WO2016139683A2 - Compositions pharmaceutiques de lurasidone et son procédé de préparation - Google Patents

Compositions pharmaceutiques de lurasidone et son procédé de préparation Download PDF

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Publication number
WO2016139683A2
WO2016139683A2 PCT/IN2016/050079 IN2016050079W WO2016139683A2 WO 2016139683 A2 WO2016139683 A2 WO 2016139683A2 IN 2016050079 W IN2016050079 W IN 2016050079W WO 2016139683 A2 WO2016139683 A2 WO 2016139683A2
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WO
WIPO (PCT)
Prior art keywords
lurasidone
composition
pharmaceutical composition
solid oral
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2016/050079
Other languages
English (en)
Other versions
WO2016139683A3 (fr
Inventor
Rakesh Jain
Ganesh Vinayak Gat
Ravikumar Nithiyanandam
Rashmi Ranjan PANDA
Dinesh Kumar
Original Assignee
Jubilant Generics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jubilant Generics Limited filed Critical Jubilant Generics Limited
Publication of WO2016139683A2 publication Critical patent/WO2016139683A2/fr
Publication of WO2016139683A3 publication Critical patent/WO2016139683A3/fr

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Classifications

    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof.
  • the present invention relates to a process for the preparation of solid oral dosage forms comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the said composition is substantially free of binder.
  • Lurasidone is a dopaminergic (D2) and serotonin (5-HT2A) receptor antagonist and is disclosed in U.S. Patent Nos. 5,780,632 and US 5,532,372. Chemically, it is (3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2-[4-(l,2-benzisothiazol-3-yl)piperazin-l-ylmethyl] cyclohexylmethyl ⁇ hexahydro-4,7-methano-2H-isoindole-l,3-dione hydrochloride having the structural formula:
  • Lurasidone is known to have psychotropic activities and is therapeutically used for the treatment of schizophrenia and senile dementia.
  • Lurasidone hydrochloride is marketed by Sunovion Pharms in the United States under the brand name Latuda ® for the treatment of schizophrenia and depressive episodes associated with bipolar I disorder.
  • Lurasidone has a low aqueous solubility (0.224 mg/ml in water) and when used in micronized form, the active pharmaceutical ingredient is difficult to process due to sticky nature. Accordingly, designing of solid oral pharmaceutical dosage form of Lurasidone hydrochloride with desired technical attributes is challenging.
  • U.S. Patent No. 7,727,553 discloses a pharmaceutical preparation in the form of a rapidly disintegrating oral formulation comprising Lurasidone granules, a first disintegrating agent, a water-soluble excipient, a water soluble polymer binder in the range of about 3% and above and a second disintegrating agent.
  • U.S. Patent No. 8,729,085 discloses a composition comprising Lurasidone, pregelatinized starch, a water-soluble excipient and a water-soluble polymer binder. This patent publication further discloses the use of water-soluble polymer binder in the range of 0.5 to 10% by weight.
  • U.S. Patent No. 8,883,794 and U.S. Patent Publication No. 2015/0056284 relates to oral preparation comprising Lurasidone in a range of 20 to 45% w/w, pregelatinized starch in range of 10 to 50% w/w, a water-soluble excipient, and a water-soluble polymeric binder in the range of 0.5 to 10% by weight.
  • U.S. Patent Publication No. 2014/0348909 discloses pharmaceutical compositions of Lurasidone with one or more water-insoluble pharmaceutical excipients and water-insoluble binders. This patent publication teaches use of water-insoluble binder in the range of about 0.5% to about 55% by total weight of the composition. It also discloses pharmaceutical composition comprising lurasidone, wherein the composition is free of water-soluble excipients and water-soluble polymer binders.
  • U.S. Patent Publication No. 2014/0343076 discloses pharmaceutical compositions of
  • Lurasidone with one or more acids wherein formulations have a similar in vitro dissolution profile to Latuda ® .
  • This patent publication discloses use of Hypromellose as a binder from 0.69% to 1.14% w/w.
  • PCT publication No. WO 2014/076712 discloses amorphous solid dispersion of Lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier. This patent publication also discloses use of binder in the formulation development.
  • compositions of Lurasidone which is substantially free of binder and which can also exhibit rapid disintegration as well as equivalent in vitro dissolution profile.
  • the composition of the present invention can be prepared by a simple and cost effective process.
  • compositions comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the composition is substantially free of binder.
  • pharmaceutical composition comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein composition is free of binder.
  • compositions comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof; a mixture of water-soluble and water- insoluble excipients, less than 10% w/w of pregelatinized starch, wherein the composition is substantially free of binder.
  • a pharmaceutical composition comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, which further comprises pharmaceutically acceptable excipients like diluent, disintegrant, glidant and lubricant.
  • a process of preparing a pharmaceutical composition comprising Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, by using wet granulation or dry granulation or direct compression method.
  • the present invention there is provided use of a pharmaceutical composition in the manufacture of a medicament for treating schizophrenia, positive and negative symptoms of schizophrenia, major depressive episodes associated with bipolar I disorder, memory or learning dysfunctions caused by schizophrenia, senile dementia, attention deficit hyperactivity disorder, central nervous system disorder responsive to modulation of glutamate levels and other associated CNS disorders.
  • the present invention relates to pharmaceutical compositions of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof, wherein the composition is substantially free of binder. It further relates to the process for preparing such composition.
  • the present invention also relates to a pharmaceutical composition of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof; wherein the composition comprises a mixture of water-soluble and water- insoluble excipients, less than 10% w/w of pregelatinized starch; and process of manufacturing the same, wherein the said composition is substantially free of binder.
  • Lurasidone' is used in broad sense to include not only Lurasidone per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable stereoisomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
  • the compositions of the present invention comprises Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof having D90 less than or equal to about 100 ⁇ and D50 less than or equal to about 40 ⁇ .
  • the D9 0 is between in range from 5 ⁇ to 50 ⁇ and D50 is less than 30 ⁇ .
  • the particle size of Lurasidone can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and any other technique known in the art.
  • the pharmaceutical compositions of present invention comprises about 10 to about 160 mg of Lurasidone, preferably about 20 to about 120 mg of Lurasidone.
  • the pharmaceutical composition comprises Lurasidone in the range of about 10% to about 85% by weight, preferably in the range of about 20% to about 45% by weight on the basis of the total weight of the composition.
  • Substantially binder free pharmaceutical composition refers to the pharmaceutical composition of Lurasidone, which comprises less than 0.5% w/w binder by total weight of the composition, preferably in the range of 0-0.4% by total weight of the composition.
  • Embodiments of the present invention relates to pharmaceutical compositions of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof; wherein the composition comprises less than 10% w/w of pregelatinized starch; a mixture of water-soluble and water-insoluble excipients and said composition releases at least 85% of Lurasidone within 30 minutes in diluted Mcllvaine buffer of pH 3.8.
  • excipient means a pharmacologically inactive component such as a diluent, disintegrant, glidant, antioxidant, stabilizer, carrier, or the like.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.
  • Water soluble excipient is selected from, but not limited to, mannitol, lactose, sucrose, glucose, maltose, hydrogenated maltose, maltotetraose, fructose, lactulose, lactitol, sorbitol, maltitol, erythritol, xylitol or mixtures thereof.
  • the water-soluble pharmaceutical excipient is mannitol.
  • the water-soluble pharmaceutical excipient is incorporated in the composition in an amount of about 5% to about 85% by weight, preferably about 20% to about 80% by weight, more preferably about 40% to about 70% by weight on the basis of the total weight of the composition.
  • Water-insoluble excipient is selected from, but not limited to, cellulose derivatives, microcrystalline cellulose, ethylcellulose, silicon dioxide, crospovidone, sodium starch glycolate, croscarmellose sodium, and methacrylate polymers, corn starch, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, triacetin.
  • the water-insoluble pharmaceutical excipient is incorporated in the composition in an amount of about 5% to about 85% by weight, preferably about 20% to about 80% by weight, more preferably about 40% to about 70% by weight on the basis of the total weight of the composition.
  • Suitable disintegrating agents includes, but are not limited to, crospovidone, sodium starch glycolate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, or mixtures thereof.
  • the disintegrant is used in the composition in an amount of about 0.5% to about 30% by weight, preferably about 2% to about 10% by weight on the basis of the total weight of the composition.
  • Suitable lubricants which may include, but are not limited to, stearic acid, Zinc stearate, sucrose stearate, sodium benzoate, hydrogenated vegetable oil type I, calcium stearate, adipic acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides, sodium stearyl Fumarate, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol, carnauba wax or mixtures thereof.
  • the Lubricant is used in the composition in an amount of about 0.10% to about 5% by weight, preferably about 0.2% to about 2% by weight on the basis of the total weight of the composition.
  • Suitable taste masking agents include, but are not limited to one or more of polymers, sweeteners and flavors.
  • polymers include one or more of cellulose acetate, ion exchange resin, polymethacrylates, and cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose; and the like.
  • sweeteners include but not limiting to one or more of aspartame, saccharin, sucralose, glycyrrhizin and the like.
  • sweeteners comprise sugarless sweeteners, hydrogenated starch hydrolysates alone or in combination.
  • suitable flavors comprise citric acid, cinnamon, wintergreen, eucalyptus, spearmint, peppermint, menthol, anise as well as fruit flavors such as apple, pear, peach, vanilla, strawberry, cherry, apricot, orange, watermelon, banana and the like; bean-derived flavors, such as coffee, cocoa and the like or mixtures thereof.
  • a pharmaceutical composition comprising:
  • composition wherein the pharmaceutical composition is substantially free of binder.
  • compositions can be formulated into solid, semi- solid or liquid preparations along with pharmaceutically acceptable excipients(s), into tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile release tablets, timed release tablets, delayed release, controlled release, extended release and sustained release tablets), pellets, beads, granules, film, sustained release compositions, pills, troches, capsules hard and soft or liquid filled soft gelatin capsules, microcapsules, minitablets, tablets in capsules and microspheres, matrix compositions, osmotic compositions, bioadhesive compositions, powder/pellets/granules for suspension, powder, solutions, suspensions, sachets or emulsions and the like.
  • the pharmaceutical composition of Lurasidone or its pharmaceutically acceptable salts, esters, solvates, polymorphs, stereoisomers or mixtures thereof can be prepared by any suitable method known in the art such as direct compression, dry or wet granulation, fluidized bed granulation, melt extrusion, melt granulation, spray coating, freeze drying, spray drying and solution evaporation.
  • the pharmaceutical composition may comprises at least one coating material in an amount ranging from about 1% to about 10% w/w by total weight of the composition.
  • macromolecular substances are used, such as modified celluloses, polymethacrylates, polyvinyl pyrroiidone, polyvinyl acetate phthalate, zein, Polyethylene glycol and/or shellac.
  • Hydroxypropyl methyl cellulose is preferably used, especially HPMC with average molecular weight of 10,000 to 150,000 g/mol.
  • the pharmaceutical composition of the present invention can be used for treatment of schizophrenia, positive and negative symptoms of schizophrenia, major depressive episodes associated with bipolar I disorder, memory or learning dysfunctions caused by schizophrenia, senile dementia, attention deficit hyperactivity disorder, central nervous system disorder responsive to modulation of glutamate levels and other associated CNS disorders.
  • compositions of the invention may also contain one or more active ingredients in addition to the Lurasidone.
  • the additional active ingredient may be another antipsychotic compound including benzisothiazol derivatives, or it may be an active ingredient having a different therapeutic activity like vitamins, antibiotics, cardiovascular agents, NSAIDs and like.
  • Lurasidone hydrochloride, lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and magnesium stearate were sifted through a suitable mesh.
  • Step 1 material was mixed in a suitable blender for suitable time and compacted using a roller compactor.
  • step 2 The compacts from step 2 were milled using suitable screen.
  • step 4 The milled material from step 3 was lubricated with magnesium stearate.
  • step 4 The blend of step 4 was compressed into tablets with a suitable tooling and optionally tablets were coated with commercially available film coating solutions.
  • Lurasidone hydrochloride, mannitol, dibasic calcium phosphate, pregelatinized starch, sodium starch glycolate and magnesium stearate were sifted through a suitable mesh.
  • Step 1 material was mixed in a blender and compacted using a roller compactor.
  • step 2 The compacts from step 2 were milled using suitable screen.
  • step 4 The milled material from step 3 was lubricated with magnesium stearate.
  • step 4 The blend of step 4 was compressed into tablets with a suitable tooling and the tablets were optionally coated with commercially available film coating solutions.
  • Lurasidone hydrochloride, mannitol, colloidal silicon dioxide, croscarmellose sodium and magnesium Stearate were sifted through a suitable mesh.
  • Step 1 material was mixed in a blender and compacted using a roller compactor.
  • step 2 The compacts from step 2 were milled using suitable screen.
  • step 4 The milled material from step 3 was lubricated with magnesium stearate.
  • step 4 The blend of step 4 was compressed into tablets with a suitable tooling and the tablets were coated with commercially available film coating solutions.
  • Lurasidone hydrochloride, mannitol, and croscarmellose Sodium were sifted through a suitable mesh.
  • Step 2 The sifted blend of Step 1 was placed in a rapid mixer granulator and mixed for a suitable time.
  • Step 2 blend was granulated by using water.
  • step 3 The granules of step 3 were dried in a fluidized bed dryer.
  • step 4 Granules obtained from step 4 were lubricated with magnesium stearate and compressed into tablets with a suitable tooling and the tablets were optionally coated with commercially available film coating solutions.
  • Example 1-4 The standardized method and equipment for testing of disintegrating time is provided in United State Pharmacopeia (USP).
  • USP United State Pharmacopeia
  • the test and reference formulation were tested according to the said method.
  • the disintegration test was conducted on the reference formulation Latuda Tablets in comparison to a solid oral tablet dosage form prepared as per quantitative composition as given in Example 1-4. Disintegration time of Example 1-4 was less than 5 minutes.
  • Dissolution profile of Example 1-4 was found to be similar (more than 85% of drug release in 30 minutes) to the dissolution profile of reference composition (Latuda ® Tablets) by using Reverse Phase High Performance Liquid Chromatography (HPLC) at wave length of 230nm.
  • HPLC Reverse Phase High Performance Liquid Chromatography

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale solide comprenant de la lurasidone ou ses sels, esters, solvates, polymorphes, stéréoisomères pharmaceutiquement acceptables, ou des mélanges de ceux-ci, ladite composition étant sensiblement exempte de liant. L'invention concerne également des procédés de préparation desdites compositions, qui comprennent de la lurasidone.
PCT/IN2016/050079 2015-03-05 2016-03-04 Compositions pharmaceutiques de lurasidone et son procédé de préparation WO2016139683A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN618/DEL/2015 2015-03-05
IN618DE2015 2015-03-05

Publications (2)

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WO2016139683A2 true WO2016139683A2 (fr) 2016-09-09
WO2016139683A3 WO2016139683A3 (fr) 2016-10-27

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018130943A1 (fr) * 2017-01-11 2018-07-19 Piramal Enterprises Limited Composition pharmaceutique orale de lurasidone et sa préparation
CN113081983A (zh) * 2021-04-19 2021-07-09 北京阳光诺和药物研究股份有限公司 一种鲁拉西酮舌下片及其制备方法
AT17300U2 (de) * 2020-12-03 2021-12-15 G L Pharma Gmbh Feste orale pharmazeutische Zusammensetzung
WO2023078366A1 (fr) * 2021-11-04 2023-05-11 上海博志研新药物技术有限公司 Composition de film orale soluble de chlorhydrate de lurasidone, procédé de préparation et utilisation associés

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1327440T5 (da) * 2000-09-22 2009-09-07 Dainippon Sumitomo Pharma Co Orale pr parater med gunstige nedbrydningsegenskaber
DK1884242T3 (da) * 2005-05-26 2013-05-06 Dainippon Sumitomo Pharma Co Farmaceutisk sammensætning omfattende lurasidon
US9433620B2 (en) * 2011-05-13 2016-09-06 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone
US20140343076A1 (en) * 2013-05-17 2014-11-20 Cadila Healthcare Limited Pharmaceutical compositions of lurasidone

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018130943A1 (fr) * 2017-01-11 2018-07-19 Piramal Enterprises Limited Composition pharmaceutique orale de lurasidone et sa préparation
US11260055B2 (en) 2017-01-11 2022-03-01 Piramal Enterprises Limited Oral pharmaceutical composition of lurasidone and preparation thereof
AT17300U2 (de) * 2020-12-03 2021-12-15 G L Pharma Gmbh Feste orale pharmazeutische Zusammensetzung
AT17300U3 (de) * 2020-12-03 2022-02-15 G L Pharma Gmbh Feste orale pharmazeutische Zusammensetzung
CN113081983A (zh) * 2021-04-19 2021-07-09 北京阳光诺和药物研究股份有限公司 一种鲁拉西酮舌下片及其制备方法
CN113081983B (zh) * 2021-04-19 2022-09-06 北京阳光诺和药物研究股份有限公司 一种鲁拉西酮舌下片及其制备方法
WO2023078366A1 (fr) * 2021-11-04 2023-05-11 上海博志研新药物技术有限公司 Composition de film orale soluble de chlorhydrate de lurasidone, procédé de préparation et utilisation associés

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