WO2007012968A2 - Forme dosifee stable d'un antidepresseur - Google Patents

Forme dosifee stable d'un antidepresseur Download PDF

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Publication number
WO2007012968A2
WO2007012968A2 PCT/IB2006/002158 IB2006002158W WO2007012968A2 WO 2007012968 A2 WO2007012968 A2 WO 2007012968A2 IB 2006002158 W IB2006002158 W IB 2006002158W WO 2007012968 A2 WO2007012968 A2 WO 2007012968A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
excipients
lactose
sodium
paroxetine hydrochloride
Prior art date
Application number
PCT/IB2006/002158
Other languages
English (en)
Other versions
WO2007012968A3 (fr
Inventor
Viswaprasad Varanasi
Haranatha Babu Balanagu
Hidaytulla Shamshuddin Aga
Kishor Dattatray Deo
Sivakumaran Meenakshisunderam
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 WO2007012968A2 publication Critical patent/WO2007012968A2/fr
Publication of WO2007012968A3 publication Critical patent/WO2007012968A3/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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a stable solid dosage form comprising an anti-depressant compound. More particularly, the present invention relates to a stable solid dosage form comprising paroxetine HCl hemihydrate prepared by wet granulation process comprising lactose.
  • Paroxetine disclosed in U.S Pat. No 4,007,196, is a serotonin re- uptake inhibitor useful for the treatment of psychiatric problems including depression, parkinson's disease, anxiety disorders, obsessive-compulsive disorders, panic disorder and post-traumatic stress disorder.
  • paroxetine is (-)-trans-3-[(l,3-benzodioxol-5- yloxy)methyl]-4-(4-fluorophenyl)piperidine and is commercially marketed under the trade name Paxil ® in the US and Seroxat ® in other countries by
  • paroxetine tablets contain paroxetine HCl hemihydrate as active ingredient and excipients such as dibasic calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
  • the commercially available tablets are prepared by wet granulation using water as solvent, where in paroxetine HCl, dibasic calcium phosphate dihydrate, sodium starch glycolate/ magnesium stearate, and hydroxypropyl methyl cellulose were granulated with water and lubricated with sodium starch glycolate/ magnesium stearate and finally film coated with opadry.
  • the tablets prepared by wet granulation using water exhibited a color change i.e., formation of pink hue, which is highly undesirable.
  • US '944 patent teaches the preparation of paroxetine tablets using processes such as dry granulation and direct compression without using water. However, using these methods there is less flexibility in excipient selection and possibility of formation of hard tablets.
  • US 2003/0144324 describes oral pharmaceutical dosage form comprising paroxetine hydrochloride, a binder selected from the group consisting of povidone and copovidone, and filler that is HCl free or non- hygroscopic. It is disclosed that paroxetine hydrochloride tablets are particularly susceptible to becoming soft during storage, especially under accelerated aging conditions. In order to improve the hardness of the tablet povidone and copovidone are used as binders. It is further disclosed that an effective amount of povidone stabilizes the anhydrous form by preventing water molecules from incorporating into a paroxetine hydrochloride anhydrous crystal to yield a hemihydrate crystal.
  • US '324 does not disclose about the stabilization of paroxetine hydrochloride hemihydrate with povidone.
  • WO 2005/034954 describes composition of paroxetine prepared by wet granulation, using microcrystalline cellulose and other excipients.
  • WO 02/069969 discloses use of microcrystalline cellulose as a filler and copovidone as binder, and discloses that the microcrystalline cellulose is the perfect excipient.
  • the above prior art references discloses apart from dry granulation and direct compression, wet granulation process using water or organic solvent and using excipients such as microcrystalline cellulose, povidone, copovidone.
  • Microcrystalline cellulose, povidone and copovidone being hygroscopic can absorb varying amounts of moisture at low relative humidities. Further, microcrystalline cellulose is an insoluble excipient where as lactose is a water-soluble excipient and is preferred over microcrystalline cellulose.
  • lactose as diluent provided tablets which have an excellent hardness and breaking load, with release properties similar to the marketed dosage form. Further, the problem of pink hue development as seen in the Paxil® tablets prepared by wet granulation process is surprisingly not observed.
  • the main objective of present invention is to provide a stable solid dosage form of paroxetine hydrochloride hemihydrate.
  • Yet another objective of the present invention is to provide a solid dosage form of paroxetine hydrochloride hemihydrate 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, and etc.
  • Yet another objective of the present invention is to provide process for preparing stable solid dosage form of paroxetine.
  • a stable solid dosage form comprising paroxetine hydrochloride hemihydrate, lactose, and one or more pharmaceutically acceptable excipients prepared by wet granulation process, wherein the excipients are not microcrystalline cellulose, povidone, and copovidone.
  • the present invention provides stable dosage form of paroxetine hydrochloride hemihydrate, which does not develop pink hue upon storage.
  • the excipients used are selected from diluents, binders, disintegrants, and lubricants.
  • the wet granulation is always preferred over dry or direct compression, since uniform distribution of the active substance within the bulk granulates is achieved without difficulty and also flexibility in selection of excipients.
  • the stable dosage form of paroxetine hydrochloride hemihydrate comprises excipients selected from about 70% to about 95% of diluent, about 1.5% to about 5% of disintegrant, about 2.5% to about 7.5% of binder and about 0.5% to about 3% of lubricant wherein the tablet is prepared by wet granulation using, aqueous, nonaqueous solvents or mixture thereof.
  • Suitable diluents of the present invention include lactose, sucrose, calcium phosphate-dibasic, calcium silicate, starch, polyols such as mannitol, sorbitol, xylitol, maltitol, or combination thereof.
  • Suitable disintegrating agents used in accordance with the present invention are selected from crosscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, alginates, polacrilin potassium, and the like or combination thereof.
  • Suitable binders of the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, gelatin, alginates, methylcellulose or starch.
  • Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, hydrogenated vegetable oil, stearic acid, calcium stearate, glyceryl behenate, sodium lauryl sulfate, talc and the like.
  • paroxetine hydrochloride hemihydrate compositions of the present invention are stable and do not substantially loose its hardness after storage at a temperature of about 80 0 C and a relative humidity of at least about 75% for at least about 24 hours.
  • the dosage form of the present invention includes tablets, capsules and powder for oral suspension.
  • the tablets may be uncoated or optionally coated with film forming materials such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, talc, colloidal silica, sodium stearyl fumarate and the like.
  • a process for preparing stable solid dosage form comprising paroxetine hydrochloride hemihydrate, lactose, and one or more pharmaceutically acceptable excipients prepared by wet granulation process, wherein the excipients are not microcrystalline cellulose, povidone, and copovidone, comprises the steps of: i) blending paroxetine hydrochloride hemihydrate with lactose, filler, and disintegrant, ii) granulating the blend of step (i) using aqueous or non-aqueous solvent or mixture thereof, iii) drying the granules obtained in step (ii) at 40 0 C, iv) blending the dried granules with extragranular excipients, v) lubricating the blended granules of step (iv) and vi) compressing the lubricated blend into tablets or filled into capsules.
  • aqueous or non-aqueous solvents used according to the present invention are selected from water, isopropyl alcohol, ethanol, acetone, methylene chloride and the like or mixture thereof.
  • the present invention also provides method of treating depression, mixed anxiety and depression, obsessive compulsive disorders, panic disorder, obesity, senile dementia, migraine, bulimia, anorexia, social phobia and the depression arising from premenstrual tension and adolescence by administering the stable solid dosage form of the present invention.
  • paroxetine hydrochloride, dibasic calcium phosphate, lactose, and sodium starch glycolate were sifted and blended, ii) granulated the blended material of step (i) with water or water/ethanol mixture and dried the granulated mass at 40 0 C, iii) dried granules were blended with extragranular dibasic calcium phosphate and sodium starch glycolate for 15 min, iv) lubricated the blended granules of step (iv) with magnesium stearate for 5 min., v) compressed the lubricated blend into tablets, and vi) finally the tablets were coated with film forming materials.
  • paroxetine hydrochloride, dibasic calcium phosphate, lactose, and sodium starch glycolate were sifted and blended
  • binder solution of low viscosity hydroxypropyl cellulose in water or water/ethanol mixture was prepared
  • granulated the blended material of step (i) with binder solution of step (ii) and dried the granulated mass at 4O 0 C iv) dried granules were blended with extragranular dibasic calcium phosphate and sodium starch glycolate for 15 min
  • vii) finally the tablets were coated with film forming materials.
  • paroxetine hydrochloride, dibasic calcium phosphate, lactose, and sodium starch glycolate were sifted and blended, ii) granulated the blended material of step (i) with water and dried the granulated mass at.40 0 C, iii) dried granules were blended with extragranular dibasic calcium phosphate and sodium starch glycolate for 15 min, iv) lubricated the blended granules of step (iv) with magnesium stearate for 5 min., v) compressed the lubricated blend into tablets, and
  • Table 1 given below shows the dissolution profile of paroxetine tablets carried out in Simulated gastric fluid without enzymes as medium according to the procedure described in the USP, Apparatus USP 11/900 ml, Paddle, @ 60 rpm speed.
  • the release profile (% of drug released in minutes) is given in table 1.
  • Stability Data Tablets of examples 5 and 6 were stored at 40°C/75%RH, for one, two, three and six months and then tested by an HPLC method to determine the amount of paroxetine hydrochloride hemihydrate. The data is given in table 2.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à une forme dosifiée stable renfermant un composé antidépresseur. Cette invention porte en particulier sur une forme dosifiée solide stable comprenant un semi-hydrate d'hydrochlorure de paroxétine préparée par un procédé de granulation par voie humide utilisant de la lactose.
PCT/IB2006/002158 2005-07-29 2006-07-25 Forme dosifee stable d'un antidepresseur WO2007012968A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1039/CHE/2005 2005-07-29
IN1039CH2005 2005-07-29

Publications (2)

Publication Number Publication Date
WO2007012968A2 true WO2007012968A2 (fr) 2007-02-01
WO2007012968A3 WO2007012968A3 (fr) 2007-05-31

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ID=37683713

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/002158 WO2007012968A2 (fr) 2005-07-29 2006-07-25 Forme dosifee stable d'un antidepresseur

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WO (1) WO2007012968A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102525966A (zh) * 2010-12-13 2012-07-04 江苏万全特创医药生物技术有限公司 一种含有帕罗西汀的片剂及其制备方法
CN109771381A (zh) * 2017-11-13 2019-05-21 北京万生药业有限责任公司 一种帕罗西汀药物制剂

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158230A1 (en) * 2001-12-28 2003-08-21 Rakefet Cohen Stable pharmaceutical formulation of paroxetine hydrochloride and a process for preparation thereof
WO2004091617A1 (fr) * 2003-04-17 2004-10-28 Glaxo Group Limited Combinaison de paroxetine et de 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl)-(2s-phenyl-piperidin-3s-yl)-amine dans le traitement de la depression et/ou de l'anxiete
WO2005034954A2 (fr) * 2003-10-08 2005-04-21 Ranbaxy Laboratories Limited Compositions pharmaceutiques de paroxetine
WO2006023347A1 (fr) * 2004-08-20 2006-03-02 Alpharma, Inc. Formulations à base de paroxétine
US20060216345A1 (en) * 2005-03-24 2006-09-28 Sun Pharmaceutical Industries Limited Oral pharmaceutical composition including paroxetine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158230A1 (en) * 2001-12-28 2003-08-21 Rakefet Cohen Stable pharmaceutical formulation of paroxetine hydrochloride and a process for preparation thereof
WO2004091617A1 (fr) * 2003-04-17 2004-10-28 Glaxo Group Limited Combinaison de paroxetine et de 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl)-(2s-phenyl-piperidin-3s-yl)-amine dans le traitement de la depression et/ou de l'anxiete
WO2005034954A2 (fr) * 2003-10-08 2005-04-21 Ranbaxy Laboratories Limited Compositions pharmaceutiques de paroxetine
WO2006023347A1 (fr) * 2004-08-20 2006-03-02 Alpharma, Inc. Formulations à base de paroxétine
US20060216345A1 (en) * 2005-03-24 2006-09-28 Sun Pharmaceutical Industries Limited Oral pharmaceutical composition including paroxetine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102525966A (zh) * 2010-12-13 2012-07-04 江苏万全特创医药生物技术有限公司 一种含有帕罗西汀的片剂及其制备方法
CN109771381A (zh) * 2017-11-13 2019-05-21 北京万生药业有限责任公司 一种帕罗西汀药物制剂

Also Published As

Publication number Publication date
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