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WO2007049304A2 - Formulation pharmaceutique enrobee, stable, d'olanzapine et son procede de preparation - Google Patents

Formulation pharmaceutique enrobee, stable, d'olanzapine et son procede de preparation Download PDF

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Publication number
WO2007049304A2
WO2007049304A2 PCT/IN2006/000430 IN2006000430W WO2007049304A2 WO 2007049304 A2 WO2007049304 A2 WO 2007049304A2 IN 2006000430 W IN2006000430 W IN 2006000430W WO 2007049304 A2 WO2007049304 A2 WO 2007049304A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
solid oral
formulation according
oral pharmaceutical
olanzapine
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.)
Ceased
Application number
PCT/IN2006/000430
Other languages
English (en)
Other versions
WO2007049304A3 (fr
Inventor
Pavak Mehta
Piyush Gupta
Rajesh Bhaskar
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.)
Jubilant Organosys Ltd
Original Assignee
Jubilant Organosys 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 Jubilant Organosys Ltd filed Critical Jubilant Organosys Ltd
Publication of WO2007049304A2 publication Critical patent/WO2007049304A2/fr
Publication of WO2007049304A3 publication Critical patent/WO2007049304A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/2004—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

Definitions

  • This invention in general relates to the pharmaceutical formulation of olanzapine and process for preparing the same. More particularly, the present invention provides solid oral formulations of olanzapine having longer shelf life and color stability.
  • This invention provides an improved and stabilized pharmaceutically elegant solid oral coated formulation of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3- b][l,5]benzodiazepine, hereinafter referred to as olanzapine, and the process for the preparation thereof.
  • Olanzapine is indicated for the management of the manifestations of psychotic disorders and for the short-term treatment of acute manic episodes associated with Bipolar I disorder.
  • Olanzapine tends to be metastable, exhibits a pharmaceutically unacceptable change in color over time, when contacted with certain excipients including powder blends, and demands care to assure homogeneity of the finished solid formulation. Further this change in color is exacerbated by ambient air conditions, at elevated temperatures, and by moist environments. Such a pharmaceutical, which changes color over a period of time, could be particularly troublesome for psychotic patients if a dosage form, such as a tablet were to be chosen, where color changes are apparent.
  • U.S. Pat. No. 5,919,485 discloses a solid oral formulation that includes olanzapine.
  • the formulation is coated with a polymer selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrollidone, dimethylaminoethyl methacrylate, methyl acrylate acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, methyl cellulose, and ethyl cellulose.
  • the formulation contain the most stable anhydrous form of Olanzapine, Form II.
  • U.S. Pat. No. 6,190,698 discloses a solid oral formulation of olanzapine.
  • the formulation is coated with hydroxypropyl methyl cellulose.
  • the hydroxypropyl methyl cellulose is further coated with an aqueous dispersion film coat and the oral formulation is imprinted using an edible ink, thus incorporating further steps into the formulation and making the entire process expensive.
  • WO 2004/035027 discloses a pharmaceutical formulation comprising a homogenous mixture of (a) olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a monosaccharide and/or oligosaccharide, and (c) a polysaccharide.
  • a pharmaceutical formulation comprising a homogenous mixture of (a) olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a monosaccharide and/or oligosaccharide, and (c) a polysaccharide.
  • solvents and high compaction pressures used for wet granulation and dry granulation techniques respectively, thus limiting their process to direct compression only.
  • WO 2005/009407 discloses coating olanzapine as such in powder or agglomerate form, wherein the coating includes lactose and/or mannitol and optionally one or more excipients, thus leading to the incorporation of several steps in the preparation of a stable olanzapine formulation.
  • the oral formulations disclosed in the prior art demand further improvements in light of the moisture sensitive and metastable nature of olanzapine. Also, improved stable oral formulations were yet desired to overcome the tendency of olanzapine to undesirably exhibit color changes in tablet formulations along with the above-mentioned limitations.
  • the present invention provides a stabilized formulation of olanzapine, possessing marked improvement in color change over shelf life employing a selective polymer for coating, which overcomes the drawbacks of processes recited in prior arts.
  • a pharmaceutical formulation of olanzapine having longer shelf-life and color stability, wherein said formulation is coated employing selective polymer system.
  • a stable pharmaceutical formulation of olanzapine wherein, said formulation comprising effective amount of olanzapine as an active ingredient intimately mixed with pharmaceutically acceptable excipients selected from bulking agent, binder, disintegrant, or a lubricant.
  • stable pharmaceutical formulation of olanzapine wherein, said formulation is further stabilized by a coating comprising of one or more polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone / vinyl acetate copolymer, pullulan gum or zein or in selective combination thereof.
  • a stable pharmaceutical formulation of olanzapine wherein, said formulation comprising effective amount of olanzapine as an active ingredient intimately mixed with pharmaceutically acceptable excipients selected from bulking agent, binder, disintegrant, or a lubricant and wherein said formulation further stabilized by a coating employing a polymer selected from polyvinyl alcohol or hydroxypropyl methyl cellulose phthalate or in combination thereof.
  • a stable pharmaceutical formulation of olanzapine wherein, said formulation is used herein may be any suitable form such as granules, granules filled in capsules, granules compressed into tablets, tablets, or minitablets.
  • a stable pharmaceutical formulation of olanzapine comprising about 1 to 10% w/w olanzapine, about 0 to 88 % w/w lactose, about 0 to 10 % hydroxypropyl cellulose, about 0.5 to 6 % w/w crospovidone, about 0 to 88% w/w microcrystalline cellulose, or about 0 to 2% magnesium stearate.
  • a stable pharmaceutical formulation of olanzapine wherein, said polymer alone or in combination thereof used herein in an amount within the range from about 10 to about 80% by weight, preferably from about 20 to about 60% by weight and more preferably from about 30 to about 50% by weight of the total weight of the coating composition.
  • a process of making a pharmaceutical formulation having longer shelf-life and color stability comprises mixing olanzapine and at least one or more pharmaceutically acceptable excipients to form a mixture, processing the mixture to make a dosage form, and coating the dosage form with a coating composition comprising of at least one coating agent selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone/vinyl acetate copolymer, pullulan gum and zein.
  • a method of treating psychotic disorders employing said formulation.
  • the method comprises of administering a dosage form comprising olanzapine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; wherein the formulation is coated with a polymer selected from hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone/vinyl acetate copolymer, pullulan gum and zein or mixtures thereof.
  • Olanzapine a potent compound having desired nervous system activity has a tendency to undergo undesired polymorphic transformation, pharmaceutically undesired degradation or color changes, and stipulates concern on the homogeneity of the finished solid formulation.
  • Applicants have surprisingly discovered that coating the solid oral formulations comprising olanzapine, with one or more polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone / vinyl acetate copolymer, pullulan gum and zein, provides uniformity, physical stability, and effectively prevents the above-mentioned drawbacks in the prior art formulations comprising olanzapine.
  • one or more polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol, polyvinyl pyrrolidone / vinyl acetate copolymer, pullulan gum and zein.
  • Most preferred polymer coats comprise of hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol and polyvinyl pyrrolidone / vinyl acetate copolymer or mixtures thereof.
  • the polymers may be used in an amount with in the range from about 10 to about 80 % by weight, preferably from about 20 to about 60 % by weight and more preferably about 30 to about 50 % by weight of the coating composition.
  • the present coating is able to provide sufficient physical and chemical stability to olanzapine and its fo ⁇ nulations and remarkably overcomes the discoloration tendency of the dosage forms as available commercially or disclosed in the prior art.
  • treating includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
  • composition may be in the form of compressed tablets, moulded tablets, products prepared by extrusion and the likes.
  • the formulation is most preferably in a tablet form; however, granule formulation and the likes are desired as well.
  • composition of the present invention is in the form of tablets prepared by either direct compression, dry granulation (slugging/roller compaction) or by wet granulation (aqueous / non-aqueous).
  • the fo ⁇ nulations of the present invention contain olanzapine, its anhydrous forms, its analogues, polymorphs, solvates, hydrates and salts.
  • Olanzapine as used herein may be in the form of particles or powder.
  • the median particle size of olanzapine used in the formulation is within the range of approximately 5 microns to 150 microns, preferably less than 100 microns.
  • the solid oral formulation comprising olanzapine or a pharmaceutically acceptable salt thereof may further include one or more pharmaceutically acceptable excipients selected from a group consisting of diluent, binder, disintegrant, lubricant.
  • a diluent or bulking agent should be selected to provide an increase in tablet size.
  • the artisan can utilize known methods to select a bulking agent, which provides hardness, friability, and disintegration time that is satisfactory for pharmaceutical usage.
  • the bulking agent should be selected to provide a tablet that has characteristics desired by the patient as well as comply with applicable regulatory guidelines.
  • One especially preferred diluent or bulking agent is lactose.
  • lactose Various forms of lactose are appropriate for such formulations including anhydrous, hydrous, and spray dried forms.
  • the most desired form of lactose can be selected based on desired dissolution, content uniformity, hardness, friability, and disintegration time.
  • the skilled artisan is aware of the regulatory requirements for hardness, friability, and disintegration time and can adjust the diluent or bulking agents using known techniques to achieve the desired physical characteristics.
  • the desired formulation includes a disintegrant to facilitate the disintegration process.
  • grade there are a variety of grades available, and the grade may be selected based on the acceptable batch variability.
  • a particularly preferred disintegrant is crospovidone.
  • a fine grade of crospovidone provides particularly desirable consistency between batches.
  • dry binders may be selected using known methods. Such binders should be selected to assure that satisfactory friability is attained. Most preferably, dry binder is microcrystalline cellulose; however, other appropriate dry binders may be selected. Such microcrystalline cellulose may be in a granular form.
  • One preferred lubricant is magnesium stearate.
  • the formulation of the present invention may comprise from about 1 to about 10 % w/w olanzapine; from about 0 to about 88 % w/w lactose; from about 0 to about 10 % w/w hydroxypropyl cellulose; from about 0.5 to about 6 % w/w crospovidone; from about 0 to about 88% w/w microcrystalline cellulose; and from about 0 to 2 % magnesium stearate.
  • the film-coating composition may comprise of polymer/s, plasticizer/s, channeling agent/s, surfactant/s and/or pigments.
  • the film coat can be prepared by dispersing/dissolving the polymer alone or in combination, in water/organic solvents.
  • a preferred embodiment of a typical coating composition comprises of polyvinyl alcohol, lactose, triacetin, talc, and titanium dioxide.
  • a preferred formulation of the invention is a solid oral formulation comprising from about 1 to about 20 mg olanzapine as an active ingredient, wherein such solid oral formulation is coated with polyvinyl alcohol.
  • the solid oral formulation is contained in packaging materials, which protect the formulation from moisture and light.
  • suitable packaging materials include amber colored high-density polyethylene bottles, amber colored glass bottles, and other containers made of a material, which inhibits the passage of light.
  • the packaging will include a desiccant pack.
  • the container may be sealed with an aluminum foil blister to provide the desired protection and maintain product stability.
  • the materials for the present invention can be purchased or prepared by a variety of procedures well known to those of ordinary skill in the art.
  • Olanzapine can be prepared as described by Chakrabarti in U.S. Pat. No. 5,229,382; herein incoiporated by reference in its entirety.
  • Olanzapine is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated.
  • dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used.
  • a once a day dosage is normally sufficient, although divided doses may be administered.
  • a dose range from 1 to 30 mg, preferably 1 to 20 mg per day is suitable.
  • the preferred weight of the tablets is 50 to lOOOmg, most preferably 100 to 500 mg.
  • Pre weighed olanzapine, lactose, hydroxypropyl cellulose low substituted, crospovidone and microcrystalline cellulose were sifted and mixed in low shear mixer.
  • the blend was lubricated using presifted magnesium stearate.
  • the final blend was compressed using 10.0 mm round shape punches into tablets.
  • Example 1 The core tablets of Example 1 were coated using the following composition
  • Example 1 The core tablets of Example 1 were also coated using the following composition
  • Pre weighed olanzapine, lactose; part of crospovidone and part of microcrystalline cellulose were sifted and mixed in high shear mixer like RMG. It was than granulated using aqueous solution of Hydroxypropyl cellulose. Granules were dried/sifted and mixed with remaining part of crospovidone and microcrystalline cellulose and finally lubricated with magnesium stearate. The final blend was compressed using 10.0 mm round shape punches into tablets.
  • Tablets of example 4 were coated with the coating composition of example 3.
  • the dosage forms made according to the examples as described above were also visually observed for discoloration under test conditions (4O 0 C/ 75% RH, open air for 2 weeks).
  • the commercially available Zyprexa® tablets were also studied and the observations made are tabulated as below.
  • the tablets of the present invention surprisingly showed remarkable improvement in color stability even over the commercially available Zyprexa® tablets which are coated with the polymers as disclosed in prior art.

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

Abstract

L'invention concerne des formulations orales enrobées, solides, stables, d'olanzapine et leur procédé de préparation. La formulation comprend une quantité efficace d'olanzapine et un excipient acceptable d'un point de vue pharmaceutique. L'enrobage stabilisé de la formulation utilise un polymère sélectif sélectionné parmi un phtalate d'hydroxypropylméthylcellulose, un phtalate d'acétate de polyvinyle, un phtalate d'acétate de cellulose, un succinate d'acétate d'hydroxypropylméthylcellulose, un alcool polyvinylique, un copolymère d'acétate de vinyle, une gomme ou zéine obtenue à partir du pullulane ou une combinaison de celles-ci.
PCT/IN2006/000430 2005-10-27 2006-10-27 Formulation pharmaceutique enrobee, stable, d'olanzapine et son procede de preparation Ceased WO2007049304A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2880DE2005 2005-10-27
IN2880/DEL/2005 2005-10-27

Publications (2)

Publication Number Publication Date
WO2007049304A2 true WO2007049304A2 (fr) 2007-05-03
WO2007049304A3 WO2007049304A3 (fr) 2007-07-26

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PCT/IN2006/000430 Ceased WO2007049304A2 (fr) 2005-10-27 2006-10-27 Formulation pharmaceutique enrobee, stable, d'olanzapine et son procede de preparation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012153347A3 (fr) * 2011-05-04 2013-01-03 Zentiva K.S. Composition pharmaceutique d'olanzapine de forme 1 à administration par voie orale

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CR5278A (es) * 1995-03-24 1996-07-04 Lilly Co Eli Formulacion oral de 2-metil-tieno-benzodiacepina
WO1998013027A1 (fr) * 1996-09-24 1998-04-02 Eli Lilly And Company Formulation de particules enrobees
AT500063A1 (de) * 1999-11-23 2005-10-15 Sandoz Ag Beschichtete tablettenkerne
EP1583519A1 (fr) * 2002-12-20 2005-10-12 St. James Associates Llc/Faber Research Series Compactage haute pression pour formulations pharmaceutiques
WO2005009407A2 (fr) * 2003-07-29 2005-02-03 Ranbaxy Laboratories Limited Formulations pharmaceutiques d'olanzapine administrees par voie orale

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012153347A3 (fr) * 2011-05-04 2013-01-03 Zentiva K.S. Composition pharmaceutique d'olanzapine de forme 1 à administration par voie orale

Also Published As

Publication number Publication date
WO2007049304A3 (fr) 2007-07-26

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