EP2403500A2 - Comprimés d'olanzapine stables et leur procédé de préparation - Google Patents

Comprimés d'olanzapine stables et leur procédé de préparation

Info

Publication number
EP2403500A2
EP2403500A2 EP10748416A EP10748416A EP2403500A2 EP 2403500 A2 EP2403500 A2 EP 2403500A2 EP 10748416 A EP10748416 A EP 10748416A EP 10748416 A EP10748416 A EP 10748416A EP 2403500 A2 EP2403500 A2 EP 2403500A2
Authority
EP
European Patent Office
Prior art keywords
tablets
olanzapine
stable
blend
microcrystalline cellulose
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Withdrawn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
EP10748416A
Other languages
German (de)
English (en)
Other versions
EP2403500A4 (fr
Inventor
Deepak Murpani
Alexaki Pandora
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.)
Genepharm India Private Ltd
Original Assignee
Genepharm India Private 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 Genepharm India Private Ltd filed Critical Genepharm India Private Ltd
Publication of EP2403500A2 publication Critical patent/EP2403500A2/fr
Publication of EP2403500A4 publication Critical patent/EP2403500A4/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Withdrawn legal-status Critical Current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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to stable olanzapine tablets and the process for its preparation; wherein the said tablets are stable to color, chemical degradation and polymorphic changes.
  • the chemical name of olanzapine is 2-methyl-4-(4-methyl-l- piperazinyl)-10H-thieno [2, 3-6] [15] benzodiazepine.
  • Olanzapine is an antagonist of 15 dopamine at D-I and D-2 receptors and. in addition, it has antimuscarinic, anticholinergic properties and antagonist activities at 5HT-2 receptor sites, with antagonist activity at noradrenergic ⁇ - receptors. The compound is useful in treating psychotic conditions such as schizophrenia, acute mania and mild anxiety states.
  • European Patent Number 454436B1 discloses pharmaceutical composition of olanzapine using conventional techniques.
  • the active ingredient is mixed with a carrier such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, 25 calcium phosphate, alignates, tragacanth, gelatin, syrup, methyl cellulose, microcrystalline cellulose, methyl and propyl- hydroxy benzoate, povidone, talc, aluminum stearate, magnesium stearate or mineral oil and converted to a suitable pharmaceutical composition.
  • a carrier such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, 25 calcium phosphate, alignates, tragacanth, gelatin, syrup, methyl cellulose, microcrystalline cellulose, methyl and propyl- hydroxy benzoate, povidone, talc, aluminum stearate, magnesium stearate or mineral oil and converted to
  • Coated formulations of olanzapine are also prepared in European Patent Publication Number 1231903 assigned to M/S Biochemie and PCT publication 2005009407.
  • Coated and uncoated formulation of olanzapine is known in the art as techniques like wet granulaton are not suitable due to problems of stability.
  • Direct compression is widely used for moderate dose active (API) as a process of choice. It involves simple mixing of active with other excipients followed by compression to tablets. However, the tablets produced by DC may possess problems of poor content uniformity. Taste masking and chemical compatability are often compromised as active is present as primary particles and completely exposed to saliva of oral cavity and also to all the excipients of tablet.
  • Lyophilised tablets e,g, Zyprexa Velotab are produced by a complex, time intensive and costly process involving freeze drying of suspension of drug/ excipients in preformed blister. This requires a dedicated facility.
  • Coating of active with tastemasking polymers is also conventionally used to improve taste and stability characteristics of API, however it is a critical and lengthy process and the taste masked granules often provide grittiness, roughness and poor content uniformity problems.
  • the object of the invention is to provide stable olanzapine tablets.
  • the tablets of the present invention are without coating.
  • the tablets are stable to color, chemical degradation and polymorphic changes for 3 months at 40 0 C / 75% relative humidity in open vials.
  • Also provided herewith is a simple process for the preparation of stable olanzapine tablets.
  • olanzapine e.g.calcium carbonate, microcrystalline cellulose
  • Taste masking can be achieved by compaction with saliva insoluble fillers which have good solubility or swellability in GIT fluids.
  • Stable olanzapine tablets comprising compacted blend of olanzapine and at least one pharmaceutical excipient; mixed with extragranular blend of diluent(s), disintegrant(s), lubricant(s) and optional sweetener(s); wherein the said tablets are stable to color, chemical degradation and polymorphic changes for 3 months at 40 0 C / 75% relative humidity in open vials.
  • the tablets of the present invention can be prepared by a simple process such as compaction of granules with olanzapine with at least one pharmaceutical excipient.
  • the stable olanzapine tablets prepared according to one embodiment of the present invention are stable to color, chemical degradation and polymorphic changes for 3 months at 40 0 C / 75% relative humidity in open vials.
  • stable as used herein is intended to encompass stability with respect to color, chemical degradation and polymorphic changes.
  • the chemical degradation impurity is ⁇ 0.5% by HPLC.
  • the formulations of the present invention may contain anhydrous fo ⁇ ns of olanzapine, which are disclosed e.g. in European Patent Number 733635 Bl , therein designated as Form I and Form II; in United States Patent Number 6,348,458, therein designated as Form III, Form IV, Form V; in United States Patent Number 2002/086993 Al, therein designated as form X. Also useful are hydrates of olanzapine which are disclosed e.g. in European Patent Number 0831098 Bl, therein designated as forms B, D, E; in PCT publication Number 02/18390A, therein designated as monohydrate I and dihydrate I.
  • a process for the preparation of stable olanzapine tablets comprises compaction, miling, mixing and compression.
  • Olanzapine tablets prepared by process comprising compacting olanzapine with atleast one pharmaceutical excipient, milling and mixing with extragranular blend of pharmaceutical excipients selected from diluents(s), lubricant(s), disintegrant(s), optional sweetener(s) are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 40 0 C / 75% relative humidity in open vials.
  • Compaction of olanzapine and at least one pharmaceutical excipient is a key step in the process of the present invention.
  • Olanzapine is effective over a wide dosage range, the actual dose administered depending on the condition treated. For example, in the treatment of adult humans, dosages of from 0.25 to 50 mg per day may be used. A once-daily dosage is normally sufficient, although divided doses may be administered. Preferred tablets of the invention thus comprise 0.25 to 50 mg of olanzapine. The preferred weight of the tablets is 50 to 1000 mg,
  • the pharmaceutical excipient may be selected from directly compressible calcium carbonate, dibasic calcium phosphate, microcrystalline cellulose tribasic calcium phosphate, celluloses, cellulose based polymers, starches and the like.
  • the ratio of olanzapine to pharmaceutical excipient may be in the range of 1 : 1 to 1 : 10.
  • Calcium carbonate when included in orally- administered solid pharmaceutical products, such as tablets, the tablets readily disintegrates in the mouth, and thus eliminates the need for swallowing the tablets in order to release the active pharmaceutical ingredient. It accelerates rapid disintegration of the tablets when the tablets contacts water and is used in conjunction with a super disintegrant.
  • the compacts of olanzapine and at least one pharmaceutical excipient obtained on compaction may be subjected to milling.
  • Granules obtained may have an average diameter of less than microns.
  • the granules may be mixed with extragranular blend comprising pharmaceutical excipients such as diluent(s), lubricant(s), disintegrate(s), binder(s), flavoring agent(s), coloring agent(s), stabilizer(s), surfactant(s), glidant(s), plasticizer(s), preservative(s) and sweetener(s).
  • pharmaceutical excipient must be compatible with olanzapine.
  • the amounts of excipients used in the formulation are for the diluent from 20 to 90 %, for the disintegrant up to 20 %, for the binder from 1 to 20 %, for the lubricant from 0.25 to 5 %, for the sweetener from 0.1% to 3%.
  • Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.
  • Binders may be selected from acacia, alginic acid, carbomer,carboxymethylcellulose calcium, carbomethylcellulose sodium,microcrystalline cellulose,powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, ploydextrose, polyethtylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose,glucose, sorbitol,
  • Suitable fillers are preferably selected from at least one of starch derivatives, such as corn starch, potato starch or rice starch, Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
  • starch derivatives such as corn starch, potato starch or rice starch
  • Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose
  • polyhydric alcohols such as xylitol and sorbitol.
  • Disintegrants may be selected from alginic acid, carbon dioxide, carbonxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose.
  • Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.
  • Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
  • Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.
  • Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavor.
  • the mixture obtained on mixing granules comprising olanzapine with at least one pharmaceutical excipient with extragranular blend is then compressed into tablets using conventional compression techniques known to a person skilled in the art.
  • Tablets of the present invention may be soluble tablet, rapidly disintegrating tablet, orally disintegrating tablet, effervescent tablet, chewable tablet, water dispersible tablet and orodispersible tablet.
  • N-Oxide is 2-methyl-4-(4-methyl-4-oxido-l-piperazinyl)-10H-thieno [2,3b][l,5] benzodiazepine (b) Visual inspection of 3 months 40 0 C / 75% relative humidity open vial samples indicates no change in color.
  • Example 5 Test for content uniformity (as per PhEur ⁇ 2.9.40) The acceptance values for Olanzapine pilot 1 , 5/10/15/20mg tablets
  • step 3 Pass the compacts of step 2 through 12-20 mesh screen to acieve granules and pass resulting granules through 30-50 mesh screen of mechanical mill, wherein at least 95% passes through 40# BSS sieve.
  • step 4 In a low shear mixer add the granules prepared in step 3 and mix for suitable time. Pass the granules through 12-20 mesh sieve along with the excipients crospovidone, lactose SD and aspartame. Add the sieved material to a low shear mixer and mix for appropriate time.
  • step 6 The homogeneous powder of step 5 is compressed into tablets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des comprimés d'olanzapine stables comprenant un mélange compacté d'olanzapine et d'au moins un excipient pharmaceutique ; mélangé avec un mélange extragranulaire d'un ou de plusieurs diluants, d'un ou de plusieurs désintégrants, d'un ou de plusieurs lubrifiants et d'un ou de plusieurs édulcorants facultatifs ; lesdits comprimés étant stables en termes de couleur, de dégradation chimique et à des changements polymorphes pendant au moins 3 mois à 40°C / 75 % d'humidité relative dans des flacons ouverts.
EP10748416.4A 2009-03-05 2010-03-05 Comprimés d'olanzapine stables et leur procédé de préparation Withdrawn EP2403500A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN481MU2009 2009-03-05
PCT/IN2010/000127 WO2010100658A2 (fr) 2009-03-05 2010-03-05 Comprimés d'olanzapine stables et leur procédé de préparation

Publications (2)

Publication Number Publication Date
EP2403500A2 true EP2403500A2 (fr) 2012-01-11
EP2403500A4 EP2403500A4 (fr) 2013-12-25

Family

ID=42710069

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10748416.4A Withdrawn EP2403500A4 (fr) 2009-03-05 2010-03-05 Comprimés d'olanzapine stables et leur procédé de préparation

Country Status (2)

Country Link
EP (1) EP2403500A4 (fr)
WO (1) WO2010100658A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014218472A (ja) * 2013-05-10 2014-11-20 エルメッド エーザイ株式会社 オランザピン乃至その塩含有錠剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009407A2 (fr) * 2003-07-29 2005-02-03 Ranbaxy Laboratories Limited Formulations pharmaceutiques d'olanzapine administrees par voie orale
WO2007134845A2 (fr) * 2006-05-18 2007-11-29 Synthon B.V. Composition pharmaceutique d'olanzapine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086343A2 (fr) * 2002-04-05 2003-10-23 Cadila Healthcare Limited Formes dosifiees orales se desintegrant rapidement
US20040121003A1 (en) * 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
JP4739217B2 (ja) * 2003-05-07 2011-08-03 サムヤン コーポレイション 速く溶ける錠剤を製造するための高可塑性顆粒
WO2005070938A1 (fr) * 2004-01-27 2005-08-04 Synthon B.V. Sels stables d'olanzapine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005009407A2 (fr) * 2003-07-29 2005-02-03 Ranbaxy Laboratories Limited Formulations pharmaceutiques d'olanzapine administrees par voie orale
WO2007134845A2 (fr) * 2006-05-18 2007-11-29 Synthon B.V. Composition pharmaceutique d'olanzapine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2010100658A2 *

Also Published As

Publication number Publication date
WO2010100658A2 (fr) 2010-09-10
WO2010100658A3 (fr) 2010-12-23
EP2403500A4 (fr) 2013-12-25

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