COMPETE AFTER PROVISIONAL LEFT ON 24 MAR 2006

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
STABLE ORAL PHARMACEUTICAL COMPOSITION
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed

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The present invention relates to stable oral pharmaceutical composition comprising therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt and one or more adjuvant(s) that prevent formation of pink hue upon storage of the composition.
BACKGROUND OF THE INVENTION
Paroxetine is a selective serotonin reuptake inhibitor indicated in the treatment of depression, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder. Paroxetine exerts its action by potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal uptake of serotonin. It is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine is commercially available as Paxil® conventional immediate release tablets, and as Paxil® CR controlled release tablets.
United States Patent No. 6,113,944 discloses a pharmaceutical composition in tablet form containing therapeutically effective amounts of paroxetine produced by a process which comprises steps of: a) dry admixing paroxetine and excipients in a mixer to form a mixture; or b) dry admixing paroxetine and excipients, compressing the resulting combination into a slug material or roller compacting the resulting combination into a strand material, and milling the prepared material into a free flowing mixture; and c) compressing the mixture into tablets using a single punch or rotary tablet machine. The patent teaches that paroxetine formulated into a tablet using a process in which water is absent, is much less likely to develop a pink hue upon storage.
United States Patent Number 6,645,523 ('523 patent) discloses that coloration problem, i.e. the pink hue, in paroxetine tablets, involves the formation of a coloring impurity identified as compound A which is a dimer formed from paroxetine free base in an aqueous alkaline environment. The '523 patent claims a solid unit dose paroxetine composition comprising a pharmaceutically effective amount of paroxetine hydrochloride, an acidic calcium phosphate, and a disintegrant, wherein said composition has a pH within the range of 4.5 to 6.0. Thus, the invention discloses a solid paroxetine composition that resists the formation of a colour hue and to processes for making the same with the aid of water, by controlling the pH of the composition to 6.5 or less. Acidic calcium phosphate, as described in the specification of the '523 patent, is a special grade obtained by removing impurities or washing. Commercially available grades of dicalcium phosphate, such as Di-Cafos AN, Anhydrous Emcompress, have a pH greater than 7, and the "Handbook of Pharmaceutical Excipients, 3rd edition, Ed by Arthur H. Kibbe, American Pharmaceutical Association, Washington DC, 2000" states that these grades should not be used with drugs which are sensitive to alkaline pH. In contrast to the teachings of the '523 patent and the Handbook of Excipients, we have surprisingly found that
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commercially available grades of dicalcium phosphate having an alkaline pH, can be used to obtain stable compositions of paroxetine.
WO2005034954 ('954 application) discloses a pharmaceutical composition comprising paroxetine, microcrystalline cellulose and one or more additional pharmaceutical inert excipients, wherein the pharmaceutical composition is prepared by wet granulation technique. In contrast to the teachings of the '954 application, we have surprisingly found that microcrystalline cellulose, in fact, does cause formation of a pink hue when wet granulated with paroxetine.
WO2004091582 describes a moisture barrier coating enveloping the individual granules of the active core, which substantially eliminates the possibility of degradation or colour development. Such a process may be tedious, time consuming and expensive.
OBJECT OF THE INVENTION
It is the object of the present invention to provide a stable oral pharmaceutical composition comprising a therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt and one or more adjuvants that prevent the formation of pink hue upon storage of the composition, wherein the composition is prepared by aqueous granulation.
SUMMARY OF THE INVENTION
The present invention provides a stable oral pharmaceutical composition comprising a therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt and one or more adjuvants that prevent the formation of pink hue upon storage of the composition, wherein the composition is prepared by aqueous granulation.
DETAILED DESCRIPTION OF THE INVENTION
It has been surprisingly found that a stable oral pharmaceutical composition comprising therapeutically effective amounts of paroxetine or its pharmaceutically acceptable salt can be obtained by incorporating one or more adjuvant(s) that prevent the formation of pink hue upon storage of the composition, while using conventional aqueous granulation process.
The stable oral pharmaceutical composition of the present invention comprises therapeutically effective amounts of paroxetine or its pharmaceutically acceptable salt. Preferably, the paroxetine is in the hydrochloride form. The paroxetine or its pharmaceutically acceptable salt that may be used in the composition of the present invention may be either in amorphous form or crystalline form, preferably in the crystalline form, most preferably in the crystalline hemihydrate form. The amount of paroxetine or its pharmaceutically acceptable salt that may be used in the composition of the present invention
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may range from about 1 mg to about 50 mg per unit dosage form, preferably from about 5 mg to about 40 mg, most preferably from about 10 mg to about 40 mg per unit dosage form.
The oral pharmaceutical composition of the present invention includes, but is not limited to, solid dosage forms such as tablets, capsules, sachets, granules and pellets.
The term "stable" as used herein refers to the colour stability of the pharmaceutical composition of paroxetine, wherein the composition when stored does not show any discoloration or formation of pink color/hue. For the purpose of determination of stability, a suitable method may e used. For example, the composition may be stored in high-density polyethylene (HDPA) bottles with child resistant caps at 40°C and 75% relative humidity for 3 months and observed for development of color. These conditions are believed in the art to be equivalent to storage on the shelf at ambient conditions for a period of two years. The stability may also be determined at other conditions, for example, storage at 60°C for one month.
The pharmaceutical composition of the present invention includes one or more diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet disintegration agents, encapsulating materials and the like as adjuvants. Various pharmaceutical compositions were prepared by mixing pharmaceutically acceptable excipients (adjuvants) with paroxetine hydrochloride hemihydrate in a drug to excipient ratio ranging from about 1: 0.1 to about 1:1, followed by aqueous granulation. The said compositions were stored at 40°C at 75% relative humidity for one month, and at 60°C for a period of one month. The compositions were visually observed for any discoloration or colour formation at the end of 1 month.
The adjuvants (the term excipient and adjuvant have been used interchangeably herein) used in the pharmaceutical composition of the present invention that prevent the formation of the pink hue upon storage of the composition, wherein the composition is prepared by aqueous granulation, are selected from the group consisting of lactose anhydrous, lactose monohydrate, pregelatinized starch, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80, silicified microcrystalline cellulose, dicalcium phosphate dihydrate having pH greater than 7.0, dicalcium phosphate anhydrous having pH greater than 7.0, and mixtures thereof.
The amount of compatible adjuvant that may be used may range from about 0.5% by weight to about 90% by weight of the composition, depending upon the function of the adjuvant.
Lactose monohydrate that may be used in the pharmaceutical compositions of the present invention is commercially available as Fast-flo, Lactochem, Microtose, Tablettose, having 4.5-5.5% water content
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and true density of about 1.552. The lactose monohydrate may be used as diluent in an amount ranging from about 5% to about 50% by weight of the composition.
Lactose anhydrous that may be used as a compatible excipient in the pharmaceutical compositions of the present invention, contains less than 1% of water, and has true density of about 1.552. Preferably, the lactose anhydrous has a bulk density of about 0.67g/cm3, a tapped density of about 0.85g/cm3 and a specific surface area of about 0.35m2/g. The preferred grade of lactose anhydrous is commercially available as Pharmatose DCL 21, having a particle size distribution such that 85% of the particles are less than 250 microns, and 50% of the particles are less than 150 microns. Lactose anhydrous may be used in the pharmaceutical compositions of the present invention in an amount ranging from about 50% to about 90% by weight of the composition.
Dicalcium phosphate anhydrous and dicalcium phosphate dihydrate that may be used as compatible excipients in the pharmaceutical compositions of the present invention have a pH greater than 7.0. They may be used typically as diluents in an amount ranging from about 5% to about 50% by weight of the composition. Preferably, a 20% slurry of the dicalcium phosphate has a pH of about 7.3 to about 7.5. Preferred commercially available dicalcium phosphate anhydrous is Anhydrous Emcompress having an average particle diameter of about 136 microns, and preferred commercially available dicalcium phosphate dihydrate has an average particle diameter of about 180 microns.
Sodium starch glycolate is another compatible excipient that may be used in the pharmaceutical compositions of the present invention as a disintegrant, in an amount ranging from about 0.5% to about 10% by weight of the composition. The preferred grade of sodium starch glycolate has a particle diameter of about 30-100 microns, and a pH of 5.5-7.5 for a 3.3% aqueous dispersion. Commercially available Explotab having an average particle size of 42 microns is the most preferred.
Pregelatinized starch is another compatible excipient that may be used as a diluent, disintegrant or binder in the pharmaceutical compositions of the present invention, in an amount ranging from about 0.5% to about 50% by weight of the composition. Preferably, the pregelatinized starch used has a pH in the range of 4.5 to 7.0 (10% w/v slurry) with particles of size 30-150 microns. Commercially available Starch 1500, having a specific surface area of about 0.26m2/g is the most preferred grade.
Silicified microcrystalline cellulose is yet another compatible excipient that may be used as a diluent or filler in the pharmaceutical compositions of the present invention and is especially suitable for compaction of tablets obtained by the process of wet granulation, such as the compositions of the present invention. It may be used in an amount ranging from about 5% to about 50% by weight of the composition. Silicified microcrystalline cellulose that may be used in the compositions of the present invention includes grades that have 2%w/w of colloidal silicon dioxide, and pH in the range of 5.0-
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7.5. Preferably, the silicified microcrystalline cellulose has a mean particle size of 90 microns, such as that commercially available under the trade name Prosolv SMCC 90. Surprisingly, although microcrystalline cellulose was found to be incompatible with paroxetine or its salts upon wet granulation, silicified microcrystalline cellulose was found to be compatible.
The pharmaceutical composition of the present invention is obtained by the conventional process of wet granulation, wherein water or a mixture of water with an organic solvent may be used for the process of granulating a mixture comprising paroxetine or its therapeutically acceptable salt and one or more adjuvants that prevent formation of pink hue upon storage of the composition.
The present invention may be summarized as follows -
a. A stable oral pharmaceutical composition comprising a therapeutically effective amount of
paroxetine or its pharmaceutically acceptable salt and one or more adjuvants that prevent the
formation of pink hue upon storage of the composition, wherein the composition is prepared by
aqueous granulation.
b. A stable oral pharmaceutical composition as described in (a) above, wherein the pharmaceutically
acceptable salt of paroxetine is paroxetine hydrochloride hemihydrate.
c. A stable oral pharmaceutical composition as described in (a) above, wherein one or more
adjuvants that prevent the formation of pink hue upon storage, are selected from the group
comprising lactose anhydrous, lactose monohydrate, pregelatinized starch, sodium starch
glycolate, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene
Glycol 6000 and polysorbate 80, silicified microcrystalline cellulose, dicalcium phosphate
dihydrate, dicalcium phosphate anhydrous.
d. A stable oral pharmaceutical composition as described in (a) above,'wherein the composition may
be in the form of capsule, tablet, pellets or granules.
e. A stable oral pharmaceutical composition as described in (a) above, wherein the composition is
stable when stored at 40°C at 75% relative humidity for 3 months in sealed high-density
polyethylene bottles with child resistant caps.
The examples that follow do not limit the scope of the invention and are merely used as illustrations.
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EXAMPLE 1
Various pharmaceutical compositions were prepared by mixing pharmaceutically acceptable excipients (adjuvants) with paroxetine hydrochloride hemihydrate in a drug to excipient ratio ranging from about 1:0.1 to about 1:1, followed by aqueous granulation. The said compositions were stored at 40°C at 75% relative humidity for one month, and at 60°C for a period of one month. The compositions were visually observed for any discoloration or color formation at the end of 1 month. The results are recorded in Table 1 below.
Table 1

Excipients Drug toexcipientsratio Visual colour Observation Results at various storage conditions
Initial 40°C at75% RHfor 1month 60°C for 1 month
Lactose monohydrate 1:1 white No change No change
Lactose anhydrous 1:1 white No change No change
Microcrystalline Cellulose (comparative example) 1:1 ... white Slightly Pink Slightly Pink
Silicified Microcrystalline Cellulose 1:1 white No change No change
Dicalcium phosphate dihydrate 1:1 white No change No change
Dicalcium phosphate anhydrous 1:1 white No change No change
Hydroxypropyl Cellulose 1:0.5 white No change No change
Polyvinyl pyrrolidone (PVP K-30) 1:0.5 white No change No change
Pregelatinized Starch 1:0.5 white No change No change
Magnesium stearate 1:0.1 white No change No change
Sodium starch glycolate 1:0.5 white No change No change
Opadry (mixture of Hydroxypropyl cellulose. Titanium dioxide, polyethylene glycol 6000, talc, iron oxide yellow) 1:0.2 Yellow No change No change
A pharmaceutical composition comprising compatible excipients of Example 1 was obtained as mentioned in Table 2 below.
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Stage of process Ingredients mg/tablet % w/w
Intragranular Paroxetine hydrochloride hemihydrate 45.5 6.90
Lactose, anhydrous 426.5 64.7
Pregelatinized Starch 64.0 9.7
Lactose, monohydrate 64.0 9.7
Extragranular
Lactose anhydrous 17.0 2.6
Sodium starch glycolate 13.0 1.97
Magnesium stearate 10.0 1.5
Coating Opadry Green 13F51312 19.2 2.9
Paroxetine hydrochloride hemihydrate, lactose monohydrate, pregelatinized starch and lactose anhydrous were sifted through ASTM (American Society for Testing and Materials) 40# mesh. The sifted ingredients were mixed and granulated with water. The granules were dried and milled. The extragranular ingredients namely, lactose anhydrous, sodium starch glycolate and magnesium stearate were sifted and blended with the granules. The lubricated granules were compressed and further film coated with Opadry Green 13F51312.
The film coated tablets were stored at 40°C at 75% RH in sealed HDPE bottles with child resistant caps. The tablets were broken and the core was observed for the formation of pink hue. Core was found to be white in appearance and no pink hue was observed in the core at the end of three months.
While the invention has been described by reference to specific embodiments, this was done for purposes of illustration only and should not be construed to limit the spirit or the scope of the invention.
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We Claim-
1. A stable oral pharmaceutical composition comprising -
(i) a therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt, and
(ii) one or more pharmaceutically acceptable adjuvants selected from the group consisting of lactose anhydrous, lactose monohydrate, pregelatinized starch, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80, silicified microcrystalline cellulose, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, wherein the composition is prepared by aqueous granulation.
2. A stable oral pharmaceutical composition comprising -
(i) a therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt,
and (ii) pharmaceutically acceptable adjuvants comprising lactose, pregelatinized starch, sodium
starch glycolate and magnesium stearate, wherein the composition is prepared by aqueous granulation.
3. A stable oral pharmaceutical composition as claimed in claim 1 wherein the pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride hemihydrate.
4. A stable oral pharmaceutical composition as claimed in claim 1 wherein the composition may be in the form of capsule, tablet, pellets or granules.
Dated this 24th day of March, 2006
DILIP SHANGHVI
CHAIRMAN AND MANAGING DIRECTOR,
SUN PHARMACEUTICAL INDUSTRIES LIMITED.
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ABSTRACT
A stable oral pharmaceutical composition comprising a therapeutically effective amount of paroxetine or its pharmaceutically acceptable salt and one or more adjuvants that prevent the formation of pink hue upon storage of the composition, wherein the composition is prepared by aqueous granulation.
To,
The Controller of Patents The Patent Office, Mumbai - 400 037
24 MAR 2006
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