition meets the requirements for the bioavailability of rifampicin, which determines its high therapeutic effect, and the presence of pyridoxine significantly reduces the toxic effect. However, this combined composition has a limited shelf life (less than 15 months).

The objective of this invention is to create a pharmaceutical composition with anti-tuberculosis action in the form of a solid dosage form containing, as an active principle, a combination of isoniazid, rifampicin, pyrazinamide, ethambutol (in the form of hydrochloride) and pyridoxine hydrochloride, which is stable for a sufficiently long period (at least 24 months) and has a high bioavailability for rifampicin and, accordingly, high therapeutic activity, which will expand the arsenal of drugs in therapy for tuberculosis.

The problem is solved in that the proposed pharmaceutical composition with anti-tuberculosis action, containing, as an active principle, a combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride, includes starch, lubricant and, optionally, microcrystalline cellulose in the following ratio: parts by weight per 1 part by weight rifampicin:

Rifampicin 1.0

Isoniazid 0.4-1.0

Pyrazinamide 2.0-3.5

Ethambutol hydrochloride 1.3-2.25

Pyridoxine hydrochloride 0.05-0.2

Starch 0.3-2.5

Lubricant 0.02-1.4

Microcrystalline cellulose 0-1.5

As a lubricant, stearic acid, a salt of stearic acid, aerosil, talc, other substances commonly used in the pharmaceutical industry as lubricants, or a mixture of the above compounds can be used. Examples of a stearic acid salt are calcium, magnesium, aluminum or other metal stearates, preferably calcium stearate and / or magnesium stearate.

The proposed ratio of ingredients is optimal, found experimentally and provides a technical result that matches the task.

Thanks to the claimed invention, the stability of the quality indicators of the dosage form during storage is achieved, which ensures its shelf life of more than 24 months.

A study of the toxic effect of the new drug showed that after two weeks of intragastric administration to rats at a dose of 500 mg / kg (according to the current principle), hematological (red blood cells, hemoglobin, white blood cells, reticulocytes, platelets) and biochemical (total lipids and glucose) blood parameters as indicators of toxicity do not differ from control. No structural abnormalities in organs and tissues were noted, and the irritating effect of the new composition on the mucous membrane of the gastrointestinal tract was also not detected.

The data of pharmacokinetic studies of the claimed drug showed that the maximum concentration of rifampicin in the blood created by the new composition was more than 2 times higher than the equivalent dose of the comparison drug, with equal half-lives (see Table 1), which indicates a higher rifampicin bioavailability (relative to prototype). This allows you to create a high concentration of rifampicin after taking the dosage form, and based on the results of biological studies, we can conclude that the new drug has high therapeutic activity and the possibility of its use as an anti-tuberculosis drug.

Table 1
Comparative pharmacokinetics of rifampicin in a medicinal mixture according to the prototype and in the claimed composition Dosage mg / kg The maximum concentration in the blood, mcg / ml Withdrawal time, T 1/2 Prototype rifampicin 10 7 (3-4 hours) 6 o'clock The inventive composition, rifampicin 10 16.3 (1.5-2 hours) 6 o'clock

The starch used according to the invention can be potato and / or corn and / or rice and / or modified starch. As the latter, it is preferable to use sodium glycolate starch (commercial products - modified starch brand "Primozhel" or brand "Explotab").

The proposed pharmaceutical composition is in the form of a solid dosage form, preferably in the form of a tablet, which may be coated. The presence of the latter improves the appearance and organoleptic properties of the dosage form, protects it from mechanical damage. Preferably, the shell is made on the basis of a derivative of cellulose, for example, hydroxypropyl methylcellulose, or a ready-made mixture of the brand "Opadry".

The preparation of the claimed dosage form can be carried out in accordance with known methods for the manufacture of solid dosage forms, for example, by wet granulation followed by the addition of a lubricant to the dry granules, molding the final mixture of ingredients with the formation of the dosage form of a given configuration and size and, if necessary, coating. In order to improve the technological parameters of the finished mixture (flowability, compressibility), the inventive composition may additionally include sodium croscarmellose (a cross-linked polymer of sodium carboxymethyl cellulose). A suitable amount of the latter is 0.1-0.6 wt.h per 1 wt.h. rifampicin.

The invention is illustrated by the following examples (see Table 2), which are merely illustrative and in no way limit the present invention.

Example 1. Wet granules obtained from 45.0 g of ethambutol hydrochloride (1.875, hereinafter - parts by weight per 1 part by weight of rifampicin), 12.0 g (0.5 parts by weight) of isoniazid, 24 0 g (1.0 parts by weight) of rifampicin, 60.0 g (2.5 parts by weight) of pyrazinamide, 7.2 g (0.3 parts by weight) of microcrystalline cellulose, 14.4 g ( 0.6 parts by weight) of croscarmellose sodium and 30.0 g of corn starch, dried at 35-40 ° C. Dry granules are crushed in a plant for producing granules from dry mixtures, and a mixture of 4 g (0.167 parts by weight) of pyridoxine hydrochloride, 6.0 g of Primrose brand starch (total amount of starch in the composition is 1.5% by weight) is added to the crushed granulate. hours) and 0.7 parts by weight lubricant (8.4 g of aerosil, 4.4 g of talc and 4.0 g of magnesium stearate). Everything is thoroughly mixed until a homogeneous mass is obtained, after which it is tabletted. The film-forming composition of the Opadry Brown brand is applied to the obtained cores until a satisfactory film is obtained. Chocolate coated brown tablets with an average weight of 1110 mg are obtained. The content of rifampicin is 119.93 mg, isoniazid - 60.28 mg, pyrazinamide - 299.07 mg, ethambutol hydrochloride - 225.55 mg, pyridoxine hydrochloride - 19.9 mg.

Example 2. Wet granules obtained from 1.33 wt.h. ethambutol hydrochloride, 0.4 wt.h. isoniazid, 1.0 parts by weight rifampicin, 2.0 parts by weight pyrazinamide and parts of starch are dried and the dry granules are crushed in a plant for producing granulate from dry mixtures and a mixture of 0.05 parts by weight is added to the crushed granulate pyridoxine hydrochloride, starch residue (the total amount of starch in the composition is 2.5 parts by weight), 0.1 parts by weight croscarmellose sodium and 0.02 parts by weight calcium stearate. Everything is thoroughly mixed until a homogeneous mass is obtained, after which it is tabletted. Get tablets with an average weight of 1110 mg.

Example 3 is performed analogously to example 1, based on 1.0 wt.h. rifampicin, 1.0 parts by weight isoniazid, 3.5 parts by weight pyrazinamide, 2.25 parts by weight ethambutol hydrochloride, 0.2 wt.h. pyridoxine hydrochloride, 0.3 wt.h. starch, 1.5 parts by weight microcrystalline cellulose, 0.7 wt.h. aerosil, 0.4 parts by weight talc and 0.3 parts by weight magnesium stearate, while part of the aerosil is introduced before wet granulation.

table 2 Ingredients Content, parts by weight per 1 part by weight rifampicin Examples 1 2 3 Rifampicin 1,0 1,0 1,0 Isoniazid 0.5 0.4 1,0 Pyrazinamide 2,5 2.0 3,5 Ethambutol hydrochloride 1,875 1.33 2.25 Pyridoxine hydrochloride 0.167 0.05 0.2 Starch 1,5 2,5 0.3 Lubricant 0.7 0.02 1.4 Microcrystalline cellulose 0.3 - 1,5 Croscarmellose sodium 0.6 0.1 -

Claims (6)

1. A pharmaceutical composition with an anti-tuberculosis action in the form of a solid dosage form containing, as an active principle, a combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride and excipients, characterized in that the composition includes starch, a lubricant in the following ratio as excipients ingredients, parts by weight per 1 part by weight rifampicin: Rifampicin 1.0, Isoniazid 0.4-1.0, Pyrazinamide 2.0-3.5, Ethambutol hydrochloride 1.3-2.25, Pyridoxine hydrochloride 0.05-0.2, Starch 0.3-2.5, Lubricant 0.02-1.4. 2. The pharmaceutical composition according to claim 1, characterized in that it further comprises microcrystalline cellulose in an amount of up to 1.5 parts by weight per 1 part by weight rifampicin. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises croscarmellose sodium. 4. The pharmaceutical composition according to claim 3, characterized in that the amount of croscarmellose sodium is 0.1-0.6 wt.h. per 1 part by weight rifampicin. 5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that it is in the form of a tablet. 6. The pharmaceutical composition according to claim 5, characterized in that it has a shell.