RU2498805C1 - Solid dosage form of azithromycin - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and concerns a solid dosage form containing azithromycin dihydrate as an active substance in the amount of 83.2-93.2% and pharmaceutically acceptable target additives. A tablet core is film-coated in the amount of 2.5-5.0% of tablet weight. The new dosage form of azithromycin contains the high absolute (1000 mg) and relative (88.2%) concentration of the active substance that enables reaching the immediate therapeutic effect.

EFFECT: therapeutic preparation is storage-stable and complies with the Pharmacopoeia requirements.

Description

The invention relates to the pharmaceutical industry and relates to a solid dosage form of an antibacterial drug azithromycin.

Azithromycin is one of the most sought-after macrolide antibiotics used to treat respiratory infections. For more than 10 years, azithromycin has been used successfully in the treatment of many infectious diseases. Community-acquired respiratory infections are one of the main indications for antibiotic administration. The undoubted advantages of azithromycin are significantly greater, compared with other macrolides, resistance to the action of hydrochloric acid of gastric juice, the absence of an inhibitory effect on the microsomal system of cytochrome P450 and, therefore, the low probability of drug interactions.

The uniqueness of azithromycin is determined by two pharmacokinetic properties of the drug: high tissue affinity and a long half-life of an average of 68 hours. Due to its high lipophilicity, azithromycin penetrates many organs, tissues and body media, where concentrations are created and retained for a long time that are tens or hundreds of times higher than serum . The greatest accumulation of the drug is observed in fibroblasts, alveolar macrophages and polymorphic nuclear leukocytes. Moreover, the degree of accumulation of azithromycin in these cells exceeds that of most other known antibiotics. When migrating to the site of inflammation, the phagocytes perform a transport function, delivering the antibiotic directly to the localization of bacteria, where under the influence of microbial stimuli it is released from the cells, which allows you to create high and long-lasting drug concentrations here. According to the results of studies, 7-10 days after the cessation of the use of azithromycin, its concentration in polymorphonuclear leukocytes exceeds 32 mg / l.

The above features of the pharmacological profile of azithromycin allow the drug to be used in a short three-day course once a day. Naturally, the drugs used once a day have greater compliance and are readily used by patients.

The creation of a new dosage form of azithromycin, the distinguishing features of which are its high content (1000 mg tablet), allows to achieve high compliance in the treatment of a certain range of diseases.

The new dosage form will be relevant in the treatment of:

- diseases of the stomach and duodenum associated with Helicobacter pylori (the recommended course of treatment is 1 g for 3 days in combination with an antisecretory agent and other drugs, a course dose of 3 g);

- sexually transmitted infections:

a) uncomplicated urethritis / cervicitis - 1.0 g once (absolute treatment compliance)

b) complicated, long-lasting urethritis / cervicitis caused by Chlamydia trachomatis - 1 g 3 times with an interval of 7 days (1-7-14), 3 g course dose. This method of treatment of complicated forms (prostatitis, total urethritis, epididymitis) urogenital chlamydial infection (pulse therapy) has existed since 2000. The proposed course of fractional therapy of 1.0 g per 1 week is able to "block" from 6 to 8 life cycles of C. Trachomatis. Observations show that with this treatment regimen, relapses even after 2 years are observed only in 1.2% of men and 2.5% of women. This scheme is included in the “Federal Manual for Doctors” (Formular System, 2002).

- in the treatment of adult patients with community-acquired pneumonia:

A treatment regimen of 1.0 g for 3 days is suggested, the course dose is 3 g. According to the results of controlled clinical trials, the effectiveness and safety of this regimen are comparable to those of standard antibiotic therapy regimens.

At present, a large number of different forms of drugs containing azithromycin are known. So, there are known drugs with controlled release of the active substance, including azithromycin and an acceptable carrier, releasing the active substance at a controlled rate (patents RU 2130311, EA 010110, Pfizer Products Inc.). Long-acting drugs have several advantages (the release of the active substance occurs gradually, the therapeutic effect is maintained for a long time). But their use to achieve a quick therapeutic effect is not always advisable. For antibiotics, slow maximum concentration may reduce the effectiveness of the drug due to increased resistance of microorganisms.

In patents RU 2188018; RU 2203670; RU 2223103 describes the preparation of an azithromycin preparation in a dose of 250 mg in capsule form.

Closest to the proposed invention in composition is the preparation "Sumamed coated tablets, 500 mg" produced by "Pliva of Khrvatsk doo." Republic of Croatia (registration certificate No. P N015662 / 04 of 07.15.2009) [6]; One coated tablet contains the active substance azithromycin (in the form of dihydrate) - 125 mg or 500 mg and auxiliary components: the core is calcium phosphate disubstituted anhydrous, hypromellose, corn starch, pregelatinized starch, microcrystalline cellulose, sodium lauryl sulfate, and magnesium stearate - hypromellose, a dye like Indigotine (E132), polysorbate 80, titanium dioxide (E171), talc.

The therapeutic dose of 1 g requires the adoption of 2 tablets of Sumamed with a dose of 500 mg or 1 tablet of Azithromycin with a dose of 1 g. It is easier for a patient to take 1 tablet than two; that is, the compatibility of tablets with a higher dose is higher.

The objective of the present invention is to develop a drug characterized by a high absolute and relative content of the active component.

The technical result is achieved by the fact that the proposed antibacterial drug is made in the form of tablets, film-coated in the amount of 2.5-5.0% by weight of the tablet, in the following ratio of ingredients, wt.%:

Core: Azithromycin 83.2-93.2 Calcium phosphate 0.5-12.0 Croscarmellose sodium or sodium starch glycolate 0.5-5.0 Hypromellose (hydroxypropyl methylcellulose) 0.5-2.5 Calcium or Magnesium Stearate 0.5-1.0 Sodium dodecyl sulfate 0.1-1.0 Sodium Stearyl Fumarate no more than 2 Shell: Hypromellose (hydroxypropyl methylcellulose) 40-90 Titanium dioxide (titanium dioxide) 1-30 Polysorbate 80 (twin-80) 5-25 Dye 0.05-0.3 Talc no more than 50 Lactose (milk sugar) no more than 40 Preferably, the following ratio of ingredients, wt.%: Core: Azithromycin 88.2 Calcium phosphate 5,6 Hypromellose (hydroxypropyl methylcellulose) 1.05 Sodium dodecyl sulfate 0.15 Calcium or Magnesium Stearate 1,0 Sodium Stearyl Fumarate 1,0 Croscarmellose sodium or sodium starch glycolate 3.0 Shell: Hypromellose (hydroxypropyl methylcellulose) 84.38 Titanium dioxide (titanium dioxide) 7.14 Polysorbate 80 (twin-80) 8.29 Dye 0.19

In order to reduce tablet weight, excipients excluded corn starch, pregelatinized starch, microcrystalline cellulose, and the amount of disubstituted calcium phosphate was reduced. The relative content of azithromycin dihydrate in the tablet is mainly 88.2%, which is 19% more than the prototype. In order to increase the bioavailability of the active substance, croscarmellose sodium or sodium starch glycolate are introduced into the tablets.

Example 1

A mixture of azithromycin dihydrate (166.6 g) and calcium dibasic dibasic dihydrate (18.94 g) is moistened with a solution of 2.1 g of hydroxypropyl methylcellulose and 0.3 g of sodium dodecyl sulfate in 27.6 ml of water. The moistened mass is mixed, dried to a moisture content of 8.2%. The dried mass is granulated. Sodium stearyl fumarate (2.4 g), sodium starch glycolate (7.2 g), calcium stearate (2.4 g) are added to the granulate. After pressing, 155 g of tablet cores are obtained. A suspension is applied containing 3.84 g of hypromellose, 0.33 g of titanium dioxide, 0.38 g of tween-80, 8 mg of dye in 50 ml of water, and 160 g of pink tablets are obtained. The azithromycin content in each tablet is 1.02 g. The resulting drug is stable during storage and meets the requirements of the Pharmacopoeia and has a shelf life of 3 years (table).

Example 2

A mixture of azithromycin dihydrate (175 g) and calcium dibasic dibasic dihydrate (14.4 g) is moistened with a solution of 4 g of hydroxypropyl methylcellulose and 0.6 g of sodium dodecyl sulfate in 28.5 ml of water. The moistened mass is mixed, dried to a moisture content of 9.1%. The dried mass is granulated. Sodium stearyl fumarate (1.0 g), croscarmellose sodium (4.0 g), calcium stearate (1.0 g) are added to the granulate. After pressing, 157 g of tablet cores are obtained. A suspension is applied containing 1.6 g of hypromellose, 0.1 g of titanium dioxide, 0.3 g of tween-80, 6 mg of dye in 29 ml of water, and 160 g of pink tablets are obtained. The content of azithromycin in each tablet is 1.0 g. The resulting drug is stable during storage and meets the requirements of the Pharmacopoeia and has a shelf life of 3 years (table).

Example 3

A mixture of azithromycin dihydrate (173.5 g) and calcium dibasic dibasic dihydrate (16.3 g) is moistened with a solution of 2.0 g of hydroxypropyl methylcellulose and 0.2 g of sodium dodecyl sulfate in 30 ml of water. The moistened mass is mixed, dried to a moisture content of 8.6%. The dried mass is granulated. Sodium starch glycolate was added to the granulate (6.0 g), calcium stearate (2.0 g). After pressing, 168 g of tablet cores are obtained. A suspension is applied containing 2.4 g of hypromellose, 0.5 g of titanium dioxide, 1.9 g of talc, 2.3 g of lactose, 0.3 g of tween-80, 7 mg of dye in 62 ml of water, 175 g of pink tablets are obtained colors. The content of azithromycin in each tablet is 0.98 g. The resulting drug is stable during storage and meets the requirements of the Pharmacopoeia and has a shelf life of 3 years (table).

Example 4

A mixture of azithromycin dihydrate (180 g) and calcium dibasic dibasic dibasic (3.6 g) is moistened with a solution of 2.1 g of hydroxypropyl methylcellulose and 0.3 g of sodium dodecyl sulfate in 27.6 ml of water. The moistened mass is mixed, dried to a moisture content of 8.5%. The dried mass is granulated. Sodium stearyl fumarate (2.0 g), sodium starch glycolate (10.0 g), calcium stearate (2.0 g) are added to the granulate. After pressing, 167 g of tablet cores are obtained. A suspension is applied containing 3.6 g of hypromellose, 0.4 g of titanium dioxide, 1.4 g of lactose, 0.7 g of tween-80, 6 mg of dye in 35 ml of water, 162 g of pink tablets are obtained. The content of azithromycin in each tablet is 1.05 g. The resulting drug is stable during storage and meets the requirements of the Pharmacopoeia and has a shelf life of 3 years (table).

Information sources

1. Patent for invention RU 2130311.

2. Patent for invention RU 2188018.

3. Patent for invention RU 2203 670.

4. Patent for invention RU 2223103.

5. Patent for the invention EA 010110.

6. Register of medicines, CLIFAR, CD.

7. Isakov V.A., Kudryavtseva L.V. Azithromycin is a new component of anti-Helicobacter pylori therapy. Clinical Pharmacology and Therapy, No. 9 (1), 2000.

8. Vakhontseva O. B. Experience with azithromycin in urological practice. Russian Medical Journal Volume 14, No. 28, 12/21/2006.

9. Search network Internet.

10. Database on inventions of Rospatent.

Table 1 Table of analytical data on the quality and stability of the drug Description Authenticity Average tablet weight Dissolution quantitation Tablets, covered with a pink film shell, oblong shape with biconvex surfaces, two layers are visible on the cross section: the outer one is pink and the inner one is white or almost white The retention time of the main peak in the chromatogram of the test solution should coincide with the retention time of the peak of azithromycin in the chromatogram of a solution of a standard sample of azithromycin 1.235 g ± 5% At least 75% in 45 minutes From 0.9 g to 1.1 g based on the average weight of one tablet at the time of manufacture Project 1 corresponds to confirmed by 1.240 + 1.7; -1.5 102.9 1,052 Project 2 corresponds to confirmed by 1.232 + 1.6; -1.8 97.3 0.940 Project 3 corresponds to confirmed by 1.236 + 0.9; -1.4 101.3 0,998 Project 4 corresponds to confirmed by 1.238 + 1.8; -1.7 98.4 1,080 after 3 years of storage - at the end of the expiration date Project 1 corresponds to confirmed by 1.228 + 1.8; -1.9 95.6 1,070 Project 2 corresponds to confirmed by 1.231 + 2.5; -3.0 93.6 0.931 Project 3 corresponds to confirmed by 1.225 + 1.6; -1.9 92.4 0.972 Project 4 corresponds to confirmed by 1.226 + 1.2; -1.8 79,4 0.919

Claims (2)

1. An antibacterial agent, characterized in that it is made in the form of tablets, film-coated in an amount of 2.5-5.0% by weight of a tablet containing azithromycin dihydrate as the active substance, as well as pharmaceutically acceptable target additives in the following ratio ingredients, wt.%:
Core:
Azithromycin dihydrate 83.2-93.2 Calcium phosphate 0.5-12.0 Croscarmellose sodium or sodium starch glycolate 0.5-5.0 Hypromellose (hydroxypropyl methylcellulose) 0.5-2.5 Calcium or Magnesium Stearate 0.5-1.0 Sodium dodecyl sulfate 0.1-1.0 Sodium Stearyl Fumarate if necessary up to 2.0
Shell:
Hypromellose (hydroxypropyl methylcellulose) 40-90 Titanium dioxide (titanium dioxide) 1-30 Polysorbate 80 (twin-80) 5-25 Dye 0.05-0.3 Talc no more than 50 Lactose (milk sugar) no more than 40 2. The antibacterial agent according to claim 1, characterized in that the ratio of ingredients is preferably, wt.%:
Core:
Azithromycin 88.2 Calcium phosphate 5,6 Hypromellose (hydroxypropyl methylcellulose) 1.05 Sodium dodecyl sulfate 0.15 Calcium or Magnesium Stearate 1,0 Sodium Stearyl Fumarate 1,0 Croscarmellose sodium or sodium starch glycolate 3.0
Shell:
Hypromellose (hydroxypropyl methylcellulose) 84.38 Titanium dioxide (titanium dioxide) 7.14 Polysorbate 80 (twin-80) 8.29 Dye 0.19