Dosage form with anti-tb activity

 

The invention relates to the field of pharmaceutical industry and relates to dosage forms with anti-TB activity. The invention consists in that the dosage form contains isoniazid, pyridoxine hydrochloride. The improved properties of the dosage form is achieved by introducing corrective substances and high-molecular compounds, which cover most of the taste buds and envelop the particles of drug substance. For the correction of taste used saccharin soluble. The composition also contains refined sugar, polyvinylpyrrolidone, ethyl alcohol 95%. The invention provides a formulation, technology and standardization corrected dosage forms of isoniazid with pyridoxine hydrochloride, which can be produced in Russia from domestic raw materials. The proposed dosage form is granules of isoniazid with pyridoxine hydrochloride in its properties meet the requirements of normative documents, eliminates side effects. 1 Il., 7 table.

The invention relates to the field of pharmacy and relates to a technology of medicinal forms.

In Russia, the pharmaceutical industry 1988 "Eastern Europe", page 212):

Isoniazid 500 mg

Water for injection 5 ml

The prototype is a dosage form Tablets of isoniazid" (Belikov Century, Synthetic and natural drugs. Quick reference. M.: Higher school, 1993. S. 249).

The composition of the tablets include GF X FS 357, page 378:

Isoniazid 0.1; 0.2 or 0.3

Excipients Enough

By isoniazid can experience different side effects in the form of neurotoxic reactions, the development of psychosis, the occurrence of peripheral neuritis, etc. the Purpose of pyridoxine hydrochloride in the treatment of various forms of tuberculosis reduces these side effects (Mashkovsky M. D. Medicines. M., 1994, H 2, page 368).

Pyridoxine hydrochloride Russian industry produces in the form of tablets of 0.02; 0.05 or 0.01 g (GF X FS No. 568, page 574):

Composition per tablet:

Pyridoxine hydrochloride 2, 5 or 10 mg

Excipients to obtain tablets with a weight of 0.2; 0.25 or 0.3 g in a 1%; 2.5% or 5% solution for injection (GF X FS No. 567, page 574) composition:

Pyridoxine hydrochloride, 10, 25 or 50 g

Water for injection Up to 1 l

The Russian pharmaceutical industry produces solid dosage who lopedia drugs Enfermagem, M., 2000, page 733).

To prevent adverse reaction of isoniazid pyridoxine hydrochloride is administered in the form of injections or tablets, which creates some inconvenience for patients and medical staff.

During the development of dosage forms for internal use must be considered psychosomatic features of the human body, dosage form should have a pleasant appearance, taste and smell, does not irritate the taste buds, mucous membranes, easily dosed.

The Russian pharmaceutical industry pharmaceutical form of isoniazid (pill) has a bitter taste and irritating taste buds.

The purpose of this invention is to provide a composition, technology and standardization corrected dosage forms of isoniazid with pyridoxine hydrochloride, which can be produced in Russia from domestic raw materials (Register of medicines of Russia, encyclopedia of drugs. Enfermagem, M., 2000, page 351, 733).

The improved properties of the dosage form can be achieved by introducing corrective substances and high-molecular compounds (IUD), which cover most of the taste buds and envelop of part of the works of methylcellulose (MC), oksipropilmetiltselljulozy (OPMC) and polyvinylpyrolidone (PVP). Due to the fact that isoniazid (in solution) is unstable as a moisturizing agent, was proposed alcoholic solution of PVP at a concentration of 5%. To adjust the taste of isoniazid used sucrose. However, it turned out that one of sucrose is not enough, therefore, was additionally used saccharin soluble, which is sweeter than sucrose in 500 times.

On the basis of the conducted researches proposed the following composition pellets:

Isoniazid 0,300

Pyridoxine hydrochloride 0,030

Refined sugar 1,640

Saccharin soluble 0,0040

Polivinilpirolidon 0,0260

Ethyl alcohol 95% 0,4240

Preparation of granules is carried out as follows.

Isoniazid and refined sugar dried in a thermostat at a temperature of 37°C to a residual moisture content of 3-5%.

Pre-balanced PVP is placed in a mixer to obtain a humidifier, measure by measure calculated amount of ethanol 95%, is poured into the mixer, mix until dissolved PVP. Next produce mixing and wetting of the powders. Part of powdered sugar add saccharin soluble, pyridoxine hydrochloride and mix for 3 minutes until smooth the Weight with the optimum moisture content is a compact wet mixture, not sticking to the hand, but scattered when compressed into separate lumps. Then the wet mass granularit through a sieve with openings of 3 mm on a sheet of parchment paper with a thin layer 1-2 cm of Wet granules are dried at a temperature of 37°C, stirring occasionally to a residual moisture content of 1.5-2.0%. Pellets have the necessary mechanical strength and good solubility in water. The solution of the granules has a sweet taste.

The chronic toxicity of granules of isoniazid with pyridoxine hydrochloride was studied in randombred bisexual adult mice and rats in 3 doses: 50, 100 and 200 mg/kg in terms of pure isoniazid. Results chronic administration (within 6 months) rats granules of isoniazid with pyridoxine hydrochloride compared to tablets of isoniazid showed that both dosage forms cause a significant increase in the level of Alt (PL.1), ASAT (PL.2) and alkaline phosphatase (table.3). High levels of Alat, ASAT, alkaline phosphatase, a comparison of the impact on these indicators isoniazid depending on the dosage form suggest that coadministration of isoniazid with pyridoxine hydrochloride in the form of granules reduces its damage (cytotoxic) and holes ryogo fields. The test results showed (table. 4) that the number of “pillars” and the total time of washing (grooming) in animals on the background of tablets more than the background granules. Thus, the combined application of isoniazid with pyridoxine hydrochloride in the form of granules, there is a decrease of excitability of the Central nervous system in comparison with the tablets of isoniazid. In comparison with the control data of the studied indicators of activity of the Central nervous system is less than or close to those. Moreover, CNS females are more sensitive to isoniazid, than in males.

Chemical and microbiological examination of the urine showed a lack of experienced series rats gross pathology of the liver and kidneys.

Hematological studies suggest the absence of gross abnormalities of these indicators when using toxic doses of isoniazid granules in combination with pyridoxine hydrochloride (PL.5).

Were conducted macro - and microscopic examination, which showed the absence of severe destructive changes in the internal organs of animals treated with toxic doses of granules of isoniazid with pyridoxine hydrochloride for 6 months.6).

The results of the study of acute toxicity of granules of isoniazid with pyridoxine hydrochloridecategories tools.

Chronic use (over 6 months) granules of isoniazid in toxic doses of 50, 100, 200 mg/kg in combination with pyridoxine hydrochloride, respectively, in doses of 5, 10, 20 mg/kg reduces neurotoxic, nephrotoxic, hepatotoxic and cholestatic steps in comparison with the impact on these bodies tablets of isoniazid in the same doses.

A comparative study of the pharmacokinetics and bioavailability of isoniazid after intragastric administration of the tablets of isoniazid and developed granules. It is established that the processes of absorption and elimination of isoniazid in the application of the studied dosage forms are the same. The conclusion is made about their bioequivalence (see the drawing table.7).

As shown, the proposed granules have low toxicity, and pharmacokinetic parameters are bio-equivalent drug comparison - tablets isoniazid 0.3 g (produced by Lugansk HFZ).

Thus, the preparation of granules of isoniazid with pyridoxine hydrochloride on the proposed medicine and technology will allow us to create a safe and effective anti-TB drugs with reduced toxicity.

An important advantage of predlagaet dosing and drug which is an important factor in the treatment of various forms of tuberculosis.

The obtained pharmaceutical form granules of isoniazid with pyridoxine hydrochloride in its properties meet the requirements of the normative documentation.

Claims

Dosage form in the form of granules containing isoniazid as a drug, characterized in that, along with the active substance contains pyridoxine hydrochloride, as auxiliary substances granules contain polyvinylpyrrolidone, soluble saccharin, sugar, ethyl alcohol in the following proportions:

Isoniazid 0,30

Pyridoxine hydrochloride 0,030

Refined sugar 1,640

Saccharin soluble 0,0040

Polyvinylpyrrolidone 0,0260

Ethyl alcohol 95% 0,4240



 

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