WO2006103506A1

WO2006103506A1 - Sertraline-containing pharmaceutical compositions and a process for preparation thereof

Info

Publication number: WO2006103506A1
Application number: PCT/IB2006/000610
Authority: WO
Inventors: Nidhi Singh; Romi Barat Singh; Vishnubhotla Nagaprasad
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-03-31
Filing date: 2006-03-17
Publication date: 2006-10-05

Abstract

The present invention relates to a tablet comprising sertraline or pharmaceutically acceptable salts thereof having a particle size wherein d90 ≤ 350 µm, a diluent, a binder, a disintegrant and a lubricant or a glidants; and process for preparation thereof.

Description

SERTRALINE-CONTAINING PHARMACEUTICAL COMPOSITIONS AND A PROCESS FOR PREPARATION THEREOF

Technical Field of the Invention

The present invention relates to a tablet comprising sertraline or pharmaceutically acceptable salts thereof having a particle size wherein dgo < 350 μm, a diluent, a binder, a disintegrant and a lubricant or a glidants; and process for preparation thereof.

Background of the Invention

Sertraline, or (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthylenamine, is a potent selective serotonin reuptake inhibitor. Sertraline is commercially sold as its hydrochloride salt under the trademark Zoloft^® which is approved by the U.S. Food and Drug Administration for the treatment of depression, obsessive- compulsive disorder, posttraumatic stress disorder and panic disorder.

Sertraline is disclosed in U.S. Patent No. 4,536,518 which describes the synthesis of certain cis-4-phenyl-l,2,3,4-tetrahydronaphthalenamine derivatives, including sertraline, and pharmaceutically acceptable salts of these compounds. It states that the compounds may exist in different polymorphic forms but do not disclose any specific polymorphic forms. Further methods of preparing sertraline are set forth in U.S. Patent Nos. 4,777,288; 4,839,104; 4,855,500; 5,463,126; 5,442,116; 5,082,970; 5,466,880; 5,196,607; 5,750,794; 5,288,916; and 6,323,500; as well as in the following published patent applications: International PCT Patent Publication No. WO 99/57089; European

Patent Publication Nos. EP 997 535 Al and EP 1 059 287 Al; and U.S. Patent Publication No. 2001-0044142 Al.

According to U.S. Patent No. 5,248,699, the sertraline hydrochloride produced by the method of the U.S. Patent No. 4,536,518 has a crystalline form denominated "Form II." It discloses four other polymorphs of sertraline hydrochloride designated

Forms I, III, IV, and V, and characterizes them by single crystal x-ray analysis, powder x- ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. U.S. Patent Nos. 4,536,518 and 5,248,699 also disclose certain dry solid pharmaceutical compositions prepared by blending sertraline with conventional ingredients used in tablet and capsule manufacturing. U.S. Patent Nos. 6,500,987; and 6,495,721; U.S. Application No. 2002/0183555, and PCT Application Nos. WO 02/96859 and WO 01/32601 disclose processes for the preparation of sertraline hydrochloride form II. They also disclose compositions comprising form II prepared by the process with conventional carriers. PCT application WO 03/93217 discloses processes for the preparation of crystalline sertraline hydrochloride form II "substantially free" of other polymorphic forms. It also discloses a tablet comprised of sertraline hydrochloride and the following excipients, in weight to weight percentages, wherein the tablet is prepared from an industrial-sized batch of sertraline hydrochloride Form II "substantially free" of sertraline hydrochloride Form I: about 20% to about 35% sertraline hydrochloride Form II, about 25% to about 40% lactose monohydrate, about 5% to about 12% croscarmellose sodium NF, about 1% to about 3% povidone, about 20% to about 40% microcrystalline cellulose and about 0.5% to about 2.5% magnesium stearate (percentages by weight of the entire formulation). The sertraline hydrochloride Form II used for preparing a tablet according to this publication has a particle size distribution such that 100% of the particles are below 200 microns, more preferably below 100 microns and most preferably below about 50 microns.

The formulation of a composition in a tablet generally involves the critical step of compression of a powder or a granulate. Thus, the compression properties and behaviour of such a powder or granulate plays a significant role in preparation of a tablet with desirable properties. Inadequacies in imparting suitable compressibility may produce tablets with many defects such as insufficient mechanical strength, sticking and picking, capping, lamination and the like.

Summary of the Invention We have discovered that dosage forms of sertraline can be prepared by careful process and excipient manipulation using a coarse particle size, particularly more than 200 μm.

In one aspect, pharmaceutical compositions comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein dg₀ < 350 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant are provided. In another aspect, pharmaceutical compositions comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein dg₀ < 250 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant are provided.

In another aspect, pharmaceutical compositions comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein d₅o ≤ 150 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant are provided.

In another aspect, pharmaceutical compositions comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein d₅₀ ≤ 60 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant are provided. In another aspect, pharmaceutical compositions comprising sertraline hydrochloride having dc_>o and dso as described in the aspects above, a diluent, a binder, a disintegrant and a lubricant or a glidant are provided.

In another aspect, tablets for oral administration comprising sertraline hydrochloride, having dc>o and dso as described in the aspects above are provided; the composition comprising; a) about 5 % to about 70 % by weight of sertraline hydrochloride; b) about 20 % to 80 % by weight of a diluen; c) about 1 % to 20 % by weight of a disintegrant; d) about 1 % to 10 % by weight of a binder; and e) about 0.5 % to 3 % by weight of a lubricant.

In yet another aspect, processes for preparing tablets comprising sertraline hydrochloride having dg₀ and d₅₀ as described in the aspects above are provided; wherein the process comprises: a) blending sertraline hydrochloride, diluent and disintegrant; b) granulating the blend with a binder solution; c) drying and sizing the granules; d) blending the dried granules with diluent, lubricant, glidant and optionally a disintegrant; - A - e) compressing the blend to form tablets; and f) optionally coating the tablets.

In another aspect, methods for treating a disorder selected from major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder in a patient, comprising administering to the patient a pharmaceutical composition comprising sertraline or pharmaceutically acceptable salt thereof having dg₀ and d₅₀ as described in the aspects above are provided.

In another aspect, pharmaceutical compositions comprising sertraline or pharmaceutically acceptable salt thereof having dgo and d₅₀ as described in the aspects above are provided; wherein the composition further comprises a drug selected from a group comprising antidepreesants, sedatives, antipsychotics, anxiolytics and anticonvulsants.

Detailed Description of the Invention The term "sertraline or pharmaceutically acceptable salts" as used herein includes non-salt, non-hydrated free base as well as pharmaceutically acceptable acid addition salt. The pharmaceutically acceptable acid addition salts salt may be present in the form of a hydrate or polymorph, more particularly sertraline hydrochloride form II. Sertraline or its pharmaceutically acceptable acid addition salt may be present in an amount ranging from about 5 % to 70 % by weight of the compostion.

The term "d₉₀" and "d₅o" as used herein denotes respectively that 90% and 50% of the particles are smaller than the specified size.

The term "sticking and picking" as described herein is intended for a defect encountered during tabletting procedure wherein the granules stick to the punch faces or to the letters, logos, or designs on the punch faces during compression.

The term "capping" as described herein is intended for a defect encountered during tabletting procedure wherein there is separation of the upper part of the tablet during ejection and handling, either spontaneously or on application of force. The term "lamination" as described herein is intended for a defect encountered during tabletting procedure wherein there is break up of the tablet into a number of layers which usually occurs in the middle of the tablet.

The term "Friability test" as described herein refers to the test for determining friability of tablets as given on page 2255 of the Unites States Pharmacopoeia (25^th edition, NF 20). The test describes an apparatus for friability measurement and states that "a maximum weigh loss of not more than 1 % of the weight of the tablets being tested is considered acceptable for most products".

The pharmaceutical compositions as described herein may include tablets and capsules. Sertraline and pharmaceutically acceptable excipients may be formulated into compositions according to methods known in the art.

A composition for tableting may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a granulating fluid that causes the powders particles to aggregate into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.

The particle size or particle size distribution of a drug may significantly affect the processing behavior and characteristics of a composition in a wet granulation process. For example, granule formation and growth in a wet granulation process is due to particle agglomeration behaviour, which may depend on the particle size. Such agglomeration also has significant effect on the granule particle size, which may have a considerable consequence on critical properties like flowablity and compressibility. Compressibility may also be affected by factors like bulk density which may be functionally related to particle size. The initial experiments which were started using narrow particle size (dgo ranging from 20 μm to 40 μm) of sertraline rendered problems such as sticking and picking of granules. It was surprisingly observed that tablet having desirable properties like adequate hardness, disintegration and friability under limits as well as devoid of problems such as sticking and picking may be obtained using a coarse particle size of sertraline. When preparing the composition by wet granulation, the pharmaceutical compositions may also include pharmaceutically acceptable excipients like diluents, disintegrants, binders, glidants and lubricants.

Diluents may be selected from cellulose-derived materials such as powdered cellulose, macrocrystalline cellulose, microfine cellulose, and the like; lactose, starch, pregelatinized starch, sugars and sugar alcohols such as mannitol, sorbitol, erythritol and the like; dextrates, dextrin, dextrose, inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, potassium chloride, sodium chloride or mixture of one or more of such diluent. Particularly suitable diluents are microcrystalline cellulose, dibasic calcium phosphate dihydrate or mixture thereof. The diluent may be present in an amount ranging from about 20 % to about 80 % by weight of the compostion.

Binders which may be used include gums like acacia, guar gum, alginic acid, sodium alginate; carbomer, dextrin, gelatin, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, and the like. The binder may be present in an amount ranging from about 1 % to about 10 % by weight of the composition. The binder may be incorporated into the composition in two ways, for example, the binder may be mixed with sertraline and other excipients and the blend may then be processed into granules by addition of water (i.e. binder in a dry form) or the blend of sertraline and excipients maybe granulated using an aqueous solution of the binder (i.e. binder in a wet form).

Disintegrants which may be used include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, magnesium aluminum silicate, powdered cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, sodium alginate, starch and the like. The disintegrant may be present in an amount ranging from about 1 % to about 20 % by weight of the compostion. The disintegrant may be present intragranulary only or both intragranularly and extragranularly. Lubricants which may be used, include magnesium stearate, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. The lubricant may be present in an amount ranging from about 0.5 % to about 3 % by weight of the compostion.

Glidants which may be used include talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate. The glidant may be present in an amount ranging from 0.5 % to 3 % by weight of the compostion. It would be appreciated that a person skilled in the art is cognizant of the fact that certain excipients can be used both as a lubricant and glidant.

The compositions may also include additional excipients such as flavoring agents, colors, and the like. Flavoring agents may be selected from common flavor enhancers for pharmaceutical compositions such as vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, tartaric acid and the like. Colors maybe selected from the group consisting of ferric oxide, titanium dioxide, F.D. & C. and D. & C. dyes and the like.

The pharmaceutical composition as described herein may be a capsule containing the composition, preferably a granulated composition as described above, within either a hard or soft shell. Tablets and granules may be coated. The coating may be an enteric coating or non-functional coating. Suitable coatings for enteric-coated composition includes cellulose acetate phthalate, hydroxypropyhnethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric- coating. Non-functional coating include coating compositions like Opadry® or Lustreclear® sold by Colorcon.

In some embodiments, a tablet of sertraline hydrochloride as described herein may be prepared by, for example, a) blending sertraline hydrochloride, diluent and disintegrant; b) granulating the blend obtained in step (a) with a binder solution; c) drying and sizing the granules; d) blending the granules obtained in step (c) with diluent, lubricant, glidant, and optionally a disintegrant; e) compressing the blend to form tablets; and f) optionally coating the tablets with a non-functional coating. In other embodiments, a tablet of sertraline hydrochloride as described herein may be prepared by, for example, a) blending sertraline hydrochloride, diluent and disintegrant; b) granulating the blend obtained in step (a) with a binder solution; c) drying and sizing the granules; d) blending the granules obtained in step (c) with a lubricant and glidant; e) compressing the blend to form tablets; and f) optionally coating the tablets with a non-functional coating.

In still another embodiment, a tablet of sertraline hydrochloride as described herein may be prepared by, for example, a) blending sertraline hydrochloride, diluent, binder and disintegrant; b) granulating the blend obtained in step (a) with water; c) drying and sizing the granules; d) blending the granules obtained in step (c) with diluent, lubricant, glidant, and optionally a disintegrant; e) compressing the blend to form tablets; and f) optionally coating the tablets with a non-functional coating.

In yet other embodiments, a tablet of sertraline hydrochloride as described herein may be prepared by, for example, a) blending sertraline hydrochloride, diluent, binder and disintegrant; b) compacting the blend obtained in step (a) with a roller compactor; c) sizing the compacts to form granules; d) blending the granules obtained in step (c) with diluent, disintegrant, lubricant and glidant; and e) compressing the blend to form tablets.

In other embodiments, a tablet of sertraline hydrochloride as described herein may be prepared by, for example, a) blending sertraline hydrochloride diluent, disintegrant, binder, lubricant and glidant; and b) compressing the blend to form tablets.

The invention described herein is further illustrated by the following examples but these do not limite the scope of the invention.

EXAMPLE l

**d₉o=24 μm; d₅₀=10 μm;

[Particle size distribution as determined by laser beam diffraction (Malvern mastersizer); dry dispersion]

PROCEDURE: Sertraline hydrochloride, microcrystalline cellulose, dicalcium phosphate and sodium starch glycolate were mixed in high shear mixer. The blend obtained above was granulated using aqueous solution of hydroxypropyl cellulose and the granules were dried and milled. Dried granules were blended with microcrystalline cellulose, sodium starch glycolate and magnesium stearate and compressed into tablets using appropriate tooling. EXAMPLES 2- 4

^##d₉₀=315 μm; d₅₀=110 μm; [Particle size distribution as determined by laser beam diffraction (Malvern mastersizer); liquid paraffin dispersion]

PROCEDURE: Sertraline hydrochloride, microcrystalline cellulose, dicalcium phosphate and sodium starch glycolate were mixed in high shear mixer. The blend obtained above was granulated using aqueous solution of hydroxypropyl cellulose and the granules were dried and milled. Dried granules were blended with microcrystalline cellulose, sodium starch glycolate (only in Example 2) and magnesium stearate and compressed into tablets using appropriate tooling. The tablets were coated using Opadry^® coating mixture (only for Example 3). Table 1: Tab letting Parameters for Examples 1- 4

As can be observed from Table 1, that tablets of Examples 1 having a narrow particle size suffered from significant sticking and picking problems which were overcome by using a coarse particle size of sertraline.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification, and as defined by the claims.

Claims

We claim:

1. A pharmaceutical composition comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein (Ϊ₉₀ ≤ 350 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant.

2. A pharmaceutical composition comprising sertraline or pharmaceutically acceptable salts thereof having a particle size wherein d₅₀ < 150 μm, a diluent, a binder, a disintegrant and a lubricant or a glidant.

3. The pharmaceutical composition of claim 1 wherein dg₀ < 250 μm.

4. The pharmaceutical composition of claim 1 wherein d₅₀ < 60 μm.

5. The pharmaceutical composition according to any of the preceding claims wherein the diluent is selected from a group consisting of powdered cellulose, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, sugar alcohols such as mannitol, sorbitol, erythritol; dextrates, dextrin, dextrose, inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, potassium chloride, sodium chloride or mixtures thereof.

6. The pharmaceutical composition according to claim 5, wherein the diluent is microcrystalline cellulose, dibasic calcium phosphate or mixtures thereof.

7. The pharmaceutical composition according to claim 6, wherein microcrystalline cellulose is present both intragranular and extragranular.

8. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from a group consisting of carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, magnesium aluminum silicate, powdered cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinized starch, alginic acid and sodium alginate.

9. The pharmaceutical composition according to claim 1, wherein the binder is selected from a group consisting of gum acacia, guar gum, alginic acid, sodium alginate; carbomer, dextrin, gelatin, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, polyvinylpyrrolidone and pregelatinized starch.

10. The pharmaceutical composition according to claim 1, wherein the glidant is selected from a group consisting of talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate.

11. The pharmaceutical composition according to claim 1, wherein the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glycerylpalmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

12. A pharmaceutical composition according to claim 1, wherein the composition comprises a) about 5 % to about 70 % by weight of sertraline hydrochloride; b) about 20 % to 80 % by weight of a diluent; c) about 1 % to 20 % by weight of a disintegrant; d) about 1 % to 10 % by weight of a binder; e) about 0.5 % to 3 % by weight of a lubricant.

13. The pharmaceutical composition according to claim 12, wherein the composition is a tablet.

14. A process for the preparation of tablet of claim 13, wherein the process comprises a) blending sertraline hydrochloride, diluent and disintegrant; b) granulating the blend with a binder solution; c) drying and sizing the granules; d) blending the dried granules with diluent, lubricant, glidants and optionally a disintegrant; and e) compressing the blend to form tablets; f) optionally coating the tablets.

15. A tablet comprising sertraline hydrochlroride having a particle size distribution as follows

d₅₀ < 150 μm; the tablet further comprising macrocrystalline cellulose, dicalcium phosphate, hydroxypropyl cellulose, sodium starch glycolate and magnesium stearate; wherein microcrystalline cellulose is present both intragranularly and extragranularly.

16. A process for the preparation of tablet of claim 15, wherein the process comprises a) blending sertraline hydrochloride, microcrystalline cellulose, dicalcium phosphate and sodium starch glycolate; b) granulating the blend with an aqueous solution of hydroxypropyl cellulose; c) drying and sizing the granules; d) blending the dried granules with microcrystalline cellulose, magnesium . stearate and optionally sodium starch glycolate; and e) compressing the blend to form tablets; f) optionally coating the tablets.

17. A pharmaceutical composition comprising sertraline or pharmaceutically acceptable salt thereof having a particle size wherein dc_>o ≤ 350 μm; and process for preparation thereof as substantially described and exemplified herein.