WO2010079506A2 - Pharmaceutical composition of aripiprazole - Google Patents

Pharmaceutical composition of aripiprazole Download PDF

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Publication number
WO2010079506A2
WO2010079506A2 PCT/IN2009/000356 IN2009000356W WO2010079506A2 WO 2010079506 A2 WO2010079506 A2 WO 2010079506A2 IN 2009000356 W IN2009000356 W IN 2009000356W WO 2010079506 A2 WO2010079506 A2 WO 2010079506A2
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WO
WIPO (PCT)
Prior art keywords
granules
aripiprazole
dried
pharmaceutically acceptable
pharmaceutical composition
Prior art date
Application number
PCT/IN2009/000356
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French (fr)
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WO2010079506A3 (en
Inventor
Rakesh Sheth
Original Assignee
Torrent Pharmaceuticals Ltd.
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Publication date
Application filed by Torrent Pharmaceuticals Ltd. filed Critical Torrent Pharmaceuticals Ltd.
Publication of WO2010079506A2 publication Critical patent/WO2010079506A2/en
Publication of WO2010079506A3 publication Critical patent/WO2010079506A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to stable, solid oral pharmaceutical composition
  • aripiprazole manufactured by wet granulation, wherein intragranular stage is devoid of diluent.
  • the present invention further relates to processes for the preparation of said solid oral pharmaceutical composition of aripiprazole.
  • Aripiprazole chemically known as 7- ⁇ 4-[4-(2, 3-Dichlorophenyl)-l-piperazinyl] butyloxy ⁇ -3, 4-Dihydrocarbo styrl is an atypical antipsychotic agent, which is used for the treatment of schizophrenia.
  • Aripiprazole was first disclosed in EP 0367141 Bl.
  • the drugs that comprise aripiprazole are approved in many countries with trademark ABILIFY ® .
  • ABILIFY ® tablet formulation includes starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose as supportive agent.
  • ABILIFY DISCMELT ® is orally disintegrating tablet of aripiprazole, which includes, 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.
  • WO 03/026659 discloses that if the anhydrous form is exposed to moisture, then it may take on water and convert into a hydrous form. As stated in WO 03/026659, this presents several disadvantages, for instance the compound may be less bioavailable and less soluble. The hygroscopicity of aripiprazole crystals makes them difficult to handle since costly and arduous measures must be taken to ensure that the crystals are not exposed to moisture during process and formulation.
  • WO 03/026659 discloses a wet granulation process for preparing pharmaceutical compositions using aripiprazole anhydride and various carriers.
  • WO 03/026659 discloses the wet granulation of conventional aripiprazole anhydride crystals or anhydride Forms B, C, D, E, F, or G, drying the granules at 70°C to 100°C and sizing the granules, followed by drying the granules for a second time at a temperature of 70°C to 100°C.
  • Anhydrous aripiprazole crystals have high hygroscopic property and when exposed to moisture, the anhydrous form can take on water and convert to hydrous form.
  • the hydrous forms of aripiprazole are less bioavailable and less solubility than the anhydrous forms of aripiprazole.
  • WO 2007081366 Al discloses method of making aripiprazole pharmaceutical compositions by wet granulation comprising: providing a mixture of aripiprazole, at least one diluent, at least one tablet binder, and water; blending the mixture to obtain a wet granulate; drying the wet granulate at a temperature of less than 70°C to obtain a dried granulate; and milling the dried granulate to obtain a milled dried granulate, with the proviso that the wet granulate is not milled prior to drying.
  • Aripiprazole has bitter taste and is a challenge to develop a stable, taste masked solid oral pharmaceutical compositions by a simple manufacturing process.
  • the inventors of the present invention have prepared stable, solid oral pharmaceutical composition of aripiprazole by wet granulation, which is substantially free from conversion to different polymorphic form, easy to manufacture and having acceptable dissolution profile and preferably having pleasant taste and good mouth feel.
  • the present invention relates to stable, solid oral pharmaceutical composition
  • aripiprazole manufactured by wet granulation comprising aripiprazole manufactured by wet granulation.
  • One embodiment of the present invention is to provide stable, solid oral pharmaceutical composition
  • aripiprazole manufactured by wet granulation wherein intragranular stage is devoid of diluent.
  • Another embodiment of the present invention is to provide stable, taste masked, solid oral- pharmaceutical composition comprising aripiprazole manufactured by wet granulation.
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one disintegrant, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 70 0 C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • organoleptic ingredient may be present in any of preceding embodiment.
  • Another embodiment of the present invention is to provide stable, solid oral pharmaceutical composition of aripiprazole wherein, the aripiprazole is at least one of anhydrous aripiprazole Type-I, Type-II, or Form III.
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising the steps of: (a) Preparing granules that comprise of Aripiprazole, diluent, binder and / or disintegrant; drying the wet granules at a temperature less than 70°C to obtain a dried granules;
  • step (b) Blending the dried granules in step (a) with lubricants and optionally other pharmaceutically acceptable excipients;
  • step (c) Compressing the blend of step (b) into a tablet
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another embodiment of the present invention is to provide stable, solid oral pharmaceutical composition of aripiprazole, wherein solid oral solid oral pharmaceutical composition has in vitro dissolution profile of at least 70% release of aripiprazole in 30 minutes.
  • pharmaceutical composition or “solid oral tablet dosage form” or “dosage form” as used herein refers to the tablet composition of predetermined quantity of active substance in association with at least one pharmaceutically acceptable excipient.
  • stable refers to dosage form which is physically, or polymorphically stable.
  • the dosage form according to present invention may remain physically stable, that is there are no substantial changes with respect to physical attributes like colour etc.
  • the dosage form according to present invention may remain polymorphically stable that is the polymorph (crystalline or amorphous) in the dosage form does not rearranges into another form upon storage.
  • drug or “active substance” or “aripiprazole” as used herein includes aripiprazole free base, or pharmaceutically acceptable salts thereof or mixtures thereof. It also includes anhydrous form, hydrous form, different crystalline forms, amorphous form or mixtures thereof. Aripiprazole may be present in an amount ranging from 1 % to 15 % by weight of the composition.
  • compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, lubricant, stabilizers, organoleptic ingredients such as flavoring agent, sweetener and others known to the skilled person in the art.
  • organoleptic ingredient refers to sweetener, flavoring agent or mixtures thereof.
  • the sweetener may be selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose or mixture thereof.
  • Preferred sweetener is aspartame.
  • the flavoring agent may be selected from cherry, black current, pineapple, orange, strawberry, banana, vanilla, mint, menthol, citric acid, fumaric acid, tartaric acid, or mixture thereof.
  • Preferred flavoring agent is cherry flavor.
  • the diluent may be selected, wherever necessary, from calcium phosphate (dibasic and/or tribasic), powdered cellulose, dextrates, dextrin, fructose, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, starch or mixture thereof or other materials known to one of ordinary skill in the art.
  • the diluent is mannitol.
  • the diluent is present in an amount of about 35% to about 90% by weight of the tablet. According to instant invention the diluent is preferably added in extragranular stage.
  • the binder may be selected from carbomer, sodium carboxymethylcellulose, dextrin, glucose, guar gum, hypromellose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone or mixture thereof or other materials known to one of ordinary skill in the art.
  • the binder is hydroxypropyl cellulose.
  • the binder is present in an amount of about 0.0% to about 3% by weight of the tablet.
  • Disintegrants may be selected from starch, sodium starch glycolate, croscarmellose sodium, crospovidone, alginic acid, low-substituted hydroxy propyl cellulose, carboxymethyl cellulose sodium, Guar gum or mixture thereof or other materials known to one of ordinary skill in the art.
  • the disintegrant is present in an amount of about 0.0% to about 20% by weight of the tablet. According to instant invention the disintegrant may be added in drug granules stage and / or extragranular stage.
  • Lubricants may be selected from stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel or mixture thereof or other materials known to one of ordinary skill in the art.
  • the lubricant is present in an amount of ' about 1% to about 5% by weight of the tablet
  • Glidants may be selected from colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel or mixture thereof or other materials known to one of ordinary skill in the art.
  • the glidant is present in an amount of about 0.0% to about 5% by weight of the tablet. According to instant invention the glidant may be added in drug granules stage and / or extragranular stage.
  • Other pharmaceutical solvents are selected from the group comprising of methanol, acetone and purified water.
  • the present invention teaches methods of making tablets by wet granulation and tablets made using wet granulation methodology using temperature that allows for energy savings during the drying step.
  • the drying step is carried out at temperature of about less than 70°C; more preferably, the drying step is carried out at an inlet temperature of about 60° or less.
  • the compressing step may be carried out using a tablet compression apparatus commonly used in tableting.
  • a general method of preparing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one disintegrant, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 7O 0 C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 7O 0 C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising the steps of:
  • step (b) Blending the dried granules in step (a) with lubricants and optionally other pharmaceutically acceptable excipients;
  • step (c) Compressing the blend of step (b) into a tablet.
  • Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70 0 C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets. ;
  • Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding at least one lubricant and atleast one diluent and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
  • dissolution achieved is at least 75 % in 30 minutes as shown in the relevant examples.
  • the ingredients used in the preparation of solid dosage form containing aripiprazole in the present invention are given below along with the method of preparation.
  • the dissolution of the prepared tablets was determined in a paddle apparatus.
  • the rotation speed was set at 60 ⁇ 2 revolutions per minute, the dissolution medium of 0.1 N HCl maintained at a fixed temperature of 37°C (pH 1.2 simulated gastric fluid).
  • the total volume of the dissolution fluid was 900 ml.
  • Aripiprazole, Colloidal silicondioxide and Crospovidone were sifted through # 60 mesh screen and mixed thoroughly.
  • the wet granules were dried in FBD at inlet air temperature of 60 ⁇ 5°C.
  • step 3 The granules of step 3 were sized through 0.5 mm sieve. 5. The drug granules from step 4 and mannitol were sifted through # 60 mesh screen and mixed thoroughly. 6. Colloidal silicondioxide, Citric acid monohydrate, Aspartame, Pineapple flavor,
  • step 3 Size the granules of step 3 through 1.0/0.8/05 mm sieve.
  • step 5 Size the granules of step 5 through 1.0/0.8/ 0.5 mm sieve.
  • step 5 Size the granules of step 5 through 1.0/0.8/ 0.5 mm sieve.
  • Aripiprazole, Mannitol, hydroxypropyl cellulose, Colloidal silicon dioxide and Crospovidone were sifted through # 60 mesh screen and mixed thoroughly.
  • step 2 The blend from step 1 was granulated with water.
  • step 3 The granules of step 3 were sized through 0.5 mm sieve.
  • step-6 The blend from step-6 was compressed into tablets. The tablets showed acceptable dissolution profile.

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Abstract

The present invention relates to stable, solid oral pharmaceutical composition comprising aripiprazole manufactured by wet granulation, wherein intragranular stage is devoid of diluent. The present invention further relates to processes for the preparation of said solid oral pharmaceutical composition of aripiprazole.

Description

PHARMACEUTICAL COMPOSITION OF AR1PIPRAZOLE
FIELD OF THE INVENTION
The present invention relates to stable, solid oral pharmaceutical composition comprising aripiprazole, manufactured by wet granulation, wherein intragranular stage is devoid of diluent.
The present invention further relates to processes for the preparation of said solid oral pharmaceutical composition of aripiprazole.
BACKGROUND OF THE INVENTION
Aripiprazole chemically known as 7-{4-[4-(2, 3-Dichlorophenyl)-l-piperazinyl] butyloxy}-3, 4-Dihydrocarbo styrl is an atypical antipsychotic agent, which is used for the treatment of schizophrenia. Aripiprazole was first disclosed in EP 0367141 Bl. The drugs that comprise aripiprazole are approved in many countries with trademark ABILIFY®. ABILIFY® tablet formulation includes starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose as supportive agent. ABILIFY DISCMELT® is orally disintegrating tablet of aripiprazole, which includes, 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.
The proceeding of "4th Japanese-Korean Symposium on Separation Technology" (October 6-8, 1996) discloses that anhydrous aripiprazole crystals are manufactured by heating aripiprazole hydrate at 80°C. The product obtained by this method is named as aripiprazole Type-I crystal. The same Proceedings disclose that Type-II crystals of aripiprazole anhydride can be prepared by heating Type-I crystals of aripiprazole anhydride at 130°C to 14O0C for 15 hours. As reported in WO 03/026659, several additional anhydrous crystal forms are known. The patent application discloses aripiprazole anhydride crystals Form B, C, D, E, F, or G and a hydrate form, known as Form A. These polymorphs may interconvert from one to the other. Further, WO 03/026659 discloses that if the anhydrous form is exposed to moisture, then it may take on water and convert into a hydrous form. As stated in WO 03/026659, this presents several disadvantages, for instance the compound may be less bioavailable and less soluble. The hygroscopicity of aripiprazole crystals makes them difficult to handle since costly and arduous measures must be taken to ensure that the crystals are not exposed to moisture during process and formulation. Despite these concerns, WO 03/026659 discloses a wet granulation process for preparing pharmaceutical compositions using aripiprazole anhydride and various carriers. WO 03/026659 discloses the wet granulation of conventional aripiprazole anhydride crystals or anhydride Forms B, C, D, E, F, or G, drying the granules at 70°C to 100°C and sizing the granules, followed by drying the granules for a second time at a temperature of 70°C to 100°C.
Anhydrous aripiprazole crystals have high hygroscopic property and when exposed to moisture, the anhydrous form can take on water and convert to hydrous form. The hydrous forms of aripiprazole are less bioavailable and less solubility than the anhydrous forms of aripiprazole.
WO 2007081366 Al discloses method of making aripiprazole pharmaceutical compositions by wet granulation comprising: providing a mixture of aripiprazole, at least one diluent, at least one tablet binder, and water; blending the mixture to obtain a wet granulate; drying the wet granulate at a temperature of less than 70°C to obtain a dried granulate; and milling the dried granulate to obtain a milled dried granulate, with the proviso that the wet granulate is not milled prior to drying.
Further, Aripiprazole has bitter taste and is a challenge to develop a stable, taste masked solid oral pharmaceutical compositions by a simple manufacturing process. The inventors of the present invention have prepared stable, solid oral pharmaceutical composition of aripiprazole by wet granulation, which is substantially free from conversion to different polymorphic form, easy to manufacture and having acceptable dissolution profile and preferably having pleasant taste and good mouth feel.
SUMMARY OF THE INVENTION
The present invention relates to stable, solid oral pharmaceutical composition comprising aripiprazole manufactured by wet granulation.
One embodiment of the present invention is to provide stable, solid oral pharmaceutical composition comprising aripiprazole manufactured by wet granulation, wherein intragranular stage is devoid of diluent.
Another embodiment of the present invention is to provide stable, taste masked, solid oral- pharmaceutical composition comprising aripiprazole manufactured by wet granulation.
Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one disintegrant, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 700C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
As another embodiment of the present invention, organoleptic ingredient may be present in any of preceding embodiment.
Another embodiment of the present invention is to provide stable, solid oral pharmaceutical composition of aripiprazole wherein, the aripiprazole is at least one of anhydrous aripiprazole Type-I, Type-II, or Form III.
Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising the steps of: (a) Preparing granules that comprise of Aripiprazole, diluent, binder and / or disintegrant; drying the wet granules at a temperature less than 70°C to obtain a dried granules;
(b) Blending the dried granules in step (a) with lubricants and optionally other pharmaceutically acceptable excipients; and
(c) Compressing the blend of step (b) into a tablet,
Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets. Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Another embodiment of the present invention is to provide stable, solid oral pharmaceutical composition of aripiprazole, wherein solid oral solid oral pharmaceutical composition has in vitro dissolution profile of at least 70% release of aripiprazole in 30 minutes.
DETAILED DESCRIPTION
The term "pharmaceutical composition" or "solid oral tablet dosage form" or "dosage form" as used herein refers to the tablet composition of predetermined quantity of active substance in association with at least one pharmaceutically acceptable excipient.
The term "stable" as used herein , refers to dosage form which is physically, or polymorphically stable. The dosage form according to present invention may remain physically stable, that is there are no substantial changes with respect to physical attributes like colour etc. The dosage form according to present invention may remain polymorphically stable that is the polymorph (crystalline or amorphous) in the dosage form does not rearranges into another form upon storage.
The term "drug" or "active substance" or "aripiprazole" as used herein includes aripiprazole free base, or pharmaceutically acceptable salts thereof or mixtures thereof. It also includes anhydrous form, hydrous form, different crystalline forms, amorphous form or mixtures thereof. Aripiprazole may be present in an amount ranging from 1 % to 15 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, lubricant, stabilizers, organoleptic ingredients such as flavoring agent, sweetener and others known to the skilled person in the art.
The term "organoleptic ingredient" as used herein refers to sweetener, flavoring agent or mixtures thereof.
The sweetener may be selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose or mixture thereof. Preferred sweetener is aspartame.
The flavoring agent may be selected from cherry, black current, pineapple, orange, strawberry, banana, vanilla, mint, menthol, citric acid, fumaric acid, tartaric acid, or mixture thereof. Preferred flavoring agent is cherry flavor.
The diluent may be selected, wherever necessary, from calcium phosphate (dibasic and/or tribasic), powdered cellulose, dextrates, dextrin, fructose, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, starch or mixture thereof or other materials known to one of ordinary skill in the art. Preferably, the diluent is mannitol. The diluent is present in an amount of about 35% to about 90% by weight of the tablet. According to instant invention the diluent is preferably added in extragranular stage.
The binder may be selected from carbomer, sodium carboxymethylcellulose, dextrin, glucose, guar gum, hypromellose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone or mixture thereof or other materials known to one of ordinary skill in the art. Preferably, the binder is hydroxypropyl cellulose. The binder is present in an amount of about 0.0% to about 3% by weight of the tablet.
Disintegrants may be selected from starch, sodium starch glycolate, croscarmellose sodium, crospovidone, alginic acid, low-substituted hydroxy propyl cellulose, carboxymethyl cellulose sodium, Guar gum or mixture thereof or other materials known to one of ordinary skill in the art. The disintegrant is present in an amount of about 0.0% to about 20% by weight of the tablet. According to instant invention the disintegrant may be added in drug granules stage and / or extragranular stage.
Lubricants may be selected from stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel or mixture thereof or other materials known to one of ordinary skill in the art. The lubricant is present in an amount of ' about 1% to about 5% by weight of the tablet
Glidants may be selected from colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel or mixture thereof or other materials known to one of ordinary skill in the art. The glidant is present in an amount of about 0.0% to about 5% by weight of the tablet. According to instant invention the glidant may be added in drug granules stage and / or extragranular stage.
Other pharmaceutical solvents are selected from the group comprising of methanol, acetone and purified water.
The present invention teaches methods of making tablets by wet granulation and tablets made using wet granulation methodology using temperature that allows for energy savings during the drying step. The drying step is carried out at temperature of about less than 70°C; more preferably, the drying step is carried out at an inlet temperature of about 60° or less. The compressing step may be carried out using a tablet compression apparatus commonly used in tableting.
As a general method of preparing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one disintegrant, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 7O0C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder, and water to obtain a wet granules; drying the wet granules at a temperature less than 7O0C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising the steps of:
(a) Preparing granules that comprise of Aripiprazole, diluent, binder and / or disintegrant; drying the wet granules at a temperature less than 700C to obtain a dried granules;
(b) Blending the dried granules in step (a) with lubricants and optionally other pharmaceutically acceptable excipients; and
(c) Compressing the blend of step (b) into a tablet.
Another embodiment of the present invention is to provide a process of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 700C to obtain a dried granules; and milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets. ;,
Another method of manufacturing stable, solid oral pharmaceutical composition of aripiprazole by wet granulation comprising: blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; milling of wet granules, drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; and milling the dried granules, followed by adding at least one lubricant and atleast one diluent and optionally other pharmaceutically acceptable excipient to the dried milled granules; and compressing the lubricated granules to form tablets.
Thus, by using the above simple and less expensive method, dissolution achieved is at least 75 % in 30 minutes as shown in the relevant examples.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps as well as compositions by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
EXAMPLES
The ingredients used in the preparation of solid dosage form containing aripiprazole in the present invention are given below along with the method of preparation. In all the subsequent examples, the dissolution of the prepared tablets was determined in a paddle apparatus. The rotation speed was set at 60 ± 2 revolutions per minute, the dissolution medium of 0.1 N HCl maintained at a fixed temperature of 37°C (pH 1.2 simulated gastric fluid). The total volume of the dissolution fluid was 900 ml.
Example 1:
Figure imgf000011_0001
Figure imgf000012_0001
Procedure:
1. Aripiprazole, Colloidal silicondioxide and Crospovidone were sifted through # 60 mesh screen and mixed thoroughly.
2. Povidone was dissolved in sufficient quantity of purified water and granulated the blend from step 1 with povidone binder solution.
3. The wet granules were dried in FBD at inlet air temperature of 60 ± 5°C.
4. The granules of step 3 were sized through 0.5 mm sieve. 5. The drug granules from step 4 and mannitol were sifted through # 60 mesh screen and mixed thoroughly. 6. Colloidal silicondioxide, Citric acid monohydrate, Aspartame, Pineapple flavor,
Crospovidone, Talc, Magnesium stearate and Ferric oxide were sifted through appropriate screen and mixed with blend from step -5. 7. The blend from step-6 was compressed into tablets. The tablets showed acceptable dissolution profile. Example 2:
Figure imgf000013_0001
Procedure:
1. Sift Aripiprazole, cross povidone, Povidone and colloidal silicon dioxide through appropriate sieve. Mix well in RMG.
2. Granulate the blend from step 1 with water.
3. Dry the granules in FBD at inlet of 60 ± 10°C.
4. Size the granules of step 3 through 1.0/0.8/05 mm sieve.
5. Sift rest of mannitol, cross povidone, colloidal silicon dioxide and talc through appropriate sieve.
6. Mix the blend from step 4 and step 5 in conta blender.
7. Mix magnesium stearate with step 6 after sifting and compress into tablets. Example 3:
Figure imgf000014_0001
Procedure:
1. Sift Aripiprazole, Mannitol, hydroxypropyl cellulose and colloidal silicon dioxide through appropriate sieve.
2. Granulate the blend from step 1 with water.
3. Dry the granules in FBD at inlet of 60 ± 10°C.
4. Size the granules of step 5 through 1.0/0.8/ 0.5 mm sieve.
5. Sift rest of mannitol, cross povidone, colloidal silicon dioxide and talc through appropriate sieve.
6. Mix step 4 and step 5 in conta blender.
7. Mix magnesium stearate with step 6 after sifting and compress into tablets. Example 4:
Figure imgf000015_0001
Procedure:
1. Sift Aripiprazole, Mannitol, Microcrystalline cellulose and colloidal silicon dioxide through appropriate sieve.
2. Granulate the blend from step 1 with water.
3. Dry the granules in FBD at inlet of 60 ± 10°C.
4. Size the granules of step 5 through 1.0/0.8/ 0.5 mm sieve.
5. Sift rest of mannitol, cross povidone, colloidal silicon dioxide and talc through appropriate sieve.
6. Mix step 4 and step 5 in conta blender.
7. Mix magnesium stearate with step 6 after sifting and compress into tablets. Example 5:
Figure imgf000016_0001
Procedure:
1. Aripiprazole, Mannitol, hydroxypropyl cellulose, Colloidal silicon dioxide and Crospovidone were sifted through # 60 mesh screen and mixed thoroughly.
2. The blend from step 1 was granulated with water.
3. The wet granules were milled and subsequently dried in FBD at inlet of 60 ± 10°C.
4. The granules of step 3 were sized through 0.5 mm sieve.
5. The drug granules from step 4 and mannitol were sifted through # 60 mesh screen and mixed thoroughly
6. Rest of mannitol, Colloidal silicon dioxide, Crospovidone, Talc, Magnesium stearate were sifted through appropriate screen and mixed with blend from step -5.
7. The blend from step-6 was compressed into tablets. The tablets showed acceptable dissolution profile.

Claims

1. Stable, solid oral pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, manufactured by wet granulation.
2. The oral pharmaceutical composition according to claim 1, wherein intragranular stage is devoid of diluent.
3. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole at least one binder and / or disintegrant using solvent; b) drying the wet granules at a temperature less than 70°C to obtain a dried granules; c) blending the dried granules of step (b) with lubricants and optionally other pharmaceutically acceptable excipients; and d) Compressing the blend of step (c) into a tablet,
4. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole, at least one disintegrant, at least one binder, and water to obtain a wet granules; b) drying the wet granules at a temperature less than 70°C to obtain a dried granules; c) milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and d) compressing the lubricated granules to form tablets.
5. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole, at least one binder, and water to obtain a wet granules; b) drying the wet granules at a temperature less than 70°C to obtain a dried granules; c) milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and d) compressing the lubricated granules to form tablets.
6. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole, diluent, binder and / or disintegrant and water to obtain a wet granules; b) drying the wet granules at a temperature less than 700C to obtain a dried granules; c) blending the dried granules in step (b) with lubricants and optionally other pharmaceutically acceptable excipients; and d) compressing the blend of step (c) into a tablet,
7. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole, at least one binder and / or disintegrant, and water to obtain a wet granules; b) milling of wet granules; c) drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; d) milling the dried granules, followed by adding diluent, at least one lubricant and optionally other pharmaceutically acceptable excipient to the dried milled granules; and e) compressing the lubricated granules to form tablets.
8. A process of preparing pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, which comprises the steps of: a) blending a mixture of aripiprazole, at least one diluent, at least one binder and / or disintegrant, and water to obtain a wet granules; b) milling of wet granules; c) drying the milled wet granules at a temperature less than 70°C to obtain a dried granules; d) milling the dried granules, followed by adding at least one lubricant and diluent and optionally other pharmaceutically acceptable excipient to the dried milled granules; and e) compressing the lubricated granules to form tablets.
9. The solid oral pharmaceutical composition comprising aripiprazole or its pharmaceutically acceptable salts thereof, as substantially described and exemplified herein
PCT/IN2009/000356 2008-06-23 2009-06-22 Pharmaceutical composition of aripiprazole WO2010079506A2 (en)

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EP2359816A1 (en) * 2010-02-09 2011-08-24 Sanovel Ilac Sanayi ve Ticaret A.S. Aripiprazole formulations
WO2013100878A1 (en) * 2011-12-27 2013-07-04 Mahmut Bilgic Pharmaceutical formulations comprising aripiprazole
WO2013133448A1 (en) * 2012-03-06 2013-09-12 Otsuka Pharmaceutical Co., Ltd. Sustained release oral solid preparation
WO2013175508A2 (en) * 2012-05-24 2013-11-28 Medreich Limited Stable pharmaceutical composition of aripiprazole
WO2014104989A1 (en) * 2011-12-27 2014-07-03 Mahmut Bilgic Pharmaceutical compositions comprising aripiprazole

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Publication number Priority date Publication date Assignee Title
EP2359816A1 (en) * 2010-02-09 2011-08-24 Sanovel Ilac Sanayi ve Ticaret A.S. Aripiprazole formulations
WO2013100878A1 (en) * 2011-12-27 2013-07-04 Mahmut Bilgic Pharmaceutical formulations comprising aripiprazole
WO2014104989A1 (en) * 2011-12-27 2014-07-03 Mahmut Bilgic Pharmaceutical compositions comprising aripiprazole
WO2013133448A1 (en) * 2012-03-06 2013-09-12 Otsuka Pharmaceutical Co., Ltd. Sustained release oral solid preparation
WO2013175508A2 (en) * 2012-05-24 2013-11-28 Medreich Limited Stable pharmaceutical composition of aripiprazole
WO2013175508A3 (en) * 2012-05-24 2014-01-09 Medreich Limited Stable pharmaceutical composition of aripiprazole

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