FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITIONS OF
PIOGLITAZONE AND PROCESS FOR
PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009, Gujarat,
India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:
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FIELD OF THE INVENTION
The present invention relates to rapidly dissolving pharmaceutical compositions of pioglitazone and process for preparing such compositions. More particularly, it relates to rapidly dissolving pharmaceutical compositions comprising pioglitazone and hydroxypropylcellulose comprising molecular weight ranging from 70,000 -200,000 dalton.
BACKGROUND OF THE INVENTION
Pioglitazone, chemically designated as [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2, 4-] thiazolidinedione, is a known oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pharmacological studies have shown that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone has also been known to improve glucose resistance while reducing circulating insulin levels, and is useful in the treatment of diabetes, particularly type II diabetes. Pioglitazone is currently marketed as its hydrochloride salt, under the brand-name ACTOS®, sold by Takeda Pharmaceuticals.
US 4,687,777 patent discloses pioglitazone and pharmacologically acceptable salts thereof, and methods for synthesis of pioglitazone and its salts. It is known that pioglitazone hydrochloride is practically insoluble in water (US Prescribing Information Leaflet of Actos®). There are instances where rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption by the body. Such a drug may be more readily bioavailable if administered in a rapidly dissolving composition.
US 2005/131027 patent application discloses pioglitazone having reduced particle size which may increase the solubility and dissolution.
WO 2000/78292 patent application discloses quickly disintegrating solid preparation comprising pioglitazone, a saccharide or sugar alcohol with a mean particle diameter
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of 30 (mm to 300 |im, a disintegrating agent and a cellulose compound. It also discloses quickly disintegrating solid preparation comprising pioglitazone, a saccharide or sugar alcohol with a mean particle diameter of 5 mm to below 90 mm, a saccharide or sugar alcohol with a mean particle diameter of 90 |im to 500 mm, a disintegrating agent and a cellulose compound.
US 6586004 patent discloses a solid preparation comprising pioglitazone, one or more sugar alcohols and low-substituted hydroxypropylcellulose having hydroxypropoxyl group contents of 7.0 to 9.9 percent by weight. The preparation is capable of buccal disintegration or dissolution.
US 7070805 patent discloses an oral rapidly disintegrable solid preparation which comprises pioglitazone hydrochloride, a sugar and a low-substituted hydroxypropylcellulose having 5% by weight or more to less than 7% by weight of hydroxypropoxyl groups. The preparation is buccally dissolved in from about 5 to about 50 seconds.
There remains a need for alternative compositions which provide rapid dissolution of pioglitazone. We have surprisingly found that rapidly dissolving pharmaceutical compositions of pioglitazone may be prepared by using excipients, such as hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton.
SUMMARY OF THE INVENTION
In one aspect, it discloses a rapidly dissolving pharmaceutical composition comprising:
(a) pioglitazone;
(b) hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton; and
(c) optionally one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, disintegrant, binder, glidant and lubricant,
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wherein the composition releases not less than 90% of pioglitazone in 10 minutes.
In another aspect, it discloses a rapidly dissolving pharmaceutical composition comprising:
(a) pioglitazone;
(b) microcrystalline cellulose;
(c) hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton; and
(d) optionally one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, disintegrant, binder, glidant and lubricant,
wherein the composition releases not less than 90% of pioglitazone in 10 minutes.
In yet another aspect, it discloses a process for preparation of a rapidly dissolving
pharmaceutical composition, wherein the process comprises:
(i) mixing pioglitazone with optionally one or more pharmaceutically acceptable
excipients;
(ii) granulating the blend of step (i) with a solution or dispersion of hydroxypropyl
cellulose comprising molecular weight in the range of 70,000 to 200,000 dalton;
(iii) optionally mixing the product of step (ii) with one or more pharmaceutically
acceptable excipients;
(iv) drying the product of step (ii) or (iii) to obtain granules;
(v) optionally lubricating the granules of step (iv); and
(vi) compressing the granules of step (iv) or (v) into tablets or filling the granules of
step (iv) or (v) into capsules to obtain the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
The term "rapidly dissolving pharmaceutical composition" as described herein is defined to include pharmaceutical compositions which releases not less than 90% of pioglitazone in 10 minutes.
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The term "pioglitazone" as described herein is defined to include pioglitazone free base or pharmaceutical^ acceptable salts, hydrates, solvates, polymorphs and enantiomers thereof, or mixtures thereof. The preferred salt of pioglitazone is pioglitazone hydrochloride. Pioglitazone may be present in amorphous form, crystalline form or mixtures thereof. Pioglitazone typically comprises from about 1 % to about 50 % by weight of the composition. Pioglitazone as described herein may be of varying particle size. The art discloses methods for increasing the solubility of pioglitazone by decreasing the particle size. However, we have found that the pharmaceutical compositions as described herein show rapid dissolution of pioglitazone without any effect of particle size. More particularly, the particle size of pioglitazone as described herein may be such that d50 varies from 1 \irr\ to 20 \xm and d90 varies from 5 \im to 50 |im.
The pharmaceutical compositions as described herein comprise hydroxypropylcellulose having a molecular weight ranging from 70,000 - 200,000 dalton. Such hydroxypropylcellulose is commercially available, for example, under the brand name Klucel®, sold by Aqualon (such as Klucel-LF, Klucel-EF, Klucel-EXF, and the like). Such hydroxypropylcellulose is used as a binder in the field of pharmaceutical manufacturing. However, we have surprisingly found that hydroxypropylcellulose increases the dissolution of pioglitazone in the composition. The amount of hydroxypropylcellulose may vary from 0.1 % to 10 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, glidant or lubricant.
Diluent as described herein may be selected from cellulose derivatives such as powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate; saccharides such as lactose, sucrose or dextrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. When a saccharide or sugar alcohol is
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used as a diluent, it is preferred that the mean particle diameter of the saccharide or sugar alcohol is less than 30 urn. Preferably, the diluent may be selected from lactose, microcrystalline cellulose, or mixtures thereof. The diluent may be present in an amount ranging from 1 % to 90 % by weight of the composition.
Disintegrant as described herein may be selected from calcium carboxymethyl
cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked
polyvinylpyrrolidone, carboxymethyl cellulose sodium, sodium starch glycolate, pregelatinized starch; low substituted hydroxypropyl cellulose; and mixtures thereof. Some of these disintegrants, such as cross-linked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, and the like, are known to the skilled person as super-disintegrants, which achieve rapid disintegration even when employed in small quantities. The disintegrant may be present in an amount ranging from 1 % to 20 % by weight of the composition.
The hydroxypropylcellulose is a preferred binder in the pharmaceutical compositions as described herein. The compositions may comprise another binder, if required, which may be selected from hydrophilic polymers such as hydroxypropyl methylcellulose and polyvinylpyrrolidone; hydroxyethyl cellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, pregelatinized starch, sodium alginate, gums, synthetic resins, and the like. The additional binder may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
Lubricant or glidant as described herein may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, magnesium trisilicate, kaolin; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
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In order to enhance the dissolution of pioglitazone compositions, various approaches had been tried, but none of these showed rapid dissolution of pioglitazone. Such approaches included the use of surfactant such as sodium lauryl sulfate (Comparative Example 1); use of super-disintegrants such as crospovidone (Comparative Example 2), low-substituted hydroxypropylcellulose (Comparative Example 3); use of hydrophilic polymers such as povidone (Comparative Example 4), and hydroxypropyl methylcellulose (Comparative Example 5).
The pharmaceutical compositions as described herein may be prepared by wet granulation. For example, pioglitazone may be mixed with hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton and one or more diluent and/or a disintegrant and the mixture may be granulated with water. Alternatively, a solution or dispersion of hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton may be prepared in a solvent, such as water, and a mixture of pioglitazone with one or more diluent and/or a disintegrant may be granulated with the solution or dispersion to obtain granules. It was observed that better results may be achieved when pioglitazone was mixed with a partial quantity of the diluent before granulation with a further quantity of the diluent being added in the wet mass before the completion of granulation. The granulation process may be followed using conventional equipments such as a rapid mixer granulator or a fluidized bed granulator. In a preferred embodiment, a mixture of pioglitazone and one or more excipients was granulated in a fluidized bed granulator by spraying an aqueous solution or dispersion of hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton using the top-spray granulation technique. The granules may be compressed into tablets or may be filled in capsules or sachets.
The term "intimately mixed" as described herein is intended to include methods which provides pioglitazone in contact with hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton. It includes, for example, mixing pioglitazone with one or more pharmaceutically acceptable excipients and
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granulating the mixture with a solution or dispersion of hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton. It also includes, alternatively, mixing pioglitazone with hydroxypropylcellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton and granulating the mixture with a solvent.
In one embodiment, a rapidly dissolving tablet of pioglitazone may be prepared by
mixing pioglitazone with a diluent selected from a saccharide or sugar alcohol and a
disintegrant,
granulating the mixture with an aqueous solution or dispersion of
hydroxypropylcellulose comprising a molecular weight ranging from 70,000 -
200,000 dalton,
mixing the product with the diluent and granulating the mixture,
drying and sizing the granules,
mixing the granules with the disintegrant and lubricating the mixture by addition of a
lubricant, and
compressing the mixture into a tablet.
In a preferred embodiment, the diluent is a saccharide or sugar alcohol having mean particle diameter less than 30 ^im.
In other embodiment, a rapidly dissolving tablet of pioglitazone may be prepared by
mixing pioglitazone with microcrystalline cellulose and a disintegrant,
granulating the mixture with an aqueous solution or dispersion of hydroxypropyl
cellulose comprising a molecular weight ranging from 70,000 - 200,000 dalton,
drying and sizing the granules,
mixing the granules with the disintegrant and lubricating the mixture by addition of a
lubricant, and
compressing the mixture into a tablet
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In another embodiment, a rapidly dissolving capsule of pioglitazone may be prepared by filling the granules as obtained in any of the above embodiments into a capsule.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
COMPARATIVE EXAMPLE 1

Ingredients Qty. (mg)
Pioglitazone hydrochloride 49.61
Lactose 113.86
Calcium carboxymethylcellulose 9.000
Sodium lauryl sulphate 1.98
Low-substituted hydroxypropylcellulose 3.60
Magnesium stearate 1.95
Purified water q.s
Total 180.1
PROCEDURE: Pioglitazone hydrochloride, calcium carboxymethylcellulose and a part of lactose were mixed and granulated with an aqueous solution of sodium lauryl sulphate. The granules obtained were dried, sized, and mixed with low-substituted hydroxypropylcellulose and remaining part of lactose. The mixture was lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
COMPARATIVE EXAMPLE 2

Ingredients Qty. (mg)
Pioglitazone hydrochloride 49.608
Lactose 109.529
Crospovidone 7.0
Maize starch 10.0
Talc 1.0
Colloidal silicon dioxide 1.0
Magnesium stearate 1.8
Purified water q.s
Total 180.0
PROCEDURE: Pioglitazone hydrochloride, a part of lactose, crospovidone and maize starch were mixed and the mixture was granulated with an aqueous solution
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of maize starch. The granules obtained were dried, sized, and mixed with remaining part of lactose, crospovidone, talc and colloidal silicon dioxide. The mixture was lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
COMPARATIVE EXAMPLE 3

Ingredients Qty. (mg)
Pioglitazone hydrochloride 49.61
Lactose 115.84
Calcium carboxymethylcellulose 9.00
Low-substituted hydroxypropylcellulose 3.60
Magnesium stearate 1.95
Purified water q.s
Total 180.0
PROCEDURE: Pioglitazone hydrochloride, calcium carboxymethylcellulose and a part of lactose were mixed and the mixture was granulated with purified water. The granules obtained were dried, sized, and mixed with low-substituted hydroxypropylcellulose and remaining part of lactose. The mixture was lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
COMPARATIVE EXAMPLES 4 AND 5

Ingredients Quantity (mg)ity (mg)
Comparative Example 4 Comparative Example 5
Pioglitazone hydrochloride 49.6 49.6
Lactose 108.4 108.4
Calcium carboxymethylcellulose 16.6 16.6
Hydroxypropyl methylcellulose 3.6 -
Polyvinylpyrrolidone - 3.6
Magnesium stearate 1.8 1.8
Purified water q.s. q.s.
Total 180.0 180.0
PROCEDURE: Pioglitazone hydrochloride, a part of lactose and calcium carboxymethylcellulose were mixed and granulated with an aqueous solution of
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hydroxypropyl methylcellulose (in case of comparative example 4) or polyvinylpyrrolidone (in case of comparative example 5). The granules obtained were dried, sized, and mixed with remaining part of lactose and calcium carboxymethylcellulose. The mixture was lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
TABLE 1: Dissolution Profile of Examples 1, 2 and 3 in 900 ml of 0.3 M KCI using USP Type II Apparatus, paddle speed 75 rpm at 37 ± 0.5 °C

Time(in min.) Amount of pioglitazone released (in %)
Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5
5 63.0 45.8 43.8 42.6 49.4
10 83.8 - 55.2 60.2 63.2
15 92.3 57.0 62.2 67.9 70.9
30 98.1 - 73.0 74.3 81.7
EXAMPLES 1 AND 2

Ingredients Qty (mg)
Example 1 Example 2
Pioglitazone hydrochloride #49.6 ** 49.6
Lactose 108.4 108.4
Calcium carboxymethylcellulose 16.6 16.6
Hydroxypropyl cellulose(Mol. Wt. =70, 000- 200,000 dalton) 3.6 3.6
Magnesium stearate 1.8 1.8
Purified water q.s. q.s.
Total 180.0 180.0
# d90= 7 mrn as measured by Malvern mastersizer
** d90 = 38 mm as measured by Malvern mastersizer
PROCEDURE: Pioglitazone hydrochloride, calcium carboxymethylcellulose and a part of lactose were mixed and granulated with an aqueous solution of hydroxypropylcellulose. The remaining part of lactose was mixed and the mixture was further granulated with the aqueous solution of hydroxypropylcellulose. The
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granules obtained were dried, sized, mixed with remaining part of calcium carboxymethylcellulose, lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
EXAMPLE 3

Ingredients Qty (mg)
Pioglitazone hydrochloride 49.6
Microcrystalline cellulose 108.4
Calcium carboxymethylcellulose 16.6
Hydroxypropyl cellulose(Mol. Wt. =70, 000- 200,000 dalton) 3.6
Magnesium stearate 1.8
Purified water qs.
Total 180.0
PROCEDURE: Pioglitazone hydrochloride, microcrystalline cellulose and calcium carboxymethylcellulose were mixed and granulated with an aqueous solution of hydroxypropylcellulose. The granules obtained were dried, sized, mixed with remaining part of calcium carboxymethylcellulose, lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
TABLE 2: Dissolution Profile of Examples 1, 2 and 3 in 900 ml of 0.3 M KCI using USP Type II Apparatus, paddle speed 75 rpm at 37 ± 0.5 °C

Time(in min.) Amount of pioglitazone released (in %)
Example 1 Example 2 Example 3
5 86.4 82.1 84.7
10 97.4 91.6 93.9
15 101.0 94.5 98.4
30 103.3 96.9 103.9
As is evident from Table 1 and Table 2, tablets comprising hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton showed rapid dissolution of pioglitazone.
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WE CLAIM :
1. A rapidly dissolving pharmaceutical composition comprising:
(a) pioglitazone;
(b) hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton; and
(c) optionally one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, disintegrant, binder, glidant and lubricant,
wherein the composition releases not less than 90% of pioglitazone in 10 minutes.
2. T he composition according to claim 1, wherein the hydroxypropylcellulose is present in an amount ranging from 0.1 % to 10 % by weight of the composition.
3. The composition according to claim 1, wherein the diluent is saccharide or sugar alcohol comprising mean particle diameter of less than 30 |xm.
4. The composition according to claim 1, wherein the hydroxypropylcellulose is intimately mixed with the pioglitazone.
5. A rapidly dissolving pharmaceutical composition comprising:

(a) pioglitazone;
(b) microcrystalline cellulose;
(c) hydroxypropylcellulose comprising molecular weight in the range of 70,000 to 200,000 dalton; and
(d) optionally one or more pharmaceutically acceptable excipients selected from the group consisting of diluent, disintegrant, binder, glidant and lubricant,
wherein the composition releases not less than 90% of pioglitazone in 10 minutes.
6. The composition according to claim 5, wherein the hydroxypropylcellulose is
present in an amount ranging from 0.1 % to 10 % by weight of the composition.
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7. The composition according to claim 5, wherein the hydroxypropylcellulose is
intimately mixed with the pioglitazone.
8. The composition according to claim 1 or 5, wherein the composition is a tablet or a capsule.
9. A process for preparation of a rapidly dissolving pharmaceutical composition, wherein the process comprises:
(i) mixing pioglitazone with optionally one or more pharmaceutically acceptable
excipients;
(ii) granulating the blend of step (i) with a solution or dispersion of hydroxypropyl
cellulose comprising molecular weight in the range of 70,000 to 200,000 dalton;
(iii) optionally mixing the product of step (ii) with one or more pharmaceutically
acceptable excipients;
(iv) drying the product of step (ii) or (iii) to obtain granules;
(v) optionally lubricating the granules of step (iv); and
(vi) compressing the granules of step (iv) or (v) into tablets or filling the granules of
step (iv) or (v) into capsules to obtain the pharmaceutical composition.
10. A rapidly dissolving pharmaceutical composition of pioglitazone as substantially
described and exemplified herein.
Dated This 9th Day of July, 2007


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For Torrent Pharmaceuticals Ltd, Sunil Sadanand Nadkarni

ABSTRACT
The present invention relates to rapidly dissolving pharmaceutical compositions of pioglitazone and process for preparing such compositions. More particularly, it relates to rapidly dissolving pharmaceutical compositions comprising pioglitazone and hydroxypropylcellulose comprising a molecular weight ranging from 70,000 -200,000 dalton.