Antitubercular composition comprising rifampicin, isoniazid, ethambutol and pyrazinamide and its process of preparation

Abstract

The present invention relates to a monolayer tablet for use in the treatment of tuberculosis comprising a mixture of: —granules comprising isoniazid, pyrazinamide, ethambutol or a pharmaceutically acceptable salt thereof and at least one granulation binder, —rifampicin in powder form, —extragranular excipients, wherein all of the granules have a particle size that is less than 0.599 mm, preferably less than 0.5 mm, more preferably less than 0.422 mm, and to its process of preparation.

Claims

1. A monolayer tablet for use in treatment of tuberculosis comprising a mixture of: granules comprising isoniazid, pyrazinamide, ethambutol or a pharmaceutically acceptable salt thereof, and at least one granulation binder; rifampicine in powder form; and extragranular excipients, wherein all of the granules have a particle size that is less than 0.5 mm.

2. The monolayer tablet according to claim 1, wherein the monolayer tablet exhibits a mass less than 1,100 mg.

3. The monolayer tablet according to claim 1, comprising 75 mg of isoniazid, 400 mg of pyrazinamide, 275 mg of ethambutol hydrochloride, and 150 mg of rifampicine.

4. The monolayer tablet according to claim 1, wherein the at least one granulation binder is selected from the group consisting of povidone, polyvinyl alcohol, maize starch, and pregelatinized starch.

5. The monolayer tablet according to claim 1, wherein the monolayer tablet comprises from 0.1 to 2% w/w of the at least one granulation binder.

6. The monolayer tablet according to claim 1, wherein the extragranular excipients comprise a disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, maize starch, low substituted hydroxypropyl cellulose, and alginic acid.

7. The monolayer tablet according to claim 1, wherein the extragranular excipients comprise a diluent, an antioxidant, a lubricant, a flavouring agent, a colorant, or mixtures of the foregoing.

8. The monolayer tablet according to claim 1, wherein the monolayer tablet comprises from 10 to 17% w/w of the extragranular excipients.

9. The monolayer tablet according to claim 7, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, calcium stearate, stearic acid, zinc stearate, and glyceryl behanate.

10. The monolayer tablet according to claim 7, wherein the monolayer tablet comprises from 0.1 to 2% w/w of the lubricant.

11. The monolayer tablet according to claim 7, wherein the antioxidant is selected from the group consisting of sodium ascorbate, 2,6-di-tert-butyl-4-hydroxytoluene (BHT), citric acid, tocopherol, and sodium metabisulfite.

12. The monolayer tablet according to claim 7, wherein the monolayer tablet comprises from 0.1 to 2% w/w of the antioxidant.

13. The monolayer tablet according to claim 1, wherein the monolayer tablet is free of surfactant.

14. The monolayer tablet according to claim 1, wherein the monolayer tablet further comprises a film coating.

15. The monolayer tablet according to claim 14, wherein the monolayer tablet exhibits a mass less than 1,150 mg.

16. The monolayer tablet according to claim 14 wherein the monolayer tablet comprises less than 5% by weight of total impurities relative to the weight of the monolayer tablet after the monolayer tablet has been aged for 2 months at 40° C. and 75% relative humidity.

17. The monolayer tablet according to claim 14, wherein the monolayer tablet comprises less than 1% by weight of 3-formyl-rifampicine-isoniazid adduct of formula (I) ##STR00002## wherein R is isoniazid, relative to the weight of the monolayer tablet after the monolayer tablet has been aged for 2 months at 40° C. and 75% relative humidity.

18. A process for preparing the monolayer tablet according to claim 1, comprising a step of wet-granulating isoniazid, pyrazinamide, and ethambutol or a pharmaceutically acceptable salt thereof with an aqueous solution of a granulation binder to obtain granules.

19. The monolayer tablet according to claim 1, wherein all of the granules have a particle size which further is more than 0.075 mm.

20. The monolayer tablet according to claim 1, wherein all of the granules have a particle size that is less than 0.422 mm.

Description

EXAMPLES

Example 1: Composition According to the Invention

(1) Table 1 below shows the quantity (in mg) of each ingredient in the tablet according to the present invention.

(2) TABLE-US-00001 TABLE 1 Ingredients Quantity (mg per tablet) Intra-granular Isoniazid 75.00 Pyrazinamide 400.00 Ethambutol Hydrochloride 275.00 Binder Solution Polyvinyl Pyrrolidone 10.00 Purified Water* q.s. Extra-granular Rifampicin 150.00 Microcrystalline Cellulose 89.30 Sodium Ascorbate 5.70 Croscarmellose Sodium 40.00 Magnesium Stearate 5.00 Total weight of Core tablets 1050.00 Film Coating Opadry II Purple 85G20180 40.00 Purified Water* q.s. Total weight of Coated tablets 1090.00 *Removed during drying, does not appear in the final product except in traces.

(3) Procedure:

(4) A. Preparation of Blend for Tablets Step 1: Sift Isoniazid, Pyrazinamide and Ethambutol HCl through 0.599 mm sieve. Step 2: Transfer the materials of Step 1, into Mixer Granulator and dry mix for 20 minutes with impeller slow speed and chopper slow speed Step 3: Dissolve polyvinylpyrrolidone in purified water with continuous stirring. Step 4: Granulate the Step 2 material using solution of Step 3 until suitable granulation end point is obtained. Step 5: Wet mill the granules through 4.0 mm screen and transfer the granules into the Fluid Bed Dryer, and dry the wet granules at inlet temperature of 60° C.±10° C. until LOD at 80° C. of below 1.0% w/w is achieved. Step 6: Sift the dried granules through 0.422 mm screen, mill the retained granules through 1.0 mm screen and pass through 0.422 mm sieve to obtain granules wherein all of the granules have a particle size that is less than 0.422 mm. Record the yield of the granules and compensate the extra-granular materials as per yield. Step 7: Sift Rifampicin, Sodium Ascorbate, Croscarmellose Sodium, and Microcrystalline Cellulose through 0.599 mm sieve. Step 8: Blend Step 6 and Step 7 using Bin Blender for 20 min at 18 rpm±1 rpm. Step 9: Sift Magnesium Stearate through 0.251 mm sieve and add to Step 8 materials present in the bin blender and lubricate the blend for 5 min at 18 rpm±1 rpm.

(5) B. Compression of Tablets Step 10: Compress the lubricated blend of step 9 using a Cadmach® Legacy tablet press with the following parameters: 45 station, single-stage, B-tooling (14.5 mm diameter, round, SCBE, plain on both sides).

(6) C. Film Coating of Core Tablets Step 11: Disperse Opadry® II Purple 85G20180 in purified water with continuous stirring for 45 minutes. Step 12: Load the tablets into Auto coater and warm the tablets at suitable pan rpm by keeping sufficient inlet and exhaust temperature to achieve the bed temperature of 40 to 50° C. Step 13: Coat the tablets of step 2 using step 1 dispersion at suitable pan rpm, suitable gun to bed distance, sufficient inlet and exhaust temperature and suitable spray rate maintaining the tablet bed temperature of 40 to 50° C. Step 14: Continue the coating until the weight gain of 3.81% is achieved.

(7) Particle Size Distribution of the Granules:

(8) The particle sizes listed in Table 2 are obtained according to the Test methods described herein.

(9) TABLE-US-00002 TABLE 2 % of granules Cumulative % of Aperture Size retained granules retained 710μ 0.40 0.40 500μ 4.37 4.77 355μ 10.74 15.51 250μ 11.93 27.44 180μ 14.31 41.75 150μ 9.54 51.29 125μ 12.13 63.42  90μ 17.50 80.91 Below 90μ 19.09 100.00

(10) Physical Parameters:

(11) The parameters listed in Table 3 are obtained for the uncoated and the coated tablets according to the Test methods described herein.

(12) TABLE-US-00003 TABLE 3 Diameter of uncoated tablet 14.5 mm ± 0.2 mm Diameter of coated tablet 14.6 mm ± 0.2 mm Average weight of uncoated tablet 1050 mg ± 3% Average weight of coated tablet 1090 mg ± 3% Hardness of uncoated tablet 50-60 N Hardness of coated tablet 125-130 N Friability of uncoated tablet 0.15% w/w Thickness of uncoated tablet 6.6 mm ± 0.2 mm Thickness of coated tablet 6.8 mm ± 0.2 mm Disintegration Time of uncoated tablet 4 min 30 sec to 5 min Disintegration Time of coated tablet 5 min 30 sec to 6 min

(13) Stability:

(14) Table 4 shows the percentage of active ingredient that is effectively measured relative to the target quantity of active ingredients that are present in the coated tablets immediately after the tablets are prepared as well as after aging of the tablets for 1 month and 2 months at 40° C. and 75% relative humidity.

(15) TABLE-US-00004 TABLE 4 Aging at 40° C. and 75% relative Limits Initial humidity (%) (%) (%) 1 month 2 months Active Rifampicin 90-105 101.3 101.4 102.0 ingredients Isoniazid 90-105 100.0 97.8 98.20 Pyrazinamide 90-105 101.3 101.2 100.5 Ethambutol HCl 90-105 100.6 100.3 101.4

(16) Table 5 shows the weight percentage of impurities based on the weight of the coated tablet that are present in the coated tablets immediately after the tablets are prepared as well as after aging of the tablets for 1 month and 2 months at 40° C. and 75% relative humidity.

(17) TABLE-US-00005 TABLE 5 Aging at 40° C. and 75% relative Limits Initial humidity (%) (%) (%) 1 month 2 months Related Rifampicin quinone <1.5 0.784 0.962 0.967 impurities Rifampicin N-oxide <0.5 0.393 0.457 0.477 3-Formyl Rifampicin <0.5 0.068 0.060 0.082 3-Formyl-Rifampicin- <4.0 0.615 0.631 0.802 Isoniazid adduct 25 Desacetyl- <0.5 0.117 0.148 0.149 Rifampicin Other Single specified <0.5 0.294 0.323 0.322 related (retention time 0.35) impurities Single specified <0.5 0.206 0.235 0.238 (retention time 0.80) Single unidentified <0.2 0.126 0.146 0.145 Total Impurities <8.0 2.803 3.291 3.506

(18) As such, the tablet obtained according to the invention is stable in time and the total level of impurities is much lower than the required standard. Specifically, the percentage of 3-formyl-Rifampicine-Isoniazid adduct in the tablet is very low which confirms that there is hardly any adverse interaction between rifampicine and isoniazid.

(19) Table 6 shows the loss on drying and the dissolution time of the coated tablets immediately after the tablets are prepared as well as after aging of the tablets for 1 month and 2 months at 40° C. and 75% relative humidity.

(20) TABLE-US-00006 TABLE 6 Aging at 40° C. and 75% relative Limits Initial humidity (%) (%) (%) 1 month 2 months Loss on drying <3.0%  1.12 0.87 0.81 % of dissolved Rifampicin >75% 101 101 100 actives Isoniazid >75% 98 98 100 at 45 min after Pyrazinamide >75% 102 102 102 beginning the Ethambutol >75% 100 100 99 Dissolution time HCl test pH 6.8 phosphate buffer 900 mL paddle 100 rpm

(21) Table 7 gives the cumulative percentage of each active released according to the Dissolution time test disclosed herein.

(22) TABLE-US-00007 TABLE 7 5 10 15 20 30 45 60 min min min min min min min Rifampicin 47 74 86 93 98 100 100 Isoniazid 86 99 100 100 100 100 100 Pyrazinamide 90 101 102 102 102 102 102 Ethambutol 84 99 99 99 99 99 99

(23) As such, the tablet obtained according to the invention is stable in time and the loss on drying and the dissolution time are within the required standards.

Comparative Example—Replacement of Disintegrant

(24) An uncoated tablet was prepared as disclosed in Example 1 except that the 40 mg of Croscarmellose Sodium are replaced with 40 mg of Crospovidone.

(25) The parameters listed in table 8 are obtained for the tablet according to the Test methods described herein:

(26) TABLE-US-00008 TABLE 8 Hardness of tablet 60 N Friability of tablet 0.3% w/w Disintegration time of tablet 6 min to 7 min

(27) As such, the replacement of croscarmellose sodium by crospovidone leads to a greater friability and dissolution time of the tablet compared to the tablet according to Example 1.

Comparative Example—Different Granule Size

(28) An uncoated tablet was prepared as disclosed in Example 1 except that in step 6 of the process of preparation, the granules are sifted through 0.853 mm screen instead of 0.422 mm screen. As such, the particle size of all of the resulting comparative granules is less than 0.853 mm.

(29) The parameters listed in table 9 are obtained for the tablet according to the Test methods described herein:

(30) TABLE-US-00009 TABLE 9 Hardness of tablet 50 N Friability of tablet failed: tablets break after 100 rotations Disintegration time of tablet 7 min

(31) As such, the change in granule size leads a decrease in the hardness of the tablet and to a greater dissolution time of the tablet compared to the tablet according to Example 1. Furthermore, the comparative tablet that is obtained is too friable to be coated.