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EP2134325A2 - Formes posologiques solides stables d'un antidépresseur - Google Patents

Formes posologiques solides stables d'un antidépresseur

Info

Publication number
EP2134325A2
EP2134325A2 EP08709891A EP08709891A EP2134325A2 EP 2134325 A2 EP2134325 A2 EP 2134325A2 EP 08709891 A EP08709891 A EP 08709891A EP 08709891 A EP08709891 A EP 08709891A EP 2134325 A2 EP2134325 A2 EP 2134325A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
escitalopram
starch
stabilizer
sodium
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08709891A
Other languages
German (de)
English (en)
Inventor
Krishna Murthy Bhavanasi
Venkata Ram Mohan Rao Visinigiri
Manoj Kanti Saha
Nagaprasad Vishnubhotla
Sivakumaran Meenakshisunderam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of EP2134325A2 publication Critical patent/EP2134325A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/2009—Inorganic compounds
    • 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 a stable solid dosage form comprising an anti-depressant. More particularly, the present invention relates to stable solid dosage form of escitalopram or its salts.
  • the present invention also relates to a process for the preparation of stable solid dosage form of escitalopram or its salts.
  • Citalopram is a selective, centrally active serotonin reuptake inhibitor. Citalopram hydrobromide was first disclosed in US 4, 136, 193. This patent also describes the manufacture of tablets containing salts of citalopram.
  • Citalopram hydrobromide has been approved by USFDA in 1998. Subsequent to this, the S-enantiomer of citalopram (escitalopram) was shown to have better activity profile and has been approved by FDA in 2002.
  • Escitalopram is an orally administered selective serotonin reuptake inhibitor (SSRI), and is indicated for the treatment of depression.
  • Escitalopram is marketed as oxalate salt under the trade name LEXAPROTM. Chemically, Escitalopram is (+)-l-(3-dimethylaminopropyl)- l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile.
  • Escitalopram oxalate was disclosed in US 4,943,590, reissued as US RE 34,712. This patent also describes the manufacture of tablets containing salts of Escitalopram.
  • Escitalopram is a poorly soluble drug and hence poses serious dissolution problems, which may affect bioavailability.
  • Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the manufacturing process, compression forces (in tablet manufacturing), the surface area available for dissolution etc.
  • the escitalopram oxalate product prepared by crystallization from acetone as outlined in US 4,943,590 has a very small particle size around 2- 20 microns resulting in poor flow properties.
  • US 2005/0196453 discloses crystalline particles of escitalopram oxalate, characterized in that the ratio between the median particle size and the particle size at the 95% quantile is less than 0.42 and the tablets prepared by direct compression method.
  • the main objective of the present invention is to provide stable solid dosage form of escitalopram or its salts, which comply with the reference product in terms of stability, in vivo parameters like C max , t ma ⁇ and AUC and in vitro parameters like dissolution, disintegration.
  • Yet another objective of the present invention is to provide simple and efficient process for preparing stable solid dosage form of escitalopram or its salts, on a commercial scale.
  • a stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients.
  • the salt of escitalopram used according to present invention includes oxalate, hydrobromide and hydrochloride.
  • the stabilizer used according to present invention is an antioxidant selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoulene (BHT), alpha tocopherol, ascorbic acid, ascorbyl palmiate, benzoic acid, cysteine hydrochloride, isoascorbic acid, propionic acid, monothioglycerol and sodium metabisulfite and the like or mixtures thereof.
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxytoulene
  • alpha tocopherol alpha tocopherol
  • ascorbic acid ascorbyl palmiate
  • benzoic acid cysteine hydrochloride
  • isoascorbic acid propionic acid
  • the amount of stabilizer(s) used in the dosage form may range from about 0.01% to about 10% w/w, and preferably from about 0.02% to about 5% w/w.
  • Escitalopram may undergo oxidation during storage thereby produces oxocitalopram.
  • the quantity of oxocitalopram may increase during long-term storage which is not acceptable.
  • Antioxidants such as BHA and BHT react with the free radicals and decrease the rate of oxidation.
  • the pharmaceutically acceptable excipients include binders, diluents, disintegrants, lubricants and/or glidants and the like.
  • the preferable stable solid dosage form according to present invention comprises about 5% to about 20% w/w of escitalopram or its salts, about 70% to about 90% w/w of diluent, about 1% to about 5% w/w of disintegrant, about 0.01% to about 5% w/w of stabilizer, about 0.1 % to about 5% w/w of glidant and about 1 % to about 5% w/w of lubricant.
  • the diluents used according to the present invention are selected from dibasic calcium phosphate, calcium carbonate, lactose, sucrose, cellulose microcrystalline. cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, polyols such as mannitol, sorbitol, xylitol, maltitol or combination thereof.
  • Suitable disintegrants used in accordance with the present invention are selected from croscarmellose sodium, crospovidone, carboxy methyl cellulose sodium, sodium starch glycolate, starch, pregelatinised starch and the like or combination thereof.
  • Suitable binders according to the present invention are selected from methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gelatin, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth, sodium alginate and the like.
  • Suitable lubricants according to the present invention are selected from sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, zinc stearate and suitable glidants include colloidal silicon dioxide and talc.
  • the particle size of the escitalopram oxalate used according to present invention is in the range of 2 to 100 ⁇ m, preferably less than 20 ⁇ m.
  • the preferable stable solid dosage form of the present invention comprises about 5% to about 20% w/vv of escitalopram or its salts, about 70% to about 90% w/w of diluent selected from silicified microcrystalline cellulose, microcrystalline cellulose, lactose, mannitol or combination thereof, about 1% to about 5% w/w of disintegrant selected from croscarmellose sodium, crospovidone and sodium starch glycolate, about 0.01 % to about 5% w/vv of stabilizer selected from butylated hydroxy anisole, burylated hydroxytoulene and alpha tocopherol or combination thereof, about 0.1 % to about 5% w/w of glidant selected from colloidal silicon dioxide and talc or combination thereof and about 1 % to about 5% w/w of lubricant selected from magnesium stearate and sodium stearyl fumarate.
  • diluent selected from silicified microcrystalline cellulose, microcrystalline cellulose, lac
  • the solid dosage form of the present invention is in the form of tablet or gelatin capsule or processed into granules for oral suspension.
  • the tablets of the present invention include uncoated tablets, tablets coated with film forming polymers such as hydroxypropylmethylcellulose, ethyl cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide and the like.
  • a method of treating depression comprising administering to patients in need thereof a dosage form of escitalopram or its salts of the present invention.
  • the stable solid dosage form of escitalopram or its salts may be prepared by direct compression, wet granulation or dry granulation.
  • a process for the preparation of a stable solid dosage form comprising escitalopram or its salts, stabilizer and one or more pharmaceutically acceptable excipients, which comprises the steps of: i) mixing escitalopram with one or more excipients, ii) dissolving the stabilizer in the solvent and granulating the blend obtained in step (i), iii) drying the granules obtained in step (ii), iv) mixing the granules of step (iii) with one or more pharmaceutically acceptable excipients, v) lubricating the blend of step (iv) and vi) compressing the blend of step (v) into tablets.
  • Suitable solvents used for granulation are selected from water or organic solvents such as acetone, alcohol, isopropyl alcohol dichloromethane and the like or mixture thereof.
  • Example 1 (Escitalopram oxalate tablets with stabilizers)
  • step (iii) granulated the blend obtained in step (ii) with water, (iii) the granules of step (iii) were blended with microcrystalline cellulose and colloidal silicondioxide,
  • step (iv) lubricated blend of the step (iv) with talc and magnesium stearate, (v) compressed the blend of step (iv) into tablets and (vi) tablets of step (v) were then coated with a solution / suspension of opadry in water.
  • Stability Data Tablets prepared according to examples 3-5 were stored at 40°C/75%RH. for two months and then tested by an HPLC method to determine the amount of oxocitalopram. The stability data is given in table 2.

Landscapes

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

Abstract

La présente invention porte sur une forme posologique solide stable comprenant un antidépresseur. Plus particulièrement, la présente invention porte sur une forme posologique solide stable d'escitalopram ou de ses sels. La présente invention porte également sur un procédé pour la préparation d'une forme posologique solide stable d'escitalopram ou de ses sels.
EP08709891A 2007-03-01 2008-02-28 Formes posologiques solides stables d'un antidépresseur Withdrawn EP2134325A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN424CH2007 2007-03-01
PCT/IB2008/000600 WO2008104880A2 (fr) 2007-03-01 2008-02-28 Formes posologiques solides stables d'un antidépresseur

Publications (1)

Publication Number Publication Date
EP2134325A2 true EP2134325A2 (fr) 2009-12-23

Family

ID=39721657

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08709891A Withdrawn EP2134325A2 (fr) 2007-03-01 2008-02-28 Formes posologiques solides stables d'un antidépresseur

Country Status (2)

Country Link
EP (1) EP2134325A2 (fr)
WO (1) WO2008104880A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104523638B (zh) * 2014-11-28 2020-02-21 浙江华海药业股份有限公司 含有草酸艾司西酞普兰的片剂及其制备方法
CN106176691A (zh) * 2016-08-31 2016-12-07 齐鲁制药有限公司 一种草酸艾司西酞普兰口溶膜剂及其制备方法
CN106860410A (zh) * 2017-03-17 2017-06-20 万全万特制药江苏有限公司 一种草酸艾司西酞普兰口崩片及其制备方法
WO2018190294A1 (fr) * 2017-04-10 2018-10-18 東和薬品株式会社 Composition médicinale comprenant de l'escitalopram
KR102089737B1 (ko) 2017-11-01 2020-03-16 한국화학연구원 에씨탈로프람을 함유한 미립구형 서방출 주사제 및 그의 제조방법
JP2023018887A (ja) * 2021-07-28 2023-02-09 共和薬品工業株式会社 エスシタロプラムシュウ酸塩含有錠剤

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8814057D0 (en) * 1988-06-14 1988-07-20 Lundbeck & Co As H New enantiomers & their isolation
US20050250838A1 (en) * 2004-05-04 2005-11-10 Challapalli Prasad V Formulation for sustained delivery
WO2006123243A2 (fr) * 2005-05-20 2006-11-23 Aurobindo Pharma Limited Formes galeniques pharmaceutiques d'un antidepresseur
TWI347942B (en) * 2005-06-22 2011-09-01 Lundbeck & Co As H Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008104880A3 *

Also Published As

Publication number Publication date
WO2008104880A2 (fr) 2008-09-04
WO2008104880A3 (fr) 2008-11-20

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