Field of the invention
The present invention relates to orally disintegrating tablet compositions of antipsychotic agents. More particularly, the present invention relates to orally disintegrating tablet compositions of aripiprazole.
The present invention also relates to a process for the preparation of orally disintegrating tablet compositions of aripiprazole.
Background of the invention
Aripiprazole is a carbostyril derivative and is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-1 -piperazinyl]butoxy]-3,4-dihydrocarbostyril. Aripiprazole is an atypical antipsychotic agent useful in the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar disorder as disclosed in US 4,734,416 and US 5,006,528. It is marketed under the trade name Abilify® in the form of tablets, oral solution, orally disintegrating tablets and injection for intramuscular use in the United States.
The development of orally disintegrating tablets which dissolve or disintegrate instantly upon contact with tongue or buccal mucosa without requiring water are advantageous for patients who have difficulty in swallowing the conventional tablets such as geriatric, infants, patients with mental problems and non-cooperative patients. The orally disintegrating tablets can be administered without the help of water. Moreover, this dosage form enhances the clinical efficacy of some drugs through pregastric absorption from mouth, pharynx, and esophagus leading to an increase in bioavailability and a reduction in side effects because of avoidance of first-pass metabolism.
Aripiprazole orally disintegrating tablets are commercially available under the trade name Abilify discmelt® in the United States. These tablets contain acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, creme de vanilla (natural and artificial flavors), magnesium stearate,

microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol and colorants include ferric oxide (yellow or red) and FD&C blue No. 2 aluminum lake as inactive ingredients. As per the disclosure of US 2002/0076437, US 2005/0019398 and US 2007/0275059, these flash melt tablets contain greater than 80% of dispersing agent comprised of calcium silicate.
US 2004/0058935, US 2007/0202181, US 2007/0203150, US 2007/0203151, US 2007/0203152, US 2007/0212421, US 2007/0213343, US 2007/0213344 disclose flash melt tablets of aripiprazole anhydride having intragranular and extragranular part comprising xylitol, avicel, calcium silicates, crospovidone, amorphous silica, aspartame, magnesium stearate along with sweetening and flavoring agent.
The use of silicates may increase the weight of the tablet and also the cost of the formulation. Further, the calcium silicate has low porosity and moreover, the use of calcium silicate may leads to weight and content variation due to poor flow properties and also imparts chalky taste to the dosage form.
US 2005/0089557 discloses orally disintegrating tablets produced by blending a powdery or granular mixture of aripiprazole and 50% by weight or more of a water-soluble filler based on the powdery or granular mixture such as sugar, sugar alcohol, water soluble substances and agar with a compressing characteristic improving agent such as corn starch, potato starch, crystal cellulose, low substituted hydroxypropyl cellulose and polyvinyl pyrrolidone. This patent publication discloses orally disintegrating tablets produced without the use of disintegrants.
US 2006/0286165 discloses taste-masked pharmaceutical particle prepared by polymer blending process and their use in the preparation of orally disintegrating tablet.
US 2007/0148100 discloses a stable nanoparticulate aripiprazole compositions comprising particles of aripiprazole having an average effective

particle size of less than about 2000 nm and at least one surface stabilizer, which is suitable for fast melt formulation.
US 2008/0020038 discloses orodispersible tablets comprising stabilized amorphous aripiprazole prepared by direct compression comprising amorphous aripiprazole and at least one stabilizing agent, and preferably 0 to 10 weight % of taste masking agent, 40 to 90 weight % of filler, 0 to 50 weight % of disintegration aids, 0.1 to 5 weight % of lubricant and 0 to 5 weight % of flavor.
WO 07/113856 discloses taste masked aripiprazole compositions comprising spray dried ODT excipients consisting of mannitol and calcium silicate prepared by direct compression.
IN 147/MUM/2006 and IN 786/MUM/2006 disclose an orally disintegrating composition comprising (a) aripiprazole or its salts or solvate thereof, (b) sugar alcohol and pharmaceutically acceptable carrier and process for preparing it using stabilizers such as sodium lauryl sulfate or ion exchange resin such as amberlite.
CN 1709256 discloses an aripiprazole orally disintegrant tablet preparation comprising aripiprazole along with disintegrant, filling agent, lubricating agent and glidanl.
Further US 5,006,528, US 2006/0257471, US 2007/0154544, US 2007/0154545, WO 2007/004061 and WO 2008/020820 disclose conventional tablet compositions of aripiprazole.
The above prior art references discloses various orally disintegrating tablet compositions comprising various excipients such as silicates, nanoparticulate aripiprazole, stabilizing agent, polymer blending for taste masking. However, still there is a need to develop orally disintegrating tablet compositions of aripiprazole, which is simple and cost effective. The inventors of the present invention during their continuous effort found that orally disintegrating tablets of aripiprazole can be prepared by simple processing steps using disintegrants and high concentrations of water-soluble diluents without using silicates or stabilizers.

Objective of the invention
Accordingly, the main objective of the present invention is to provide orally disintegrating tablet compositions of aripiprazole.
Yet another objective of the present invention is to provide orally disintegrating tablet compositions of aripiprazole in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration etc.
Yet, another embodiment of the present invention is to provide simple, cost effective and efficient process for preparing orally disintegrating tablet compositions of aripiprazole.
Summary of the invention
Accordingly, the main embodiment of the present invention is to provide orally disintegrating tablet compositions of aripiprazole comprising at least 70% w/w of one or more water-soluble or swellable diluent, 0.5 to 10 % w/w of disintegrant, 0.05 to 2% w/w of sweetening agent, 0.5 to 3% w/w of lubricant, wherein the composition is free of silicates or stabilizers.
Detailed description of the invention
The aripiprazole used according to the present invention may be in the form of crystalline or amorphous or a mixture of both.
The orally disintegrated tablet compositions of aripiprazole of the present invention disintegrates within 60 seconds. Further, the orally disintegrating tablet compositions of the present invention is free of effervescent excipients, stabilizers, ion exchange resins or organic acids.
Suitable water-soluble or swellable diluents used according to the present invention are selected from sucrose, dextrose, mannitol, sorbitol, starch, lactose, starlac, microcrystalline cellulose and the like or mixtures thereof The diluent may be used in the range of at least 70% w/w or more.

Starlac® is a spray dried compound consisting of 85% alpha-lactose monohydrate and 15% maize starch dry matter. The addition of starch makes the tablet to disintegrate more rapidly. It also provides good compressibility and allows the production of hard, robust tablets with good flowability.
Suitable disintegrants used according to the present invention are selected from pregelatinized starch, starch, sodium starch glycolate, carboxymethylcellulose and its salts, crospovidone, croscarmellose sodium and the like or mixtures thereof in the range of 0.5 to 10 %w/w.
Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc and the like or mixtures thereof in the range of about 0.5 to 3 % w/w.
Suitable sweeteners according to the present invention are selected from sugars such as sucrose, lactose and glucose; saccharin and salts thereof, acesulfame potassium, glycerrhizinate salt and aspartame and the like or mixtures thereof in the range of 0.05 to 2%w/w.
Suitable glidants include talc, colloidal silicon dioxide, cornstarch and the like.
Suitable flavoring agents include strawberry guarana, peppermint, cherry, mint, caramel, raspberry, lemon, orange, vanilla, tuttifruity, banana, bubble gum, preferably strawberry guarana, juicy orange, peppermint flavor and the like or mixtures thereof.
In yet another embodiment, the amount of aripiprazole used is in the range of about 1% to about 20% w/w.
In a preferred embodiment of the present invention, the orally disintegrating tablet composition of aripiprazole comprises at least 70% w/w of water-soluble or swellable diluent selected from starlac, lactose, starch, mannitol and microcrystalline cellulose or mixtures thereof; 0.5% to 10% w/w of disintegrant selected from sodium starch glycolate, carboxymethylcellulose and crospovidone or

mixtures thereof; 0.05 to 2% w/w of sweetening agent selected from acesulfame potassium, glycerrhizinate salt and aspartame or mixtures thereof and 0.5 to 2% w/w of lubricant selected from magnesium stearate and calcium stearate.
The process that can be employed for making the orally disintegrating tablet compositions of aripiprazole of the present invention include wet granulation, dry granulation such as slugging / compaction and direct compression.
In yet another embodiment of the present invention, there is provided a process for the preparation of orally disintegrating tablet compositions of aripiprazole comprising at least 70% w/w of one or more water-soluble or swellable diluent, 0.5 to 10 % w/w of disintegrant, 0.05 to 2% w/w of sweetening agent, 0.5 to 3% w/w of lubricant, wherein the composition is free of silicates or stabilizers, comprises the steps of:
i). sifting aripiprazole, water soluble diluent, disintegrant, sweetening agent, glidant and flavoring agent,
ii). mixing the ingredients of step (i) in a blender, iii). lubricating the blend obtained in step (ii),
iv). compressing the lubricated blend of step (iii) to obtain orally disintegrating tablet.
In yet another embodiment, there is provided a method for the treatment of schizophrenia, acute manic and mixed episodes associated with bipolar disorder and agitation associated with schizophrenia and bipolar mania, by administering orally disintegrating tablet composition of aripiprazole of the present invention.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

S. No. Ingredients Quantity (mg)
1 Aripiprazole 2.0
2 Starlac 83.36
3 Sodium starch glycoUate 2.60
4 Aspartame 0.18
5 Vanilla flavor 0.06
6 Colloidal silicon dioxide 0.60
7 Microcrystalline cellulose 10.00
8 Magnesium stearate 1.20
The processing steps involved in the preparation of orally disintegrating tablets are
given below:
i) Aripiprazole, starlac, sodium starch glycolate, aspartame, vanilla flavor,
microcrystalline cellulose, colloidal silicon dioxide were sifted through suitable
sieves,
ii) sifted ingredients of step (i) were mixed in a blender,
iii) lubricated the blend obtained in step (ii) with magnesium stearate,
iv). compressed the lubricated blend obtained in step (iii) to obtain orally
disintegrating tablets.
The compositions given in examples 2 to 12 were prepared using the similar procedure as described in example 1.
Example 2

S. No. Ingredients Quantity (mg)
1 Aripiprazole 5.00
2 Starlac 80.36

The aripiprazole orally disintegrating tablets prepared according to the present invention were tested for drug release in 900ml media for 45 minutes followed by buffer of pH 1.20 using USP apparatus 2 with paddle speed at 60 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for aripiprazole content. The dissolution profile is given in Table 1.

We claim:
1. An orally disintegrating tablet composition of aripiprazole comprising at least 70% w/w of one or more water-soluble or swellable diluent, 0.5 to 10% w/w of disintegrant, 0.05 to 2% w/w of sweetening agent, 0.5 to 3% w/w of lubricant, wherein the composition is free of silicates or stabilizers.
2. The dosage form as claimed in claim 1, wherein the water soluble diluent is selected from sucrose, dextrose, mannitol, sorbitol, starch, lactose, starlac, microcrystalline cellulose or mixtures thereof.
3. The dosage form as claimed in claim 1, wherein the disintegrant is selected from pregelatinized starch, starch, sodium starch glycolate, carboxymethylcellulose and its salts, crospovidone, croscarmellose sodium or mixtures thereof.
4. The dosage form as claimed in claim 1, wherein the sweetening agent is selected from sugars such as sucrose, lactose and glucose; saccharin and salts thereof, acesulfame potassium, glycerrhizinate salt and aspartame or mixtures thereof.
5. The dosage form as claimed in claim 1, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc or mixtures thereof.
6. An orally disintegrating tablet composition of aripiprazole comprising at least 70% w/w of water-soluble or swellable diluent selected from starlac, lactose, starch, mannitol and microcrystalline cellulose and mixture thereof; 0.5% to 10% w/w of disintegrant selected from sodium starch glycolate, carboxymethylcellulose and crospovidone or mixtures thereof; 0.05 to 2% w/w of sweetening agent selected from acesulfame potassium, glycerrhizinate salt and aspartame or mixtures thereof and 0.5 to 2% w/w of lubricant selected from magnesium stearate and calcium stearate.
7. A process for the preparation of orally disintegrating tablet composition of aripiprazole comprising at least 70% w/w of one or more water soluble diluent, 0.5

to 10 % w/w of disintegrant, 0.05 to 2% w/w of sweetening agent, 0.5 to 3% w/w of
lubricant, wherein the composition is free of silicates or stabilizers, comprises the
steps of:
i). sifting aripiprazole, water soluble diluent, disintegrant, sweetening agent,
glidant and flavoring agent,
ii). mixing the ingredients of step (i) in a blender,
iii). lubricating the blend obtained in step (ii),
iv). compressing the lubricated blend of step (iii) to obtain orally disintegrating
tablet.