WO2010100658A2 - Stable olanzapine tablets and the process for its preparation - Google Patents

Stable olanzapine tablets and the process for its preparation Download PDF

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Publication number
WO2010100658A2
WO2010100658A2 PCT/IN2010/000127 IN2010000127W WO2010100658A2 WO 2010100658 A2 WO2010100658 A2 WO 2010100658A2 IN 2010000127 W IN2010000127 W IN 2010000127W WO 2010100658 A2 WO2010100658 A2 WO 2010100658A2
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Prior art keywords
tablets
olanzapine
stable
blend
microcrystalline cellulose
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PCT/IN2010/000127
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French (fr)
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WO2010100658A3 (en
Inventor
Deepak Murpani
Alexaki Pandora
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Genepharm India Private Limited
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Priority to EP10748416.4A priority Critical patent/EP2403500A4/en
Publication of WO2010100658A2 publication Critical patent/WO2010100658A2/en
Publication of WO2010100658A3 publication Critical patent/WO2010100658A3/en

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    • 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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Abstract

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 at least 3 months at 40°C / 75% relative humidity in open vials.

Description

STABLE OLANZAPINE TABLETS AND THE PROCESS FOR ITS
PJIEPARATION
i O
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 α- receptors. The compound is useful in treating psychotic conditions such as schizophrenia, acute mania and mild anxiety states.
20 BACKGROUND OF THE INVENTION
European Patent Number 454436B1, assigned to M/S Eli Lilly, 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.
30 Formulations of coated olanzapine are exemplified in European Patent Number 733367, Bl assigned to M/S Eli Lilly. Olanzapine being moisture sensitive and metastable in nature, the patentees have observed that coating olanzapine with a polymer prevents the undesired discoloration. Further, the patentees believe that dry blend direct compression or dry granulated process for preparing solid oral formulation may create poor dose
35 uniformity. Coated formulations of olanzapine are also prepared in European Patent Publication Number 1231903 assigned to M/S Biochemie and PCT publication 2005009407.
'The" formulation presently on the market is coated in order to assure protection of the active substance from moisture and light.
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 (DC) 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.
We have surprisingly found stable olanzapine tablets and the process of its preparation using compaction as the key operation. This process does not create homogeneity or uniformity problems as anticipated by direct compression methods. OBJECT OF THE INVENTION
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 400C / 75% relative humidity in open vials. Also provided herewith is a simple process for the preparation of stable olanzapine tablets.
The advantages of the process of the present invention are 1. Compaction of olanzapine with one or more relatively protective excipient
(e.g.calcium carbonate, microcrystalline cellulose) can protect olanzapine from direct contact with relatively incompatible but crucial excipients like aspartame and crospovidone.
2. Taste masking can be achieved by compaction with saliva insoluble fillers which have good solubility or swellability in GIT fluids.
3. Due to the formation of granules prior to tablet compression the content uniformity/ segregation problems, sticking or compressibility problems are reduced considerably.
4. Color changes and color variations between tablets are avoided. 5. Less polymorphic changes as the operation is free of solvent or heat.
6. The process can be carried out with conventional infrastructure hence economically viable.
SUMMARY OF THE INVENTION
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 400C / 75% relative humidity in open vials. DESCRIPTION OF THE INVENTION
According to the present invention there is provided stable olanzapine tablets without any undesirable discoloration or poor dose uniformity and the process of its preparation. 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 400C / 75% relative humidity in open vials.
The term "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 foπns 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.
According to another embodiment of the present invention is provided a process for the preparation of stable olanzapine tablets. The process 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 400C / 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).The 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.
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.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
EXAMPLES Example 1
Figure imgf000009_0001
Analytical data (a) HPLC analysis
Figure imgf000009_0002
* op4 is 2-methyI-10H-thieno[2,3-b][l,5]benzodiazepine-4-one
*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 400C / 75% relative humidity open vial samples indicates no change in color.
(c) XRD analysis of 3 months 400C / 75% relative humidity open vial samples indicates retention of Form I.
Examples 2, 3 & 4
Figure imgf000010_0001
Example 5 ; Test for content uniformity (as per PhEur §2.9.40) The acceptance values for Olanzapine pilot 1 , 5/10/15/20mg tablets
Figure imgf000010_0002
Example 6:
Figure imgf000011_0001
Tabletting Process
1. Pass olanzapine through 12-20 mesh sieve. Pass calcium carbonate through 12-20 mesh sieve. Mix sieved olanzapine and calcium carbonate for appropriate time in a low shear mixer. Add magnesium stearate and mix for suitable time.
2. Compact the blend at suitable hardness.
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.
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.
5. Lubricate blend resulted from step 4 with magnesium stearate for appropriate time in low shear mixer.
6. The homogeneous powder of step 5 is compressed into tablets.

Claims

We Claim:
1. Stable olanzapine tablets comprising compacted blend of olanzapine and at least one pharmaceutical excipient; mixed with extragranular blend comprising diluent(s), disintegrant(s), lubricant(s) and optional sweetener(s); wherein the said tablets are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 400C / 75% relative humidity in open vials.
2. Stable olanzapine tablets as claimed in claim 1 wherein the tablets are not coated.
3. Stable olanzapine tablets as claimed in claim 1 wherein pharmaceutical excipient is selected from directly compressible calcium carbonate, dibasic calcium phosphate, microcrystalline cellulose, tribasic calcium phosphate, celluloses, cellulose based polymers and starches.
4. A process for the preparation of stable olanzapine tablets comprising compacting blend of olanzapine and at least one pharmaceutical excipient, milling compacts to granules, mixing granules with extragranular blend and compressing into tablets.
5. A process as claimed in claim 4 wherein the said tablets are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 400C / 75% relative humidity in open vials.
6. A process as claimed in claim 4 wherein the tablets are not coated.
7. A process as claimed in claim 4 wherein the pharmaceutical excipient is selected from directly compressible calcium carbonate, dibasic calcium phosphate, microcrystalline cellulose, tribasic calcium phosphate, celluloses, cellulose based polymers and starches.
8. A process as claimed in claim 4 wherein the extragranular blend comprises diluent(s), lubricant(s), disintegrant(s) and optional sweetener(s).
9. Stable olanzapine tablets comprising compacted blend of olanzapine, pharmaceutical excipient selected from directly compressible calcium carbonate or microcrystalline cellulose or dibasic calcium phosphate; mixed with extragranular blend of lactose, magnesium stearate, crospovidone or microcrystalline cellulose and aspartame, wherein the said tablets are stable to color, chemical degradation and polymorphic changes for at least 3 months at
400C / 75% relative humidity in open vials.
10. Stable olanzapine tablets-^s claimed in claim 9 wherein the tablets are not coated.
1 1. A process for the preparation of stable olanzapine tablets comprising compacting blend of olanzapine, directly compressible calcium carbonate or microcrystalline cellulose or dibasic calcium phosphate; milling the compacts to granules; mixing the granules with e\tragranular blend comprising lactose, magnesium stearate, crospovidone or microcrystalline cellulose and aspartame; and compressing into tablets.
12. A process as claimed in claim 1 1 wherein the said tablets are stable to color, chemical degradation and polymorphic changes for atleast 3 months at 400C /
75% relative humidity in open vials.
13. A process for preparing stable olanzapine tablets as claimed in claim 1 1 wherein the tablets are not coated.
PCT/IN2010/000127 2009-03-05 2010-03-05 Stable olanzapine tablets and the process for its preparation WO2010100658A2 (en)

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IN481/MUM/2009 2009-03-05
IN481MU2009 2009-03-05

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WO2005009407A2 (en) * 2003-07-29 2005-02-03 Ranbaxy Laboratories Limited Oral pharmaceutical formulations of olanzapine
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WO2010100658A3 (en) 2010-12-23
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