CLIAMS:We Claim:

1. A solid oral pharmaceutical composition comprising aripiprazole or salts thereof, wherein the composition is devoid of binder.

2. The solid oral pharmaceutical composition of claim 1, wherein the composition exhibits no substantial change in the aripiprazole polymorphic form during storage at 30°C and 60% relative humidity for at least 3 months

3. The solid oral pharmaceutical composition of claim 1, wherein the composition retains at least 90% by weight of the total potency of aripiprazole after storage at 30°C and 60% relative humidity for at least 3 months.

4. The stable pharmaceutical composition of claim 1, wherein more than 90% by weight of initial amount of aripiprazole in the composition releases more than 85% by weight of initial aripiprazole when measured in 900 ml of hydrochloric acid having pH 1.2 using USP type II dissolution apparatus.

5. The stable pharmaceutical composition of claim 1, wherein composition exhibits no significant difference in one or both of the rate and extent of absorption of aripiprazole or salts thereof as compared to formulation of aripiprazole marketed under the trade name Abilify®.

6. The stable pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet or capsule.

7. Method of use of compositions of claim 1, for the treatment of psychotic disorders in particular schizophrenia wherein the composition is bioequivalent to the commercially available aripiprazole tablet formulation (Abilify®) 10 and 30 mg.

8. A process of preparing the solid oral pharmaceutical composition of claim 1, which process comprises steps of:
a) mixing aripiprazole or salts thereof with one or more pharmaceutical excipients to form a dry blend;
b) preparing the wet mass by mixing the dry blend with granulating composition;
c) drying the wet mass to form granules;
d) mixing one or more pharmaceutical excipients (extragranular material) with the dried granules followed by lubrication; and
e) compressing the granules to form tablets.

Dated this 12TH day of February 2013 For Wockhardt Limited
(Dr. Mandar Kodgule)
Authorized Signatory
,TagSPECI:Description

The present invention relates to solid oral pharmaceutical compositions of aripiprazole or salts thereof. In particular, the present invention relates to the compositions of aripiprazole or salts thereof comprising one or more diluent and one or more disintegrant wherein the composition is free of binder. The invention also relates to a process of preparing such compositions and method of use of such compositions for treating schizophrenia.

Aripiprazole is a psychotropic drug of which the mechanism of action is unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at Dopamine 2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Aripiprazole is marketed in United States and in the form of tablets under the brand name Abilify® and are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths.

Chemically aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]-3,4-dihydrocarbostyril with the following structure:

Abilify® tablet contains cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and iron oxide as inactive ingredients. It is well known that the hydroxypropyl cellulose is used in the tablet as a binder.

Also, various attempts have been made so far to develop aripiprazole compositions. In one such example, European patent number EP 1,808,165 A1 discloses a pharmaceutical composition of aripiprazole by dry granulation. The patent further exemplifies tablet compositions of Aripiprazole containing binder.

European patent number EP 1,808,164 B1 discloses a pharmaceutical composition of aripiprazole by wet granulation. All the examples disclosed in the patent contain binder.

It is well known in the art that aripiprazole, as reported in the literature, can exist in multiple crystal forms. PCT publication number WO2003/026659 discloses at least nine crystal forms, including a hydrate and anhydrous form and reports that multiple polymorphs may convert from one to the other form. This has particular relevance in the formulation of such active pharmaceutical ingredients, because polymorphic transformations may occur during manufacturing and/or storage and such transformations are often unwanted. The manipulation of polymorphs (e.g. by hydration) may induce such undesirable polymorphic transformations. Some polymorphic forms of aripiprazole may potentially induce unwanted polymorphic transformations, which in turn may reduce the bioavailability of the drug. Therefore, it is necessary to develop a composition and a process which may resist such polymorphic transformation during manufacture and storage.

The present invention provides an improved and stable alternative aripiprazole composition, which may exhibit excellent release profile or prevent inter-conversion of drug polymorphs during manufacture or during storage. In particular, the aripiprazole solid oral pharmaceutical composition of the invention does not contain binder.

The inventors of the present invention have empirically found that when aripiprazole formulations contain binder (e.g. hydroxy propyl cellulose or starch), the dissolution rate of such formulations was slow as compared to marketed product of aripiprazole (Abilify®). In other words when binder was used in the formulation, aripiprazole release of more than 85% was not achieved within 30 minutes when measured in 900 ml of hydrochloric acid having pH 1.2 using USP type II dissolution apparatus.

Surprisingly, the inventors of the present invention have found that if aripiprazole composition is prepared without using any binder, such composition may exhibit improved dissolution properties. Moreover, such composition may exhibit in vitro drug release profile that is equivalent to marketed aripiprazole formulation (Abilify®).

In one general aspect, the present invention provides a solid oral pharmaceutical composition of aripiprazole or salts thereof, wherein the composition is devoid of binder.

In another general aspect, the solid oral composition is in the form of mini-tablets, granules, pellets, powder, capsules, tablets, or capsules filled with mini-tablets, granules, pellets, or combination thereof.

In another general aspect, the present invention provides a process of preparing solid oral pharmaceutical composition of aripiprazole or salts thereof, wherein the composition is devoid of binder and the composition exhibits no substantial change in the aripiprazole polymorphic form during preparation.

In another general aspect, the present invention provides a stable solid oral pharmaceutical composition of aripiprazole or salts thereof, wherein the composition is devoid of binder and the composition exhibits no substantial change in the aripiprazole polymorphic form during storage at 30°C and 60% relative humidity for at least 3 months.

In another general aspect, the present invention provides a solid oral pharmaceutical composition of aripiprazole or salts thereof, wherein the composition is devoid of binder and retains at least 90% w/w of total potency of aripiprazole after storage at 40°C and 75% relative humidity for at least 3 months.

In another general aspect, the present invention provides a solid oral pharmaceutical composition of aripiprazole or salts thereof, wherein the composition is devoid of binder and releases more than 85% by weight of initial aripiprazole when measured in 900 ml of hydrochloric acid having pH 1.2 using USP type II dissolution apparatus.

In another general aspect, the present invention provides a solid oral pharmaceutical composition of aripiprazole or salts thereof wherein the composition is devoid of binder and composition exhibits no significant difference in one or both of the rate and extent of absorption of aripiprazole or salts thereof as compared to formulation of aripiprazole marketed under the trade name Abilify®.

In another general aspect, the present invention provides a process of preparing solid oral pharmaceutical composition of aripiprazole or salts devoid of binders, which process comprises of dry granulation, wet granulation and direct compression.

In another general aspect, the present invention provides of preparing a solid oral pharmaceutical composition of aripiprazole or salts thereof wherein the composition is devoid of binder, which process comprises steps of:
a) mixing aripiprazole or salts thereof with one or more pharmaceutical excipients to form a dry blend;
b) preparing the wet mass by mixing the dry blend with granulating composition;
c) drying the wet mass to form granules;
d) mixing one or more pharmaceutical excipients (extragranular material) with the dried granules followed by lubrication; and
e) compressing the granules to form tablets.

In another general aspect, the present invention provides a method of treating psychotic disorders (e.g. schizophrenia) in a patient which method comprises administering the solid oral pharmaceutical composition of aripiprazole or salts thereof as substantially described herein.

The term “aripiprazole” as used throughout the specification refers to not only aripiprazole per se, but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers and polymorphs.

The composition of the present invention is in the form of a solid oral pharmaceutical composition of aripiprazole or salts thereof and the composition is devoid of binder.

The solid oral composition may be provided in the form of mini-tablets, granules, pellets, powder, capsules, tablets, or capsules filled with mini-tablets, granules, pellets, powder or combination thereof.

The solid oral composition of the present invention may resist change in the polymorphic form of aripiprazole during manufacturing and/or storage. Preferably, the composition exhibits no substantial change in the aripiprazole polymorphic form during storage at 30°C and 60% relative humidity for at least 3 months.

In an embodiment, the composition retains at least 90% w/w of total potency of aripiprazole after storage at 40°C and 75% relative humidity for at least 3 months.

Further, the solid oral composition of the present invention may exhibit excellent release profile.

In an embodiment, the composition releases more than 85% and preferably more than 90% by weight of initial aripiprazole when measured in 900 ml of hydrochloric acid having pH 1.2 using USP type II dissolution apparatus.

In another embodiment, the composition exhibits no significant difference in one or both of the rate and extent of absorption of aripiprazole or salts thereof as compared to formulation of aripiprazole marketed under the trade name Abilify®.

The solid oral composition of the present invention may be prepared by various processes known to the person skilled in the art. In an embodiment, the process of preparing the composition involves dry granulation, wet granulation or direct compression.

In an embodiment, the process for preparing solid oral pharmaceutical composition of aripiprazole or salts thereof comprises steps of:
a) mixing aripiprazole or salts thereof with one or more pharmaceutical excipients to form a dry blend;
b) preparing the wet mass by mixing the dry blend with granulating composition;
c) drying the wet mass to form granules;
d) mixing one or more pharmaceutical excipients (extragranular material) with the dried granules followed by lubrication; and
e) compressing the granules to form tablets.

In another embodiment, the process for preparing solid oral pharmaceutical composition of aripiprazole or salts thereof comprises steps of:
a) mixing aripiprazole or salts thereof with lactose monohydrate, microcrystalline cellulose, corn starch, low substituted hydroxypropyl cellulose and red iron oxide
b) preparing the wet mass by mixing the dry blend with granulating composition using purified water as vehicle;
c) drying the wet mass below 70°C for less than 90 minutes to form granules;
d) mixing one or more pharmaceutical excipients (extragranular material) with the dried granules followed by lubrication; and
e) compressing the granules to form tablets.

The solid oral composition of the present invention may include one or more conventional excipients, except binder, to enable formation of a present composition. The pharmaceutical excipients includes, but not limited to one or more diluents, disintegrants, glidants, lubricants, and colorants.

Examples of suitable diluents include, but not limited to microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, mannitol, powdered cellulose and sorbitol.

Examples of suitable disintegrants include, but not limited to carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, pregelatinized starch, sodium starch glycolate, and starch.

Examples of suitable glidants include, but not limited to colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and talc.

Examples of suitable lubricants include, but not limited to magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

All the excipients used in the compositions of the present invention are used in the concentration and form (e.g. slurry, dispersion, solution or suspension) such that it should not be considered to act or perform as a binder. For example, corn starch is not used in the form of slurry and L-HPC is used in concentration less than 10% by weight.

In a further embodiment, the composition is in the form of a tablet prepared by wet granulation and comprises aripiprazole or salts thereof, one or more diluents, optionally one or more disintegrants, optionally one or more lubricants and optionally one or more colorants.

In a yet another embodiment, the composition is in the form of a tablet prepared by wet granulation and comprises aripiprazole or salts thereof, lactose monohydrate, microcrystalline cellulose, corn starch, low substituted hydroxypropyl cellulose and red iron oxide.

In a further embodiment, the invention provides compositions comprising of aripiprazole or salts thereof in about 10% by weight, lactose monohydrate in about from 20 to 80% by weight, microcrystalline cellulose in about from 10 to 50% by weight, corn starch in about from 2 to 20% by weight, low substituted hydroxypropyl cellulose in about from 0.1 to 10% by weight and red iron oxide in about from 0.005 to 0.05% by weight.

In a further embodiment, the invention provides compositions comprising of aripiprazole in about 10% by weight, lactose monohydrate preferably in about from 50 to 70% by weight, microcrystalline cellulose preferably in about from 15 to 25% by weight, corn starch about from 5 to 10% by weight, low substituted hydroxypropyl cellulose in about from 2 to 8% by weight and red iron oxide in about from 0.01 to 0.03% by weight.

The invention further provides a method of treating psychotic disorders (e.g. schizophrenia) in a patient which method comprises administering the solid oral pharmaceutical composition of aripiprazole or salts thereof as substantially described herein.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 & 2:
Aripiprazole tablet compositions are disclosed in Table 1 containing hydroxy propyl cellulose as binder.
Table 1
Example 1 Example 2
Sr. No. Ingredients % w/w % w/w
Intragranular
1 Aripiprazole 10 10
2 Lactose monohydrate 62.18 62.18
3 Microcrystalline cellulose 7.05 6.05
4 Corn starch 8.00 9.00
5 L-HPC 5.00 5.00
6 Red iron oxide 0.02 0.02
Binder
7 Hydroxy propyl cellulose 2.00 1.00
8 Water q.s. q.s.
Extragranular
9 Microcrystalline cellulose 5.00 5.00
10 Magnesium stearate 0.75 0.75

The dissolution characteristics of the prepared formulations as per example 1 and 2 in 900 ml of pH 1.2 USP buffer (hydrochloric acid) using USP apparatus II are mentioned in Table 2.
Table 2
Time points Example1 Example 2
15 82 81
30 83 83
45 85 85

Example 3, 4 & 5:
Aripiprazole tablet compositions are disclosed in Table 3 containing corn starch as binder.
Table 3
Example 3 Example 4 Example 5
Sr. No. Ingredients % w/w % w/w % w/w
Intragranular
1 Aripiprazole 15 15 15
2 Lactose monohydrate 57.10 57.10 55.25
3 Microcrystalline cellulose 7.05 7.05 7.05
4 Corn starch 9.00 9.75 9.75
5 L-HPC 5.00 5.00 5.00
6 Yellow iron oxide 0.10 0.20 0.20
Binder
7 Corn starch 1.00 0.25 2.00
8 Water q.s. q.s. q.s.
Extragranular
9 Microcrystalline cellulose 5.00 5.00 5.00
10 Magnesium stearate 0.75 0.75 0.75

The dissolution characteristics of the prepared formulations as per example 3, 4 and 5 in 900 ml of pH 1.2 USP buffer (hydrochloric acid) using USP apparatus II are mentioned as below:
Table 4
Time points Example 3 Example 4 Example 5
15 78 85 90
30 80 86 91
45 81 85 92

Example 6 & 7:
Aripiprazole tablet compositions are disclosed in Table 5 wherein hydroxy propyl cellulose is used as binder.
Table 5
Example 6 Example 7
Sr. No. Ingredients % w/w % w/w
Intragranular
1 Aripiprazole 10 10
2 Lactose monohydrate 59.98 59.98
Microcrystalline cellulose - 10.00
3 Corn starch 7.75 7.75
4 Red iron oxide 0.02 0.02
Binder
5 Hydroxy propyl cellulose 1.5 1.5
6 Water q.s. q.s.
Extragranular
7 Microcrystalline cellulose 10.00 -
8 Corn starch 10.00 10.00
9 Magnesium stearate 0.75 0.75

The dissolution characteristics of the prepared formulations as per example 6 and 7 in 900 ml of pH 1.2 USP buffer (hydrochloric acid) using USP apparatus II are mentioned as below:
Table 6
Time points Example 6 Example 7
15 73 81
30 80 85
45 83 85

Example 8:
Aripiprazole tablet composition is disclosed in Table 7 wherein composition is devoid binder.
Table 7
Sr. No. Ingredients % w/w
1 Aripiprazole 10.00
2 Lactose monohydrate 62.18
3 Microcrystalline cellulose 7.05
4 Corn starch 10.00
5 L-Hydroxypropyl cellulose 5.00
6 Iron Oxide Red 0.02
7 Purified water q.s.
8 Microcrystalline cellulose 5.00
9 Magnesium stearate 0.75

The dissolution characteristics of the prepared formulation as per example 8 in 900 ml of pH 1.2 USP buffer (hydrochloric acid) using USP apparatus II is mentioned as below:
Table 8
Time points AbilifyÒ Tablet Example 8
15 99 98
30 101 99
45 101 98