RU2811905C1 - Clofazimine in dosage form - film-coated tablets - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the dosage form of clofazimine, which can be used for the treatment of multidrug-resistant tuberculosis, the said dosage form is a film-coated tablet, and it has the following composition per 100 mg of active ingredient: clofazimine as an active ingredient — 95.00–105.00 mg; excipients in the tablet core: polyoxyl hydrogenated castor oil (macrogol glyceryl hydroxystearate) – 25.00± 1.25 mg; povidone-K25 – 40.00± 0.15 mg; polysorbate-80 – 5.00± 0.25 mg; betadex – 97.00± 4.85 mg; microcrystalline cellulose type 101 – 242.00± 1.21 mg; colloidal silicon dioxide – 22.00± 1.6 mg; crospovidone – 5,300± 4.0 mg; sodium stearyl fumarate – 12.00± 0.6 mg; tablet shell – 15± 1.1 mg, including (wt.%): hypromellose – 6 cP – 67.00± 7%; triacetin – 7.00± 7%; titanium dioxide – 22.39± 7%; red iron oxide dye – 0.49± 7%; iron oxide yellow dye – 3.12± 7%. The invention also relates to a method of obtaining the specified dosage form.

EFFECT: implementation of the intended purpose, as well as increased stability over time of the proposed dosage form.

2 cl, 1 tbl

Description

The present invention relates to the field of medicine, in particular, to a dosage form of clofazimine, which can be used for the treatment of multidrug-resistant tuberculosis, as well as a method for its preparation.

Clofazimine, also called N ,5- bis (4-chlorophenyl)-3-(1-methylethylimino) -5H -phenazin-2-amine, has a molecular formula of 1

(1).

Clofazimine was developed in the 1950s by Vincent Barry to treat tuberculosis. Moreover, according to studies on a mouse model of tuberculosis, its bactericidal effect was superior to isoniazid. There was no further research into the use of clofazimine for the treatment of tuberculosis, and since 1962, clofazimine has been used to treat leprosy (see G. N. Mozhokina et al., Clofazimine: history and prospects, Tuberculosis and Lung Diseases, Vol. 99 , No. 5, 2021, pp. 64-70).

Later, information appeared that clofazimine has anti-tuberculosis activity, including against some strains of multidrug-resistant tuberculosis (Guide to the programmatic management of drug-resistant tuberculosis. WHO, Geneva, 2007, 217 pp.), which gave rise to subsequent studies in this direction. A number of regimens have also been developed using clofazimine, both alone and in combination with other drugs, for the treatment of multidrug-resistant and extensively drug-resistant forms of tuberculosis (see, for example, Ahmad N. et al., Treatment correlates of successful, outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis, Lancet. - 2018. - No. 392 (10150). - R. 821-834; RU 2547753 C2, 06.27.2015; Thomas J. Hwang et al., Safety and availability of clofazimine in treatment of multidrug-resistant and extensively drug-resistant tuberculosis: analysis of published recommendations and meta-analysis of cohort studies, BMJ Open, 11.2013).

The mechanism of action of clofazimine on Mycobactérium tuberculosis is not fully understood, but, in all likelihood, the intracellular redox cycle, including the oxidation of reduced clofazimine, leads to the formation of reactive oxygen species (ROS), hydrogen superoxide (H ₂ O ₂ ). Secondly, the interaction of clofazimine with membrane phospholipids leads to the formation of complexes that disrupt membrane functions (including K ⁺ uptake). Both mechanisms lead to changes in cellular energy metabolism and disruption of ATP formation. Third, clofazimine inhibits replication by binding guanine to mycobacterial DNA.

However, no prior art document focuses on which dosage form of clofazimine may be most preferable for use.

Thus, the objective of the present invention is to develop a new dosage form of clofazimine with increased storage stability, which can be used for the treatment of multidrug-resistant tuberculosis, and a method for its preparation, as well as expanding the arsenal of drugs for the treatment of multidrug-resistant tuberculosis.

The technical result of the present invention is the provision of a new dosage form of clofazimine, which has increased storage stability, and, as a consequence, an increased shelf life of the drug, as well as a method for producing this dosage form.

Thus, we offer a dosage form of clofazimine, which is a film-coated tablet, with the following composition for 95.00 - 105.00 mg of active substance:

Clofazimine as an active ingredient - 95.00 - 105.00 mg;

Excipients in the tablet core, including:

Polyoxyl hydrogenated castor oil

(Macrogol glyceryl hydroxystearate) - 25.00±1.25 mg;

Povidone-K25 - 40.00±0.15 mg;

Polysorbate-80 - 5.00±0.25 mg;

Betadex - 97.00±4.85 mg;

Microcrystalline cellulose type 101 - 242.00±1.21 mg;

Colloidal silicon dioxide - 22.00±1.6 mg;

Crospovidone - 53.00±4.0 mg;

Sodium stearyl fumarate - 12.00±0.6 mg;

Tablet shell 15 ± 1.1 mg, including (wt.%):

Hypromellose - 6 sP - 67.00±7%;

Triacetin -7.00±7%;

Titanium dioxide -22.39±7%;

Red iron oxide dye - 0.49±7%;

Yellow iron oxide dye - 3.12±7%.

Studies were conducted to confirm the stability of the proposed dosage form for 36 months.

Drug stability study report Page 1 of 4 Drug: Clofazimine film-coated tablets, 100 mg Control in accordance with the draft ND “Clofazimine film-coated tablets, 100 mg” Storage conditions: In a place protected from light at a temperature not exceeding 25°C Quantities allocated for studying this type of stability:
434 tablets Packaging: 50 or 100 tablets in a polymer jar without a polypropylene membrane with a screw cap Series number: 0010419-ops LS series type:
□ laboratory □ pilot-industrial □ industrial Production date: 04.2019 Shelf life: 3 years Manufacturer: PharmConcept LLC, Russia Date bookmarked for stability: 04/08/2019 Completion date of the stability study: 04/08/2022 (36 months, full cycle) Manufacturer of the substance, country:
Clofazimine - McLeod's Pharmaceuticals Ltd, India Substance production date:
Clofazimine – 01.2019
Substance batch number:
Clofazimine - E/1233/B19003 Shelf life of the substance:
Clofazimine – 2 years

Conditions for studying stability

Temperature Humidity Placement for stability 25°С±2°С 60±5% KAnL OKK room 2(b)

Notes

Additional Information

Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side.

Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0010419-ops Page 2 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1.Compliant
2. Compliant -
- -
- -
- -
- -
- Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 80.2% 80.1% 79.9% 79.8% 79.6% 79.4% Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0010419-ops Page 3 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in which case:
minimum ≥ (1 - L2 x 0.01) M,
maximum ≤ (1 + L2 x 0.01) M,
where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC (AV) ≤ L1 (7.3<15) - - - - - Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.057%
Impurity B - 0.065%
Single not identified
impurity - 0.045%
Total impurities - 0.159% Impurity A - 0.058%
Impurity B - 0.065%
Single not identified
impurity - 0.047%
Total impurities - 0.161% Impurity A - 0.059%
Impurity B - 0.067%
Single unidentified
impurity - 0.047%
Total impurities - 0.162% Impurity A - 0.059%
Impurity B - 0.068%
Single unidentified
impurity - 0.048%
Total impurities - 0.163% Impurity A - 0.061%
Impurity B - 0.070%
Single unidentified
impurity - 0.050%
Total impurities - 0.165% Impurity A - 0.062%
Impurity B - 0.071%
Single unidentified
impurity - 0.051%
Total impurities - 0.166% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Compliant Compliant Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 102.9 mg 102.8 mg 102.6 mg 102.4 mg 102.3 mg 102.1 mg Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0010419-ops Page 4 of 4 Index Specification Requirements Methods Actual result, months 24 36 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1. -
2. - 1. Compliant
2. Compliant Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 79.1% 78.7% Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in this case: minimum ≤ (1 - L2 x 0.01) M, maximum ≤ (1 + L2 x 0.01) M, where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC - (AV) ≤ L1 (7.5<15) Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.064%;
Impurity B - 0.072%;
Single unidentified impurity - 0.053%; Total impurities - 0.169% Impurity A - 0.066%;
Impurity B - 0.075%;
Single unidentified impurity - 0.056%; Total impurities - 0.171% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 101.9 mg 101.6 mg

Conclusion: Meets the requirements of the ND in terms of quality indicators over a period of 36 months. long term test

Drug stability study report Page 1 of 4 Drug: Clofazimine film-coated tablets, 100 mg Control in accordance with the draft ND “Clofazimine film-coated tablets, 100 mg” Storage conditions: In a place protected from light at a temperature not exceeding 25°C Quantities allocated for studying this type of stability:
434 tablets Packaging: 50 or 100 tablets in a polymer jar without a polypropylene membrane with a screw cap Series number: 0020419-ops LS series type:
□ laboratory □ pilot-industrial □ industrial Production date: 04.2019 Shelf life: 3 years Manufacturer: PharmConcept LLC, Russia Date bookmarked for stability: 04/08/2019 Completion date of the stability study: 04/08/2022 (36 months, full cycle) Manufacturer of the substance, country:
Clofazimine - McLeod's Pharmaceuticals Ltd, India Substance production date:
Clofazimine - 01.2019
Substance batch number:
Clofazimine - E/1233/B19003 Shelf life of the substance:
Clofazimine - 2 years

Conditions for studying stability

Temperature Humidity Placement for stability 25°С±2°С 60±5% KAnL OKK room 2(b)

Notes

Additional Information

Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side.

Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0020419-ops Page 2 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1.Compliant
2. Compliant
-
- -
- -
- -
- -
- Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 80.1% 79.9% 79.8% 79.7% 79.5% 79.3% Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0020419-ops Page 3 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in which case:
minimum ≥ (1 - L2 x 0.01) M,
maximum ≤ (1 + L2 x 0.01) M,
where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC (AV) ≤ L1 (7.6<15) - - - - - Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.055%
Impurity B - 0.066%
Single not identified
impurity - 0.047%
Total impurities - 0.160% Impurity A - 0.056%
Impurity B - 0.067%
Single not identified
impurity - 0.048%
Total impurities - 0.162% Impurity A - 0.057%
Impurity B - 0.069%
Single not identified
impurity - 0.049%
Total impurities - 0.163% Impurity A - 0.059%
Impurity B - 0.070%
Single not identified
impurity - 0.049%
Total impurities - 0.164% Impurity A - 0.060%
Impurity B - 0.072%
Single not identified
impurity - 0.051%
Total impurities - 0.165% Impurity A - 0.062%
Impurity B - 0.073%
Single not identified
impurity - 0.052%
Total impurities - 0.167% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Compliant Compliant Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 102.8 mg 102.6 mg 102.5 mg 102.3 mg 102.2 mg 102.0 mg Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0020419-ops Page 4 of 4 Index Specification Requirements Methods Actual result, months 24 36 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1. -
2. - 1. Compliant
2. Compliant Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 79.0% 78.6% Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in this case: minimum ≥ (1 - L2 x 0.01) M, maximum ≤ (1 + L2 x 0.01) M, where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC - (AV) ≤ L1 (7.3<15) Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.064%;
Impurity B - 0.076%;
Single unidentified impurity - 0.055%; Total impurities - 0.170% Impurity A - 0.067%;
Impurity B - 0.078%;
Single unidentified impurity - 0.058%; Total impurities - 0.172% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 101.7 mg 101.4 mg

Conclusion: Meets the requirements of the ND in terms of quality indicators over a period of 36 months. long term test

Drug stability study report Page 1 of 4 Drug: Clofazimine film-coated tablets, 100 mg Control in accordance with the draft ND “Clofazimine film-coated tablets, 100 mg” Storage conditions: In a place protected from light at a temperature not exceeding 25°C Quantities allocated for studying this type of stability:
434 tablets Packaging: 50 or 100 tablets in a polymer jar without a polypropylene membrane with a screw cap Series number: 0030419-ops LS series type:
□ laboratory □ pilot-industrial □ industrial Production date: 04.2019 Shelf life: 3 years Manufacturer: PharmConcept LLC, Russia Date bookmarked for stability: 04/08/2019 Completion date of the stability study: 04/08/2022 (36 months, full cycle) Manufacturer of the substance, country:
Clofazimine - McLeod's Pharmaceuticals Ltd, India Substance production date:
Clofazimine - 01.2019
Substance batch number:
Clofazimine - E/1233/B19003 Shelf life of the substance:
Clofazimine - 2 years

Conditions for studying stability

Temperature Humidity Placement for stability 25°С±2°С 60±5% KAnL OKK room 2(b)

Notes

Additional Information

Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side.

Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0030419-ops Page 2 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. On cross-section, the tablets are brick-red in color. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1.Compliant
2. Compliant -
- -
- -
- -
- -
- Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 80.2% 80.0% 79.8% 79.7% 79.7% 79.4% Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0030419-ops Page 3 of 4 Index Requirements
according to specification Methods Actual result, months 0 3 6 9 12 18 Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in which case:
minimum ≥ (1 - L2 x 0.01) M,
maximum ≤ (1 + L2 x 0.01) M,
where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC (AV) ≤ L1 (7.7<15) - - - - - Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.056%
Impurity B - 0.065%
Single not identified
impurity - 0.049%
Total impurities - 0.158% Impurity A - 0.057%
Impurity B - 0.066%
Single not identified
impurity - 0.050%
Total impurities - 0.159% Impurity A - 0.059%
Impurity B - 0.068%
Single not identified
impurity - 0.051%
Total impurities - 0.161% Impurity A - 0.060%
Impurity B - 0.069%
Single not identified
impurity - 0.053%
Total impurities - 0.162% Impurity A - 0.061%
Impurity B - 0.070%
Single not identified
impurity - 0.054%
Total impurities - 0.164% Impurity A - 0.062%
Impurity B - 0.072%
Single not identified
impurity - 0.056%
Total impurities - 0.165% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Compliant Compliant Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 102.9 mg 102.7 mg 102.6 mg 102.4 mg 102.3 mg 102.1 mg Drug stability study report
Clofazimine film-coated tablets, 100 mg, series 0030419-ops Page 4 of 4 Index Specification Requirements Methods Actual result, months 24 36 Description Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. On cross-section, the tablets are brick-red in color. Visual Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Slightly brown, biconvex, oval-shaped tablets, film-coated with a score on one side. Authenticity 1. The retention time of the main peak in the chromatogram of the test solution should correspond to the retention time of the main peak in the chromatogram of the standard solution of clofazimine
2. The UV absorption spectra of the test and standard solutions must correspond to each other and must have absorption maxima at the same wavelengths 1. State Fund of the Russian Federation, HPLC
2. State Fund of the Russian Federation, UV spectrophotometry 1. -
2. - 1. Compliant
2. Compliant Dissolution At least 75% (Q) of clofazimine from the declared amount after 45 minutes State Fund of the Russian Federation,
UV spectrophotometry 79.0% 78.6% Dosing uniformity Acceptability score (AV) ≤ L1 (n = 10) or Acceptability score (AV) ≤ L1 (n = 30), in this case: minimum ≥ (1 - L2 x 0.01) M, maximum ≤ (1 + L2 x 0.01) M, where L1 = 15.0; L2 = 25.0 State Fund of the Russian Federation,
HPLC - (AV) ≤ L1 (7.5<15) Related impurities Impurity A - no more than 0.1%
Impurity B - no more than 0.3%
Single unidentified impurity - no more than 0.1%
The amount of impurities is no more than 0.5% State Fund of the Russian Federation,
HPLC Impurity A - 0.064%;
Impurity B - 0.073%;
Single unidentified impurity - 0.058%; Total impurities - 0.167% Impurity A - 0.066%;
Impurity B - 0.075%;
Single unidentified impurity - 0.060%; Total impurities - 0.170% Microbiological purity Category 3A State Fund of the Russian Federation Compliant Compliant Quantitative
definition 95 to 105 mg clofazimine per tablet HPLC 101.8 mg 101.7 mg

Conclusion: Meets the requirements of the ND in terms of quality indicators over a period of 36 months. long term test

The noted dosage form is obtained by the following method: sifting of raw materials, where clofazimine, povidone K-25, polyoxyl hydrogenated castor oil (macrogol glyceryl hydroxystearate), microcrystalline cellulose type 101, crospovidone are sifted through a sieve with a mesh diameter of 1 mm, and colloidal silicon dioxide, sodium steryl fumarate are sifted through sieve with cell diameter 0.5 mm; Next, a humidifier is prepared, including obtaining a solution of Povidone K-25 with the addition of polyoxyl hydrogenated castor oil (macrogol glyceryl hydroxystearate) and polysorbate-80 and the addition of purified water; subsequent production of mass for tableting, according to which raw materials and auxiliary components are loaded into the mixer-granulator in the following sequence: microcrystalline cellulose type 101; clofazimine; betadex. and the dry components are mixed, then with the mixer turned on, the humidifier is introduced and further mixing is carried out, the wet granulate is calibrated through a sieve with a diameter of 3-5 mm; subsequent drying at an incoming air temperature of no more than 70 ° C, the temperature of the semi-product should not exceed 40 ° C, drying is carried out until the granulate moisture content is 2 ± 0.5 May. %, upon completion of drying, the dry granulate is calibrated on a sieve with a cell diameter of 1 mm; Next, the granulate dusting stage is carried out, according to which sifted and weighed colloidal silicon dioxide, crospovidone, sodium stearyl fumarate are mixed in a container, and the dry granulate is directly powdered using trituration, followed by feeding to the tableting stage, at which core tablets are obtained using a tablet press; coating the kernels in parallel with a prepared coating suspension, including hypromellose - 6 cP, triacetin, titanium dioxide, red iron oxide dye, yellow iron oxide dye, and the suspension is obtained by mixing purified water and shell components for at least 15 minutes.

The noted method is also an invention according to another aspect of the present application.

Claims (19)

1. Dosage form of clofazimine, which is a film-coated tablet, with the following composition for 95.00-105.00 mg of active substance: Clofazimine as an active ingredient – 95.00-105.00 mg; Excipients in the tablet core, including: Polyoxyl hydrogenated castor oil (Macrogol glyceryl hydroxystearate) – 25.00±1.25 mg; Povidone-K25 – 40.00±0.15 mg; Polysorbate-80 – 5.00±0.25 mg; Betadex – 97.00±4.85 mg; Microcrystalline cellulose type 101 – 242.00±1.21 mg; Colloidal silicon dioxide – 22.00±1.6 mg; Crospovidone – 53.00±4.0 mg; Sodium stearyl fumarate – 12.00±0.6 mg; Tablet shell – 15±1.1 mg, including (wt.%): Hypromellose – 6 cP – 67.00±7%; Triacetin – 7.00±7%; Titanium dioxide – 22.39±7%; Red iron oxide dye – 0.49±7%; Iron oxide yellow dye – 3.12±7%. 2. The method of obtaining a dosage form of clofazimine according to claim 1, including sifting the raw materials, where clofazimine, povidone K-25, betadex, microcrystalline cellulose type 101, crospovidone are sifted through a sieve with a mesh diameter of 1 mm, and colloidal silicon dioxide, sodium steryl fumarate are sifted through sieve with cell diameter 0.5 mm; Next, the humidifier is prepared, including obtaining a solution of Povidone K-25 with the addition of polyoxyl hydrogenated castor oil and polysorbate-80 and the addition of purified water; subsequent production of mass for tableting, according to which raw materials and auxiliary components are loaded into the mixer-granulator in the following sequence: microcrystalline cellulose type 101, clofazimine, betadex, and the dry components are mixed, then, with the mixer turned on, the humidifier is introduced and further mixing and calibration of the wet granulates are produced through a sieve with a diameter of 3-5 mm; subsequent drying at an incoming air temperature of no more than 70°C, the temperature of the semi-product should not exceed 40°C, drying is carried out until the granulate moisture content is 2±0.5 wt. %, upon completion of drying, the dry granulate is calibrated on a sieve with a cell diameter of 1 mm; Next, the granulate dusting stage is carried out, according to which sifted and weighed colloidal silicon dioxide, crospovidone, sodium stearyl fumarate are mixed in a container, and the dry granulate is directly dusted using trituration, followed by feeding to the tabletting stage, at which core tablets are obtained using a tablet press; coating the kernels in parallel with a prepared coating suspension, including hypromellose - 6 cP, triacetin, titanium dioxide, red iron oxide dye, yellow iron oxide dye, and the suspension is obtained by mixing purified water and shell components for at least 15 minutes.