WO2007142546A2

WO2007142546A2 - Sustained release coated tablet with precisely regulated release profile

Info

Publication number: WO2007142546A2
Application number: PCT/PL2007/000036
Authority: WO
Inventors: Jaroslaw Mazgalski; Frank Ross Malcolm Stewart
Original assignee: Zaklady Farmaceutyczne Polpharma S.A.
Priority date: 2006-06-02
Filing date: 2007-06-01
Publication date: 2007-12-13
Also published as: WO2007142546A3; PL204780B1; PL379831A1; EP2023904A2

Abstract

The present invention relates to a novel stable pharmaceutical composition in the form of a sustained release coated tablet comprising an active ingredient, carbomer and pharmaceutically acceptable excipients with a release profile that is precisely regulated by the parameters of the coating process, the use of carbomer for manufacturing the tablet and the process of coating the tablet using a water-based coating suspension.

Description

Sustained release coated tablet with precisely regulated release profile

The active ingredient is preferably selected from the group consisting of Indapamide and Tramadol or pharmaceutically acceptable salts thereof.

Indapamide is a compound indicated for the treatment of hypertension and is used as sole therapy or with other antihypertensive agents. Indapamide and the process for manufacturing thereof was described in GB 1203691.

Tramadol is an analgesic used as sole therapy or in combination with other active ingredients. Tramadol and the process for manufacturing thereof was described in US 3,652,589.

Technology of choice in the manufacture of sustained release tablets comprising

Indapamide or Tramadol is direct compression. See, EP 1057479, EP 800384, EP 519820,

WO 2004/002475 and WO 2005/074884 for Indapamide compositions prepared by direct compression method and EP 642788 and WO 03/080031 for Tramadol compositions prepared by direct compression method.

Surprisingly, it was found that the use of carbomer as a sustained release agent in a formulation prepared by direct compression provides a stable tablet, which release profile can be precisely regulated by the parameters of the coating process employing a water-based coating suspension. Thus, the present invention provides a process for obtaining a sustained release tablet with a desired release profile, comparable to the reference product.

In particular, the tablet according to the invention comprises an active substance, preferably Indapamide, Tramadol or any pharmaceutically acceptable salt thereof, carbomer as a sustained release agent and pharmaceutically acceptable excipients and is coated with a water-based coating suspension.

Pharmaceutically acceptable excipients include, but are not limited to, extended release-matrix formers, diluents, glidants and lubricants.

In one of its embodiments, the present invention provides the use of carbomer for preparing sustained release tablets according to the invention.

Carbomer is a pharmaceutical excipient used mainly for obtaining semisolid dosage forms. Combining carbomer with an extended release-matrix former in solid state unexpectedly results in obtaining suitable for direct compression tabletting mass with exceptional features. Carbomer has a relatively very small particle size (2 - 7 μm) comparing to high-molecular weight extended release-matrix formers, therefore they suit together well and compose direct compression tabletting mass with flowability much greater than those of tabletting masses comprising polymers typically used for preparing sustained release dosage forms. Compression of the tabletting mass according to the invention results in obtaining a matrix tablet swelling very evenly when contacted with water. Additionally, the release profile of the active ingredient from the tablet is independent of the tablet's hardness, and thus also of the compression force applied due to the small particle size of carbomer, which prevents it from fragmentation during compression.

Sustained release coated tablet according to the invention comprises carbomer in an amount of 10 to 30% by weight. Preferably, the carbomer is Carbopol 974P NF Polymer (Noveon). Extended release-matrix former, according to the invention, is present in the composition in an amount of 10 to 40% and is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, Eudragit NE, Eudragit RS and mixtures thereof.

Preferably, when Carbopol 974P NF Polymer is employed in the composition as the carbomer, the extended release-matrix former is hydroxypropyl cellulose.

Sustained release coated tablet according to the invention comprises the active ingredient in an amount of 0,6 to 40% by weight. For low dosage tablets, for instance 1,5 mg Indapamide tablets, a premix of the active ingredient with diluent may be employed to afford dosage content uniformity. Diluent, according to the invention, is present in the composition in an amount of 10 to 70% and is selected from the group consisting of dedicated for direct compression technology lactose, dibasic calcium phosphate, sucrose and mannitol. Preferably, the diluent is DC lactose, e.g., commercially available DCL-11, Flowlac.

Sustained release coated tablet according to the invention comprises glidants. In a preferred embodiment of the invention, a mixture of talc and colloidal anhydrous silica is employed as the glidant. The use of said mixture of glidants greatly contributes to the flowability of the tabletting mass.

Accordingly, in a another preferred embodiment of the invention, the coated tablet comprises further pharmaceutically acceptable excipients, for instance lubricants, e.g., magnesium stearate, stearic acid.

The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

Composition of a stable sustained release tablet comprising Indapamide according to the invention is given in Example 1. Manufacturing process for a batch size of 304 kg (1 600 000 tablet cores) is given in Example 2.

Example 1 Composition of a stable sustained release tablet comprising Indapamide according to the invention.

* water content included Example 2

Manufacturing process of Indapamide SR tablets as presented in Example 1 for a batch size of 304 kg (1 600 000 tablet cores, 190 mg each).

Indapamide (2,44 kg) was pre-mixed with lactose DCL-I l (151,96 kg) in a 800-litre bin mixer for 1 hour at the speed of 18 rpm. Subsequently, the blended material was placed in a 1200-litre bin mixer. Next, lactose DCL-Il (43,5 kg), Klucel HXF (59,74 kg), Carbopol 974P NF Polymer (38,456 kg), Aerosil 200 (1,52 kg) and talc (1,824 kg) were added and the material was blended for 1 hour at the speed of 12 rpm. Finally, magnesium stearate (4,56 kg) was added and the material was blended for 10 minutes at the speed of 12 rpm. Thus obtained mixture was compressed into 190 mg tablet cores using a rotary tabletting machine equipped with 8 mm diameter biconvex punches.

Composition of a stable sustained release tablet comprising Tramadol according to the invention and process for manufacturing thereof are given respectively in Examples 3 and 4.

Example 3

Composition of a stable sustained release tablet comprising Tramadol according to the invention.

Example 4

Manufacturing process of Tramadol SR tablets as presented in Example 3 for a batch size of 18 kg (30 000 tablet cores, 600 mg each).

Tramadol HCl (6,0 kg), Carbopol 974P NF Polymer (2,7 kg), Klucel HXF (5,4 kg),

Aerosil 200 (0,072 kg), talc (0,108 kg) and dibasic calcium phosphate (3,54 kg) were blended in a 50-litre bin mixer for 1 hour at the speed of 12 rpm. Next, magnesium stearate (0,18 kg) was added and the material was blended for 5 minutes at the speed of 12 rpm. Thus obtained mixture was compressed into 600 mg tablet cores using a rotary tabletting machine equipped with 15,5 x 8,5 mm elongated punches.

In one of its embodiments, the invention also relates to the coating process of the sustained release tablet comprising an active ingredient, carbomer and pharmaceutically acceptable excipients using a water-based coating solution. During the process, the water present in the coating solution penetrates the core of the tablet and causes the matrix composed of carbomer and extended release-matrix former to swell. In the subsequent step of drying the coated cores, which is an integral part of the coating process, the water evaporates from the tablets forming micropores. The release profile of the active ingredient from the tablet is directly dependent on the amount of micropores formed in the tablet core during the coating process.

Employing appropriate parameters of the coating process, a person skilled in the art is able to precisely regulate the release profile of the coated tablet using coating solution of constant formula. These variable parameters of the coating process are coating suspension feeding rate, air inlet temperature and air flow rate, and their values depend on the type, size and brand of the perforated coating pan used for the process and the amount of tablet cores placed into the perforated coating pan. One should aim for optimal filling of the apparatus with tablet cores, which is a characteristic value for each perforated coating pan.

Coating of the tablet cores employing appropriate parameters of the process according to the invention allows for obtaining a coated tablet with any desirable release profile at the same level or higher than the release profile of the uncoated core. The value ranges for the parameters of the coating process that regulate the release profile of the active ingredient from the coated tablet are given below:

A person skilled in the art given the degree of filling the coating apparatus with tablet cores will be able to determine the value of parameters of the coating process using routine experimentation and without undue burden. The parameters of the coating process according to the invention affording

Indapamide SR tablets with a release profile that is comparable to the reference product for a batch size of 304 kg (1 600 000 tablet cores, 190 mg each) performed in a perforated coating pan Glatt GCl 500 using water-based coating solution Opadry 33G24509 are given in Example 5.

Example 5

The parameters of the coating process affording Indapamide SR tablets with a release profile comparable to the reference product for a batch size of 304 kg (1 600 000 tablet cores, 190 mg each) performed in a perforated coating pan Glatt GCl 500 using water-based coating solution Opadry 33G24509.

The parameters of the coating process of Indapamide SR tablet cores prepared according to the method described in Example 2 using Opadry 33G24509 water-based coating suspension composed of 8,0 kg Opadry 33G24509 and 45,0 kg purified water in a perforated coating pan Glatt GCl 500 are given below.

The coating process resulted in obtaining sustained release Indapamide coated tablets characterised by total mass of 195 mg and the release of the active ingredient at 95% within 24 hours. The release profile of the tablet, which is comparable to the reference product, and the release profile of the uncoated tablet core (71% within 24 h) are presented in Fig. 1.

As stated before, the coating process according to the invention allows for obtaining a coated tablet with any desirable release profile at the same level or higher than the release profile of the uncoated core. The parameters of the coating process affording Indapamide SR coated tablets which release 89% of the active ingredient within 24 hours are given in

Example 6.

Example 6

The parameters of the coating process affording Indapamide SR coated tablets which release 89% of the active ingredient within 24 hours for a batch size of 304 kg (1 600 000 tablet cores, 190 mg each) performed in a perforated coating pan Glatt GCl 500 using water- based coating solution Opadry 33G24509.

The coating process resulted in obtaining sustained release Indapamide coated tablets characterised by total mass of 192,5 mg and the release of the active ingredient at 89% within 24 hours. The release profile of the coated tablet and the release profile of the uncoated tablet core (71 % within 24 h) are presented in Fig. 2. Stability tests were performed for the sustained release coated tablet comprising Indapamide as presented in Example 1, prepared according to the method described in Example 2 and coated employing the process parameters presented in Example 5. The results of the tests are given below.

hi addition to satisfying stability, said coated tablet is also characterised by very good physical properties, i.e. friability at 0,00% and hardness in the range from 50 to 150 N.

The parameters of the coating process according to the invention affording Tramadol SR tablets with a release profile that is comparable to the reference product for a batch size of 18 kg (30 000 tablet cores, 600 mg each) performed in a perforated coating pan Glatt GMPC2 using water-based coating solution Opadry 33G24509 are given in Example 7.

Example 7

The parameters of the coating process affording Tramadol SR tablets with a release profile comparable to the reference product for a batch size of 18 kg (30 000 tablet cores, 600 mg each) performed in a perforated coating pan Glatt GMPC2 using water-based coating solution Opadry 33G24509. The parameters of the coating process of Tramadol SR tablet cores prepared according to the method described in Example 4 using Opadry 33G24509 water-based coating suspension composed of 0,45 kg Opadry 33G24509 and 1,55 kg purified water in a perforated coating pan Glatt GMPC2 are given below.

The coating process resulted in obtaining sustained release Tramadol HCl coated tablets characterised by total mass of 615 mg and the release of the active ingredient at 86% within 8 hours. The release profile of the tablet, which is comparable to the reference product, and the release profile of the uncoated tablet core (76% within 8 h) are presented in Fig. 3.

Thus obtained sustained release Tramadol HCl coated tablets are stable and have very good physical properties, i.e. friability at 0,00% and hardness in the range from 110 to 120 N.

Claims

1. A sustained release coated tablet prepared using direct compression method comprising an ^active ingredient and pharmaceutically acceptable excipients, characterised in that the tablet core comprises carbomer as a controlled-release ingredient and the release profile of the coated tablet is precisely regulated by the parameters of the coating process which involves the use of a water based coating suspension.

2. The sustained release coated tablet according to claim 1, wherein the active ingredient is selected from the group consisting of indapamide and tramadol or any pharmaceutically acceptable salt thereof.

3. The sustained release coated tablet according to claim 1, wherein the active ingredient is present in an amount of 0,6 to 40% by weight.

4. The sustained release coated tablet according to claim 1, wherein carbomer is present in an amount of 10 to 30% by weight.

5. The sustained release coated tablet according to claim 4, wherein the tablet preferably comprises Carbopol 974P NF Polymer.

6. The sustained release coated tablet according to claim 1, wherein the pharmaceutically acceptable excipients comprise an extended release-matrix former, which is present in the tablet in an amount of 10 to 40% by weight.

7. The sustained release coated tablet according to claim 6, wherein the extended release- matrix former is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, Eudragit NE, Eudragit RS or a mixture thereof.

8. The sustained release coated tablet according to claim 7, wherein the extended release- matrix former is hydroxypropyl cellulose.

9. The sustained release coated tablet according to claim 1, wherein the pharmaceutically acceptable excipients comprise a diluent, which is present in the tablet in an amount of 10 to 70% by weight.

10. The sustained release coated tablet according to claim 9, wherein the diluent is selected from the group consisting of lactose, sucrose, mannitol and dibasic calcium phosphate.

11. The sustained release coated tablet according to claim 1, wherein the pharmaceutically acceptable excipients comprise a glidant, preferably a mixture of talc and anhydrous silica dioxide.

12. The use of carbomer for preparing a sustained release, coated tablet comprising an active ingredient by direct compression method, characterised in that the release profile of the active ingredient from the coated tablet is precisely regulated by the parameters of the coating process with a water containing coating suspension.

13. The use of carbomer according to claim 12, wherein the active ingredient is selected from the group consisting of indapamide and tramadol or any pharmaceutically acceptable salt thereof.

14. The use of carbomer according to claim 12, wherein carbomer is present in the tablet in an amount of 10 to 30% by weight.

15. The use of carbomer according to claim 14, wherein the tablet comprises Carbopol 974P NF Polymer.

16. The use of carbomer according to claim 12, wherein the active ingredient is present in the tablet in an amount of 0,6 to 40% by weight.

17. The use of carbomer according to claim 12, wherein the tablet further comprises an extended release-matrix former, which is present in the tablet in an amount of 10 to

40% by weight.

18. The use of carbomer according to claim 17, wherein the extended release-matrix former is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, Eudragit NE, Eudragit RS or a mixture thereof.

19. The use of carbomer according to claim 18, wherein the extended release-matrix former is hydroxypropyl cellulose.

20. The use of carbomer according to claim 12, wherein the tablet further comprises a diluent in an amount of 10 to 70% by weight.

21. The use of carbomer according to claim 20, wherein the diluent is selected from the group consisting of lactose, sucrose, mannitol and dibasic calcium phosphate.

22. The use of carbomer according to claim 12, wherein the tablet further comprises a glidant, preferably a mixture of talc and anhydrous silica dioxide.

23. A process of coating of a sustained release tablet prepared by direct compression method comprising an active ingredient, carbomer as a controlled-release ingredient and pharmaceutically acceptable excipients using a water based coating suspension, characterised in that the release profile of the tablet is precisely regulated by the following parameters of coating process: a) inlet temperature, b) slow rate of coating suspension, c) volume of air.

24. The process of coating according to claim 23, wherein the active ingredient is selected from the group consisting of indapamide and tramadol or any pharmaceutically acceptable salt thereof.

25. The process of coating according to claim 23, wherein the tablet core undergoing the coating process comprises carbomer in an amount of 10 to 30% by weight, the active ingredient in an amount of 0,6 to 40% by weight and pharmaceutically acceptable excipients.

26. The process of coating according to claim 25, wherein the pharmaceutically acceptable excipients comprise an extended release-matrix former in an amount of 10 to 40% by weight, a diluent in an amount of 10 to 70% by weight and a glidant.