Composition for treatment of tuberculosis

 

(57) Abstract:

The invention relates to medicine and can be used in the treatment of tuberculosis. The composition comprises tuberculostatic - rifampicin, targeted supplements - magnesium basic carbonate or calcium carbonate, calcium or magnesium stearate, sugar and dairy-based, which use the cocoa butter and beeswax, fatty basis, linolevuyu basis, "witepsol H-15", polietilenoksidnoy basis. Dosage form of the composition in the form of a suppository in comparison with the known pharmaceutical forms for oral and intravenous has better bioavailability of the active substance and high antituberculosis activity, and also reduces the side effects of rifampicin and prevent the development of pronounced dysbacteriosis. 8 C.p. f-crystals, 9 tab., 1 Il.

The invention relates to medicine, pharmacy and the pharmaceutical industry and relates to tools used to treat tuberculosis.

The leading place in the treatment of TB patients is chemotherapy as causal method, which consists in suppressing the multiplication of tubercle bacilli in the body of the patient.

In the present writecookie (isoniazid, ftivazid, metazid, fenazid, sodium paraaminosalicylic, ethambutol, ethionamide, protionamide, pyrazinamide, solution, ofloxacin, lomefloxacin) and antibiotics (rifampicin, rifabutin, rifampicin, kanamycin, streptomycin, amikacin) (2, 6).

Despite the wide range of drugs used to treat tuberculosis, the development of new anti-TB drugs and their various dosage forms remains relevant due to the fact that in recent years there has been a significant deterioration of the epidemiological situation of tuberculosis (1, 2).

Rifampicin, as tuberculostatic included in category a according to the international classification of anti-TB drugs, as it, along with isoniazid is the most effective anti-TB means.

Rifampicin (Rifampicinum) - 3[[(4-methyl-1-piperazinil)-imino] methyl] - rifamycin SV is a semisynthetic antibiotic derivative of rifamycin SV, produced by Streptomyces mediteranei.

Synonyms: Minimizin, Rifadin, Rimactane, Retamar, Tobien, Rifampin, Reftex, Referen (7).

Produced rifampicin in the form of capsules 0.15; 0,3; 0.45 g, solution for intramuscular injection in ampoules: 1.5 ml (125 mg ulah: 10 ml (500 mg rifamycin sodium salt). The injectable solutions are produced under the name "Rivoal" (7).

Published results of studies of the bioavailability of rifampicin in the introduction of it in different dosage forms (tablets, capsules, syrup) (14, 17). Data on the effectiveness of rifampicin in his appointment in these dosage forms are contradictory. So, it is reported that with the introduction of rifampicin in syrup concentration in serum is almost 2 times higher than the levels achieved after administration of the drug in capsules and tablets. While rifampicin tablets is absorbed much faster than capsules (14). Other studies indicate the same degree of absorption of rifampicin capsules and tablets (17).

The study of the levels of rifampicin in the serum when introduced intravenously within 3 hours of the drug rifampicin for intravenous administration after its dissolution in 500 ml glucose at doses of 300, 450 and 600 mg showed that the levels of antibiotic practically do not differ from those after oral administration of rifampicin in the same doses in capsule form (15).

It is known that oral administration of rifampicin is often accompanied dyspeptic phenomena, negative is s and enzymes of the gastrointestinal tract. In some cases, may be contraindicated, intravenous antibiotic (age-related pathology of the veins, complications such as phlebitis and others).

The method of introduction of medicinal substances in suppositories has a number of advantages over oral and intravenous routes of administration. Thus, the appointment of a medicinal product per rectum significant part introduced medicinal substance enters the bloodstream, bypassing the liver. This increases the speed of absorption of injected drugs, they are not metabolizing the influence of liver enzymes. This route of administration allows to significantly reduce the adverse effects of drugs on the body. In addition, the rectal route of administration avoids undesirable side reactions observed after oral administration of many drugs. This method also eliminates the problem of pain introduction and infection of patients, which is possible with intravenous drugs (3, 8, 9). The above applies to the intravaginal administration of drugs.

A lot of work suggests the possibility of using some of antibiot is. the setting ability rectal oleandomitsina, oxytetracycline, chlortetracycline, tetracycline, streptomycin, dihydrostreptomycin, neomycin, erythromycin, potassium salt of phenoxymethylpenicillin, sodium salt of benzylpenicillin(3, 5, 10, 11, 12, 13). However, an effective composition for use suppositories with rifampicin in the treatment of tuberculosis today is not known.

Closest to our proposed composition for the treatment of tuberculosis is enteral oral dosage form of rifampicin capsules "Rifampicin 0.15 g in capsules". The disadvantages of this dosage form is oral, which is accompanied by undesirable side reactions, and can also be difficult, particularly when treating children, especially the first years of life, which medication capsules are contraindicated. In the case of treatment of children during the first months of life oral administration of rifampicin capsules impossible, and for the older children is highly undesirable.

The objective of the invention is the creation of an effective suppozitornyj composition with rifampicin to treat tuberculosis, which is sicnosti, to reduce side effects caused by rifampicin oral introduction, and to increase a therapeutic effect of the antibiotic.

The task is implemented the proposed composition in the form of a suppository containing tuberculostatic and a forming agent, which includes a base and a possible target additives that facilitate accurate dosing and homogeneity. As tuberculostatic used rifampicin in the amount of 0.04-0.05 g in 1 g of the composition. As an additional target of additives used magnesium basic carbonate or calcium carbonate to 0.005 g, calcium or magnesium stearate to 0.001 g sugar and milk until 0,044 g per 1 g of the composition. As the framework is the basis of the cocoa butter and beeswax in the following ratio of ingredients, grams per 1 g of the composition:

Beeswax - 0,038-0,042

Cocoa butter - Rest

or fatty base, including cooking oil "Frying", paraffin wax and cocoa butter, in the following ratio of ingredients, grams per 1 g of the composition:

Cocoa butter - 0.29 to 0.31 in

Paraffin - 0,10-0,21

Cooking fat "Frying" - Rest

or lanalia basis, including lanai, hydrogenated fat and paraffin, in the following ratio phrases the BR> or polietilenoksidnoy basis, including polyethylene oxide 400 and polyethylene oxide 1500, in the following ratio of ingredients, grams per 1 g of the composition:

The polyethylene oxide 400 - 0,048-0,052

The polyethylene oxide 1500 - Rest

or the basis of witepsol.

The weight of the finished suppositories from 0.5 to 6.0 g

The invention is illustrated by the following examples:

Example 1.

Rifampicin - 0,04-0,05

Magnesium basic carbonate or calcium carbonate - 0-0,005

Calcium or magnesium stearate - 0-0,001

Milk sugar - 0-0,044

Basis with cocoa butter and beeswax To 1 g

Beeswax was melted on a water bath, was added 70% of the total number of cocoa butter while stirring until a homogeneous mass was cooled to 33oSince, then, under continuous stirring was added the remainder of the cocoa butter. Rifampicin was ground in a warm mortar with a mixture of magnesium basic carbonate (or calcium carbonate) and calcium (or magnesium stearate. Then add the milk sugar. The resulting mixture was mixed with part of the molten base, then added the rest and thoroughly mixed until a homogeneous mass. Poured with stirring to obtain suppositories military suppositories fully comply with the requirements of article GF XI "Suppositories" (see table 1).

Example 2.

Rifampicin - 0,04-0,05

Magnesium basic carbonate or calcium carbonate - 0-0,005

Calcium or magnesium stearate - 0-0,001

Milk sugar - 0-0,044

Fat basis, Up to 1 g

Rifampicin was ground in a warm mortar with a mixture of magnesium basic carbonate (or calcium carbonate) and calcium (or magnesium stearate. Then add the milk sugar. The resulting mixture was mixed with part of the molten base, then added the rest and thoroughly mixed until a homogeneous mass. Poured with stirring to obtain suppositories weighing 1 g was placed in the freezer for 15-20 minutes. Form pre-smeared with soap and alcohol. Received suppositories fully comply with the requirements of article GF XI "Suppositories" (see table 2).

Example 3.

Rifampicin - 0,04-0,05

Magnesium basic carbonate or calcium carbonate - 0-0,005

Calcium or magnesium stearate - 0-0,001

Milk sugar - 0-0,044

Lanalia basis, Up to 1 g

Rifampicin was ground in a warm mortar with a mixture of magnesium basic carbonate (or calcium carbonate) and calcium (or magnesium stearate. Then add the milk sugar. The resulting mixture smese homogeneous mass. Poured with stirring to obtain suppositories weighing 1 g was placed in the freezer for 15-20 minutes. Form pre-smeared with soap and alcohol. Received suppositories fully comply with the requirements of article GF XI "Suppositories" (see table 3).

Example 4.

Rifampicin - 0,04-0,05

Magnesium basic carbonate or calcium carbonate - 0-0,005

Calcium or magnesium stearate - 0-0,001

Milk sugar - 0-0,044

Polietilenoksidnoy basis, Up to 1 g

Rifampicin was ground in a warm mortar with a mixture of magnesium basic carbonate (or calcium carbonate) and calcium (or magnesium stearate. Then add the milk sugar. The resulting mixture was mixed with part of the molten base, then added the rest and thoroughly mixed until a homogeneous mass. Poured with stirring to obtain suppositories weighing 1 g was placed in the freezer for 15-20 minutes. Form pre-smeared vaseline oil. Received suppositories fully comply with the requirements of article GF XI "Suppositories" (see table 4).

Example 5.

Rifampicin - 0,04-0,05

Magnesium basic carbonate or calcium carbonate - 0-0,005

He kamerali in a warm mortar with a mixture of magnesium basic carbonate (or calcium carbonate) and calcium (or magnesium stearate. Then add the milk sugar. The resulting mixture was mixed with part of the molten base, then added the rest and thoroughly mixed until a homogeneous mass. Poured with stirring to obtain suppositories weighing 1 g was placed in the freezer for 15-20 minutes. Form pre-smeared with soap and alcohol. Received suppositories fully comply with the requirements of article GF XI "Suppositories" (see table 5).

The main characteristics of the proposed suppositories with rifampicin.

Description: suppositories with rifampicin have the same torpedo-shaped form, smooth surface, have sufficient hardness, on the outer surface and on the cut flakes, sequins and pieces of the framework is not observed, the color of suppositories - brick-red.

Deviations from the average mass - 1,0-2,8%

Melting point - 28-37oWITH

The full strain - 165-258

The time of dissolution - 25 min

The quantitative content of rifampicin - 0,04-0,05 g per 1 g of the composition

To compare the bioavailability of rifampicin in his introduction per os in the form of suppositories on different bases were studied its contents in Mac ferritina with the introduction of it in the form of rectal suppositories at all bases compared with oral administration (see the drawing).

In experiments on rabbits infected with Mycobacterium tuberculosis, the comparative assessment of the specific activity of rifampicin, administered orally in the form of a suspension in the form of suppositories. Found that rifampicin is much more effective when the last route of administration (table 6).

In experiments on rabbits studied three aspects of possible adverse reactions to rifampicin: a damaging effect on the liver, an irritating effect on the mucous membrane of the rectum, the impact on the intestinal flora.

Not marked marked disorders of liver function by oral administration of rifampicin and suppositories.

On the state of the liver to be judged by the results of biochemical determinations blood levels of bilirubin and alanine aminotransferase (AAT) (table 7).

Not found significant differences in the structure of the rectal wall in the study of rifampicin in rectal suppositories.

To study the normal intestinal flora of rabbits during treatment with rifampicin using bacteriological method was studied the contents of the large intestine. It was established that the use of rifampicin is ω by the following characteristic changes in the composition of the normal microflora of the large intestine. The number of microorganisms in the treatment process increased sharply (100-1000 times), and this increase was due to decrease until the disappearance of the permanent representatives of normal microflora and the emergence of microorganisms that are not characteristic of constant composition. Also noted the identification of microorganisms with signs of pathogenicity, namely, the manifestation of hemolysis. These results allow to consider the condition of the intestinal flora of rabbits treated with rifampicin orally, as a condition expressed dysbacteriosis.

Treatment of animals with rifampicin in the form of suppositories was not accompanied by the development of pronounced goiter (table 9). This is evidenced by the qualitative composition of the microflora of the large intestine of rabbits, which had not changed, either increased or decreased in the same order. As for the qualitative part, he kind of changed. Constant (obligate) microorganisms (Bacillus, micrococci) remained in quantities close to the norm. Increased or decreased the amount of E. coli, enterococci. Appeared microorganisms, is not peculiar to the control (untreated) rabbits: Klebsiella and Proteus. Drawing a parallel with acecourse, which is not characterized by a strong degree of manifestation of its microbiological characteristics.

There is an experience of treatment in the hospital children, TB patients, using suppositories rifampicin. Group of children (more than 60 people, mostly children under the age of 1 year) with the most severe tuberculosis in complex drugs were given rifampicin for 2.5-3 months. Rifampicin was administered in the form of rectal suppositories 1 time per day in a dose of 10 mg per 1 kg of body weight. This method of treatment has improved the efficiency and reduce the time of treatment compared with other chemotherapy regimens.

Thus, first proposed the composition in the form of suppositories with rifampicin to treat tuberculosis, which is:

1. It has high biological availability, significantly higher than the bioavailability of oral dosage forms.

2. It has high anti-TB activity significantly greater than that by oral administration of the antibiotic.

3. Can significantly reduce the side effects of rifampicin.

4. Helps prevent the development of pronounced dysbacteriosis characteristic peroral basis (cocoa butter, lanalia base, a fatty basis and witepsol N-15) and hydrophilic bases (PEO).

6. Characterized satisfactory lubricating properties, which provides the convenience of its application.

7. Convenient storage and transportation.

8. Can easily be made not only in the pharmaceutical companies, but also in terms of pharmacies.

Sources of information

1. Large Target Magazine about TB. 1999. 3. - 50 S.

2. Galician L. A. , Brown N. T. Basic principles of treatment of newly diagnosed patients with pulmonary tuberculosis // Terra medica. 2000. 2, S. 17-19.

3. Kravchinsky L. Candle in modern medical practice. - Warsaw, 1970. - 131 C.

4. Moldaver B. L. , Alexandrov A. E., Borisova O. A. and others, the Influence of surfactants on the kinetics of streptomycin sulfate introduced into the suppositories // pharmacy, 1981, 5, S. 20-24.

5. Nikolaenko, N. S., Senatorova M. I., Krupennikova N. L. and other Medicinal product containing erythromycin. RF patent 2125444. A 61 K 9/02 // the Invention, 1999, 3, S. 417.

6. The Ministry of health of the Russian Federation 33 dated 02 February 1998 "On approval of standards (Protocol models) in the treatment of tuberculosis".

7. References: I. C. Dosage form and therapeutic effectiveness of drugs. - M.: Medicine, 1974. - 336 S.

9. ANCOVA A. I., Tyurin N. A., University A. N., Kiselev, S., Sollogoub L. C. , Senchenkova L. C. prospects for the development of suppositories in Pediatrics. Symposium Suppositories in modern medicine" (Moscow, 1972). - Budapest, 1972, S. 16-23.

10. Backe-Hansen K. Rectal absorption of bensylpenicillin // Scandinav. J. clin. Lab. Invest., 1957, v. 9, 2, p.170-173.

11. Ban I., Ciocanelea V. Czitrom and E. M. Studiu asurpra supozitoarelor penicilina // Farmacia (Bucuresti), 1965, 1, p.1-6.

12. Guglielmetti, P. And F. Zini Rectal absorption of streptomycin and isonicotinoyl hydrazid //Rass. Patol. Apparto respirat., 1955, 5, p.547-554.

13. Kelentey Century, Stenszky E. Uber die rectale Resorption der Antibiotica // Die Pharmazie, 1960, v. 15, 4, s. 158-160.

14. M. Mannisto P. Absorption of Rifampin from Varius Preparation and Pharmaceutic Forms // Clin. Pharmacol. Ther., 1977, v. 21, 3, p.370-374.

15. Nitti V., Virgilio R., Particolo M. R. and A. Iuliano Parmacokinetic Study of Intravenous Rifampicin //Chemotherapy, 1977, v. 23, 1, p.1-6.

16. Touitou E. , Donbrow M., Azaz E. New Hydrophilic Vehicle Enabling Rectal and vaginal Absorption of Insulin, Heparin, Phenol Red and Gentamicin // J. Pharm. Pharmacol., 1978, v. 30, 10, p.662-663.

17. Virtanen S. and Tala E. Serum concentrations of rifampicin after oral administration // Clin. Pharmacol. Ther., 1974, 16, p.817-820.

1. Composition for treatment of tuberculosis rifampicin-containing as an active ingredient and a forming agent, characterized in that it is a fact, it contains as a formative agent based out of cocoa butter and beeswax in the following ratios, g in 1 g of the composition:

Beeswax - 0,038 - 0,042

Cocoa butter - Rest

3. The composition according to p. 1, characterized in that as the forming agent contains fat basis, including cocoa butter, cooking fat "Frying" and paraffin in the following ratio, g per 1 g of the composition:

Cocoa butter - 0.29 to 0.31 in

Paraffin - 0,10 - 0,21

Cooking fat "Frying" - Rest

4. The composition according to p. 1, characterized in that as the forming agent contains linolevuyu basis, including lanai, hydrogenated fat and paraffin in the following ratio, g per 1 g of the composition:

Hydrogenated fat - 0.10 to 0.020

Paraffin - 0,10 - 0,20

Lenol - Rest

5. The composition according to p. 1, characterized in that as the forming agent contains witepsol N-15.

6. The composition according to p. 1, characterized in that as the forming agent contains polietilenoksidnoy basis, including polyethylene oxide 400 and polyethylene oxide 1500 in the following ratio, g per 1 g of the composition:

The polyethylene oxide 400 - 0,048 - 0,052

The polyethylene oxide 1500 - Rest
Magnesium basic carbonate or calcium carbonate To 0.005

Calcium or magnesium stearate Up to 0,001

Sugar milk To 0,044

8. Composition according to any one of paragraphs. 1-7, characterized in that the weight of the suppository is 0.5 to 6.0 g

9. Composition according to any one of paragraphs. 1-8, characterized in that the weight of the suppository is 0.5-1.5 g, mainly for pediatric dosage forms.

 

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