WO2012153347A2 - Oral pharmaceutical composition of olanzapine form 1 - Google Patents
Oral pharmaceutical composition of olanzapine form 1 Download PDFInfo
- Publication number
- WO2012153347A2 WO2012153347A2 PCT/IN2012/000322 IN2012000322W WO2012153347A2 WO 2012153347 A2 WO2012153347 A2 WO 2012153347A2 IN 2012000322 W IN2012000322 W IN 2012000322W WO 2012153347 A2 WO2012153347 A2 WO 2012153347A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- olanzapine
- pharmaceutical composition
- composition
- sodium starch
- starch glycolate
- Prior art date
Links
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical group C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 102
- 239000008203 oral pharmaceutical composition Substances 0.000 title claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 83
- 239000003826 tablet Substances 0.000 claims description 41
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 239000008109 sodium starch glycolate Substances 0.000 claims description 24
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 24
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 24
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 16
- 229930195725 Mannitol Natural products 0.000 claims description 16
- 239000000594 mannitol Substances 0.000 claims description 16
- 235000010355 mannitol Nutrition 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical group OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 claims description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 12
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 9
- -1 hydroxyl propyl Chemical group 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000007941 film coated tablet Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 230000001050 lubricating effect Effects 0.000 claims description 3
- 239000003607 modifier Substances 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 abstract description 19
- 238000006731 degradation reaction Methods 0.000 abstract description 19
- 238000002845 discoloration Methods 0.000 abstract description 16
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 description 23
- 238000009472 formulation Methods 0.000 description 21
- 238000007907 direct compression Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 4
- 229940126534 drug product Drugs 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 239000008380 degradant Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229940057948 magnesium stearate Drugs 0.000 description 3
- 238000010525 oxidative degradation reaction Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000464 adrenergic agent Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000012505 colouration Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000000742 histaminergic effect Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000011028 process validation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229940039925 zyprexa Drugs 0.000 description 1
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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/2004—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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to a new pharmaceutical composition for the oral administration of olanzapine or of one of its pharmaceutically acceptable salts.
- the present invention relates to a stable pharmaceutical composition for the oral administration of olanzapine that comprises olanzapine Form 1 or one of its pharmaceutically acceptable salts thereof, as active ingredient, which are stable to discoloration, degradation and exhibits dose uniformity.
- Olanzapine (2-mehtyl-4-(4-mehtly-l-piperazinyl)-10 H-thieno [2, 3 - b] [1, 5] benzodiazepine) belongs to the class of drugs known as thienobenzodiazepine of formula
- Olanzapine is market in several dosages (2.5, 5, 7.5, 10, 15 mg) for oral administration. The market final forms include coated tablets and quick dissolvable tablets. Olanzapine and its application as a pharmaceutical have been suggested in EP 454436 (herein after referred to as EP '436) and corresponding US 5,229,382. This patent does not refer to or identify any specific crystalline form of olanzapine.
- EP 733635 US 5,736,541 (herein after referred to as EP '635) that olanzapine base may exist in various crystalline modifications and in hydrated/solvated forms that are stable at ambient conditions.
- the term 'olanzapine Form ⁇ was later designated in EP '635 to the anhydrous olanzapine product that was stated to be obtainable according to the process of EP '436.
- EP '635 discloses olanzapine Form II which appears to be more stable than Form I, but is convertible to Form I.
- EP '635 observes that olanzapine Form I is metastable in nature therefore prone to discoloration and degradation. Olanzapine Form I typically exhibit a colour which is undesirable for commercial pharmaceutical use, especially since the colour was found to change over time on exposure to air. Since olanzapine Form II is more stable than Form I, it is chemically stable and has satisfactory colour stability. However, Form II is rather difficult to prepare in substantially pure Form that is free from Form I or solvates.
- EP '436 describes that pharmaceutical compositions can be prepared by using conventional techniques.
- EP 733367/US 5,919,485 (herein after referred to as EP '367) indicates that the known olanzapine tablets had the tendency to discolour, which can be especially problematic to a psychotic patient.
- EP '367 applicants discovered that olanzapine undergoes discolouration when contacted with certain excipients including powder blends and discoloration enhances under ambient conditions of the air, at high temperatures and in wet environments.
- EP '367 attempts to address this problem by coating the solid oral formulation with a polymer. It is especially preferred that the formulation contain the most stable Form II of olanzapine.
- the process for the preparation of the formulation comprises the steps of wet granulation, drying, blending with additional excipients and compression.
- the obtained cores are first sub-coated with hydroxypropyl methyl cellulose in order to avoid a direct contact of the active ingredient with polyethylene glycol and subsequently coated with a coating suspension.
- olanzapine may form an undesired crystal form in the presence of certain solvents and excipients, therefore it is desired to prepare the formulation using a method which does not require dissolution of the Olanzapine substance. They believe that a dry blend direct compression process or a dry granulation process for preparing solid oral formulations create a greater chance for poor dose uniformity to occur.
- EP 0830858 and published US application 2001/0020032 also relates to solving the discoloration problem of olanzapine tablets.
- the formulation of the invention preferably contains the most stable Form II of olanzapine.
- the olanzapine powder is coated with a polymer to protect it from discolouration.
- the technique is especially useful in making granules which can be compressed into tablets. The examples use wet granulation.
- WO 2004/035027 recites an olanzapine pharmaceutical composition
- an olanzapine pharmaceutical composition comprising a homogeneous mixture of (a) olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a monosaccharide and/or oligosaccharide, and (c) a polysaccharide.
- the composition can additionally contain a binder, disintegrant, and a lubricant.
- the composition is an uncoated tablet which is preferably prepared by direct compression. The tablets are reported .as being stable and not suffering from discoloration.
- the discoloration is caused by the conversion of olanzapine into olanzapine hydrates but this could be prevented by homogenously mixing the olanzapine with certain excipients and then performing direct compression.
- the dose uniformity is stated to be excellent despite the use of direct compression.
- WO 2005/0009407 discloses olanzapine pharmaceutical compositions that are also supposed to be stable against discoloration.
- the proposal involves coating olanzapine particles or powder with a coating that includes lactose and/or mannitol and optionally other excipients.
- the coated olanzapine particles can be formulated into granules or tablets.
- the examples use a number of excipients (seven or eight including typically two kinds of microcrystalline cellulose) and steps (a coating step and wet granulation step, etc) before obtaining granules ready for tabletting or filling into capsules.
- WO 2007/134845 attempts stabilizing olanzapine pharmaceutical composition using anhydrous calcium hydrogen phosphate as the main excipient. It attempts to reduce the amount of the lactam impurity formed during prolonged storage of olanzapine compositions due to the presence of water in the composition and the micro environmental pH of the composition by using large amounts of anhydrous calcium hydrogen phosphate.
- a stable pharmaceutical composition comprising olanzapine, particularly Form I olanzapine which efficiently address the colour stability and dose uniformity in a simple and effective way. It is desirable to form an olanzapine tablet that does not need a special coating or excipients to maintain an ambient environment for the tablet to remain stable and that preferably avoid significant discolouration upon storage and as well provides dose uniformity.
- the present invention successfully solves the problem of stabilizing Form I olanzapine and achieving dose uniformity.
- the present invention provides a pharmaceutical composition of olanzapine that has good stability to discoloration, degradation and has good dose uniformity.
- a first aspect of the invention relates to a stable, scalable, homogenous solid oral pharmaceutical composition
- a stable, scalable, homogenous solid oral pharmaceutical composition comprising 3 to 5% by weight of the total composition of olanzapine, preferably Form I olanzapine, or one of its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients are selected from the group consisting of a diluent, glidant, binder, lubricant and mixtures thereof.
- the pharmaceutical composition comprising 3 to 5% of Form I olanzapine, lactose anhydrous, mannitol, hydroxyl propyl cellulose, sodium starch glycolate and magnesium stearate.
- the pharmaceutical composition can be formed into a film coated tablet having a weight of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg or an orodispersible tablet having a weight of 100 mg, 200 mg, 300 mg and 400 mg.
- the present inventors have found surprising effect on the stability of the colouration and degradation of the olanzapine of Form I when the formulation contains 3 to 5% by weight of the total composition of olanzapine, in addition to improving the dose uniformity of said formulation by using sodium starch glycolate as one of the pharmaceutically acceptable excipients.
- a process for the preparation of the pharmaceutical composition that is stable to discoloration, degradation and has good dose uniformity. The process involves
- step (d) Lubricating the blend of step (c) and ;
- step (e) Compressing the blend of step (d) into tablets.
- the present invention has the object of solving the problem of colour stability, degradation and dose uniformity of formulation that contains Form I olanzapine by providing a particular drug to excipients proportion.
- composition having a particular drug to excipient ratio have low tendency to degrade and to change color.
- the stable pharmaceutical composition of olanzapine which does not show any degradation and undesired discoloration, can be prepared with an excellent dose uniformity in a simple direct compression process by using sodium starch glycolate as one of the excipients.
- sodium starch glycolate is commonly used for the manufacturing of tablets, the finding that it allows the production of uniform dose of olanzapine formulation was totally unexpected.
- olanzapine product e.g., Zyprexa
- olanzapine crystalline polymorphic Form II is the stable polymorph compared to Form I which is metastable in nature therefore prone to discoloration and degradation.
- the present invention explains the vital role of the drug to excipient ratio for the stabilization of the formulation and minimizes the generation of the potential degradants formed during the stability studies of the drug product.
- the first embodiment of the invention relates to a stable, scalable, homogenous solid oral pharmaceutical composition
- olanzapine preferably Form I olanzapine, or one of its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients wherein the olanzapine constitute about 3 to 5% by weight of the total composition.
- the pharmaceutically acceptable salts of olanzapine are those e.g. disclosed in EP 0454436.
- the pharmaceutically acceptable excipients are selected from the group consisting of a diluent, glidant, binder, lubricant, bulk density modifier and mixtures thereof.
- Suitable diluents are lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate. The diluent constitute 38-88% by weight of the total composition.
- Suitable glidants / lubricants are colloidal silicon dioxide, talc, magnesium carbonate, magnesium stearate, cellulose, starch and calcium phosphate. The glidants/lubricant constitutes 1% by weight of the total composition.
- Suitable binders are microcrystalline cellulose, hydroxy propyl cellulose, and copovidone.
- the binder constitutes 2.5% by weight of the total composition.
- Suitable bulk density modifier is Sodium Starch Glycolate.
- the said excipient constitutes 1% by weight of the total composition.
- the pharmaceutical composition comprising 3 to 5% by weight of the total composition of Form I olanzapine, lactose anhydrous, mannitol, hydroxyl propyl cellulose, sodium starch Glycolate and magnesium stearate.
- the pharmaceutical composition comprises
- magnesium stearate 1% of magnesium stearate.
- Tablets can be made from the final dosage Form of the composition.
- the tablet may either be a film coated tablet or an orodispersible.
- the term 'coated olanzapine' as used herein refers to olanzapine powder coated by at least one excipient.
- the coating can be achieved by conventional technique. Protective coating of the tablets is, in essence, not necessary.
- a tablet may be film- coated to improve its appearance and handling using conventional film-coating materials and techniques. This technique comprises mixing suitable film forming polymer with water to form dispersion and spraying the dispersion over the compressed tablets using suitable tablet coating machine.
- 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, preferably 1 to 30 mg and most preferably 1 to 20 mg per day may be used.
- the preferred weight of the tablets is 50 to 1000 mg, most preferably 100 to 500 mg.
- the present inventors surprisingly observed that homothetic blend could be possible only by improving the flow properties of active ingredient by co sifting it by excipients especially sodium starch glycolate.
- the bulk density of this blend was found to 0.672 g/ml. This bulk density was found to matching with the cosifting blend of lactose anhydrous and Hydroxy Propyl Cellulose which was 0.610 g/ml.
- Sodium starch glycolate has been conventionally know to exhibit the property of a super disintegrant, stabilizer, dissolution aid for tablets/capsules/pellets and/or suspending vehicle.
- the property of sodium starch glycolate to improve the flow property of the poorly flow active materials, found by the present inventors, is novel and is not be obvious to a person skilled in the art. This property helped in achieving a homogenous formulation.
- a process for the preparation of a stable, scalable homogenous solid oral pharmaceutical composition comprising olanzapine, preferably Form I olanzapine that is stable to discoloration, degradation and has good dose uniformity.
- the process involves
- step (d) Lubricating the blend of step (c) and ;
- step (e) Compressing the blend of step (d) into tablets.
- the process comprises the following steps:
- STEP 1 Dispense all excipients in double lined clear polythene bags and
- Olanzapine (Form 1) in clear double lined polythene bags.
- STEP 2 Co - sift Olanzapine, Sodium Starch Glycolate and Mannitol through
- STEP 3 Co - sift Lactose Anhydrous & Hydroxy Propyl Cellulose and pass through BSS Sieve no. 36 [425 micron size] and collect in the same double lined polythene bags containing sifted materials of Step 2.
- STEP 4 Sift Magnesium Stearate through BSS Sieve no. 60 [250 micron size] and collect in double lined polythene bags.
- STEP 7 Blend the Step 6 materials for 3 min at 18 ⁇ 1 rpm.
- STEP 8 Compress the Step 7 lubricated blend on a tablet press.
- STEP 10 Pack the tablets of step 8 in Alu / Alu blister pack.
- the stability of the composition is determined by the generation of the potential degradants formed during the stability studies of the drug product.
- the potential degradants like N-oxide and deaminated oxidative impurity formed was found to be controlled in the composition wherein the olanzapine concentration in the said composition was 3 to 5 % by weight of total composition.
- the discoloration of the olanzapine with concentration between 3-5 % by weight of total composition were found to be negligible in comparison to the drug product with 2.5 %.
- Example No. 1 Analysis of impurities in a composition containing 2.5% by weight of the total composition of olanzapine by a stability indicating related substances method: Raw Materials % w/w mg per tablet
- Olanzapine Form 1 2.50 2.50
- Olanzapine, mannitol, lactose anhydrous, hydroxy propyl cellulose, sodium starch glycolate and magnesium stearate were sifter through suitable mesh and compressed into tablets and charged for open exposure stress degradation studies and for 1 month and in finished alu/alu pack at accelerated stability conditions. Samples were withdrawn at definite time intervals and subjected for analysis of impurities by a stability indicating related substances method. The results of individual and total impurities are tabulated here underwith.
- Example No. 2 Analysis of impurities in a composition containing 3.57% by weight of the total composition of olanzapine by a stability indicating related substances method:
- Olanzapine, mannitol, lactose anhydrous, hydroxy propyl cellulose, sodium starch glycolate and magnesium stearate were sifter through suitable mesh and compressed into tablets and charged for open exposure stress degradation studies and for 1 month and in finished alu/alu pack at accelerated stability conditions. Samples were withdrawn at definite time intervals and subjected for analysis of impurities by a stability indicating related substances method. The results of individual and total impurities are tabulated here underwith.
- Example 3 Analysis of impurities in a composition containing 5% by weight of the total composition of olanzapine by a stability indicating related substances method:
- the pharmaceutical composition is produced according to the method of the present invention and analyzed for its dose uniformity.
- Blending time 03 Blending time: 05
Abstract
The present invention relates to a stable pharmaceutical composition for the oral administration of olanzapine that comprises olanzapine Form 1 or one of its pharmaceutically acceptable salts thereof, as active ingredient, which are stable to discoloration, degradation and exhibits dose uniformity.
Description
ORAL PHARMACEUTICAL COMPOSITION OF OLANZAPINE FORM 1
FILED OF THE INVENTION
The present invention relates to a new pharmaceutical composition for the oral administration of olanzapine or of one of its pharmaceutically acceptable salts.
In particular, the present invention relates to a stable pharmaceutical composition for the oral administration of olanzapine that comprises olanzapine Form 1 or one of its pharmaceutically acceptable salts thereof, as active ingredient, which are stable to discoloration, degradation and exhibits dose uniformity.
BACK GROUND
Olanzapine (2-mehtyl-4-(4-mehtly-l-piperazinyl)-10 H-thieno [2, 3 - b] [1, 5] benzodiazepine) belongs to the class of drugs known as thienobenzodiazepine of formula
Later, it became known through EP 733635 US 5,736,541 (herein after referred to as EP '635) that olanzapine base may exist in various crystalline modifications and in hydrated/solvated forms that are stable at ambient conditions. The term 'olanzapine Form Γ was later designated in EP '635 to the anhydrous olanzapine product that was stated to be obtainable according to the process of EP '436. EP '635 discloses olanzapine Form II which appears to be more stable than Form I, but is convertible to Form I.
EP '635 observes that olanzapine Form I is metastable in nature therefore prone to discoloration and degradation. Olanzapine Form I typically exhibit a colour which is undesirable for commercial pharmaceutical use, especially since the colour was found to change over time on exposure to air. Since olanzapine Form II is more stable than Form I, it is chemically stable and has satisfactory colour stability. However, Form II is rather difficult to prepare in substantially pure Form that is free from Form I or solvates.
The original olanzapine patent i.e., EP '436 describes that pharmaceutical compositions can be prepared by using conventional techniques. However, EP 733367/US 5,919,485 (herein after referred to as EP '367) indicates that the known olanzapine tablets had the tendency to discolour, which can be especially problematic to a psychotic patient. In EP '367 applicants discovered that olanzapine undergoes discolouration when contacted with certain excipients including powder blends and discoloration enhances under ambient conditions of the air, at high temperatures and in wet environments. EP '367 attempts to address this problem by coating the solid oral formulation with a polymer. It is especially preferred that the formulation contain the most stable Form II of olanzapine. The process for the
preparation of the formulation comprises the steps of wet granulation, drying, blending with additional excipients and compression. The obtained cores are first sub-coated with hydroxypropyl methyl cellulose in order to avoid a direct contact of the active ingredient with polyethylene glycol and subsequently coated with a coating suspension. In the description it is pointed out that olanzapine may form an undesired crystal form in the presence of certain solvents and excipients, therefore it is desired to prepare the formulation using a method which does not require dissolution of the Olanzapine substance. They believe that a dry blend direct compression process or a dry granulation process for preparing solid oral formulations create a greater chance for poor dose uniformity to occur. In the light of the potent nature of olanzapine, consistent dose uniformity is imperative therefore they used high-shear aqueous wet granulation with fluid bed drying as the most effective method for preparing pharmaceutically elegant and stable oral olanzapine formulations. Though the presence of solvents can cause undesirable conversions they could not avoid the use of wet granulation.
EP 0830858 and published US application 2001/0020032 also relates to solving the discoloration problem of olanzapine tablets. The formulation of the invention preferably contains the most stable Form II of olanzapine. Instead of the tablet being coated, however, here the olanzapine powder is coated with a polymer to protect it from discolouration. The technique is especially useful in making granules which can be compressed into tablets. The examples use wet granulation.
WO 2004/035027 recites an olanzapine pharmaceutical composition comprising a homogeneous mixture of (a) olanzapine or a pharmaceutically acceptable salt thereof as an active ingredient, (b) a monosaccharide and/or oligosaccharide, and (c) a polysaccharide. The composition can additionally contain a binder, disintegrant, and a lubricant. Preferably the composition is an uncoated tablet which is preferably prepared by direct compression. The tablets are reported .as being stable and not suffering from discoloration. According to this
publication, the discoloration is caused by the conversion of olanzapine into olanzapine hydrates but this could be prevented by homogenously mixing the olanzapine with certain excipients and then performing direct compression. The dose uniformity is stated to be excellent despite the use of direct compression.
WO 2005/0009407 discloses olanzapine pharmaceutical compositions that are also supposed to be stable against discoloration. The proposal involves coating olanzapine particles or powder with a coating that includes lactose and/or mannitol and optionally other excipients. The coated olanzapine particles can be formulated into granules or tablets. The examples use a number of excipients (seven or eight including typically two kinds of microcrystalline cellulose) and steps (a coating step and wet granulation step, etc) before obtaining granules ready for tabletting or filling into capsules.
WO 2007/134845 attempts stabilizing olanzapine pharmaceutical composition using anhydrous calcium hydrogen phosphate as the main excipient. It attempts to reduce the amount of the lactam impurity formed during prolonged storage of olanzapine compositions due to the presence of water in the composition and the micro environmental pH of the composition by using large amounts of anhydrous calcium hydrogen phosphate.
Therefore, there still remains a need for a stable pharmaceutical composition comprising olanzapine, particularly Form I olanzapine which efficiently address the colour stability and dose uniformity in a simple and effective way. It is desirable to form an olanzapine tablet that does not need a special coating or excipients to maintain an ambient environment for the tablet to remain stable and that preferably avoid significant discolouration upon storage and as well provides dose uniformity. The present invention successfully solves the problem of stabilizing Form I olanzapine and achieving dose uniformity.
SUMMARY
The present invention provides a pharmaceutical composition of olanzapine that has good stability to discoloration, degradation and has good dose uniformity.
Accordingly, a first aspect of the invention relates to a stable, scalable, homogenous solid oral pharmaceutical composition comprising 3 to 5% by weight of the total composition of olanzapine, preferably Form I olanzapine, or one of its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are selected from the group consisting of a diluent, glidant, binder, lubricant and mixtures thereof.
In particular, the pharmaceutical composition comprising 3 to 5% of Form I olanzapine, lactose anhydrous, mannitol, hydroxyl propyl cellulose, sodium starch glycolate and magnesium stearate.
The pharmaceutical composition can be formed into a film coated tablet having a weight of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg or an orodispersible tablet having a weight of 100 mg, 200 mg, 300 mg and 400 mg.
In addition to development of the scalable and direct compression formulation across all strength, the present inventors have identified that the presence of sodium starch glycolate as one of the excipient is important to achieve a homogenous formulation having dose uniformity.
The present inventors have found surprising effect on the stability of the colouration and degradation of the olanzapine of Form I when the formulation contains 3 to 5% by weight of the total composition of olanzapine, in addition to improving the dose uniformity of said formulation by using sodium starch glycolate as one of the pharmaceutically acceptable excipients.
In another aspect of the invention there is provided a process for the preparation of the pharmaceutical composition that is stable to discoloration, degradation and has good dose uniformity. The process involves
(a) Co-sifting olanzapine, mannitol and sodium starch glycolate ;
(b) Separately sifting lactose and hydroxy propyl cellulose;
(c) Mixing the material of step (a) and (b);
(d) Lubricating the blend of step (c) and ;
(e) Compressing the blend of step (d) into tablets.
These and other aspects, features and advantages of the present invention will become better understood with reference to the following description and claims.
DESCRIPTION
The present invention has the object of solving the problem of colour stability, degradation and dose uniformity of formulation that contains Form I olanzapine by providing a particular drug to excipients proportion.
Number of attempts have been made, as evident in prior art, to avoid the degradation of olanzapine in the formulation. It has been studied that olanzapine Form I and pharmaceutical dosage Forms compounded with Form I were found to be sensitive to acid hydrolysis and oxidative degradation which are triggered specifically by temperature and light. Therefore formulating a pharmaceutical composition using Form I and stabilizing the same in order to control the degradation is a challenge.
Several experiments were carried out by the present inventors in order to achieve a stabilized pharmaceutical composition of olanzapine Form 1 wherein it
was surprisingly observed that the drug to excipients proportion played a vital role in stabilizing the formulation. It was found that composition having a particular drug to excipient ratio have low tendency to degrade and to change color.
It was studied that since olanzapine polymorphic form-1 is a metastable form and prone to oxidative degradation pathways along with discoloration, therefore compounding them into a tablet formulation containing excipients exacerbate the oxidative degradation of the compound. Therefore in order to minimize the effect of excipients on the stability of the formulation it becomes necessary to reduce the olanzapine particle to excipient particle contact which was found to be best achieved only in composition wherein olanzapine concentration was found to be 3 to 5% by weight of the total composition, owing to which the deaminated oxidative impurity concentration was found to be least.
It was further observed by the present inventors that the stable pharmaceutical composition of olanzapine, which does not show any degradation and undesired discoloration, can be prepared with an excellent dose uniformity in a simple direct compression process by using sodium starch glycolate as one of the excipients. In view of the fact that sodium starch glycolate is commonly used for the manufacturing of tablets, the finding that it allows the production of uniform dose of olanzapine formulation was totally unexpected.
The most obvious advantage of direct compression is economy. Savings can occur in a number of areas including reduced processing time and thus reduced labour costs, fewer manufacturing steps and pieces of equipment, less process validation, and a lower consumption power.
It has been studied that the commercially available olanzapine product (e.g., Zyprexa) is chemically stable due to olanzapine Form II been used in the formulation. As available in the prior art, olanzapine crystalline polymorphic Form
II is the stable polymorph compared to Form I which is metastable in nature therefore prone to discoloration and degradation.
It was been studied that in order to formulate Olanzapine tablets using Form 1 polymorphic Form it is necessary to stabilize the same so that they meet the quality standards of the commercially available products.
The present invention explains the vital role of the drug to excipient ratio for the stabilization of the formulation and minimizes the generation of the potential degradants formed during the stability studies of the drug product.
Accordingly, the first embodiment of the invention relates to a stable, scalable, homogenous solid oral pharmaceutical composition comprising olanzapine, preferably Form I olanzapine, or one of its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients wherein the olanzapine constitute about 3 to 5% by weight of the total composition.
The pharmaceutically acceptable salts of olanzapine are those e.g. disclosed in EP 0454436.
The pharmaceutically acceptable excipients are selected from the group consisting of a diluent, glidant, binder, lubricant, bulk density modifier and mixtures thereof.
Suitable diluents are lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate. The diluent constitute 38-88% by weight of the total composition.
Suitable glidants / lubricants are colloidal silicon dioxide, talc, magnesium carbonate, magnesium stearate, cellulose, starch and calcium phosphate. The glidants/lubricant constitutes 1% by weight of the total composition.
Suitable binders are microcrystalline cellulose, hydroxy propyl cellulose, and copovidone. The binder constitutes 2.5% by weight of the total composition.
Suitable bulk density modifier is Sodium Starch Glycolate. The said excipient constitutes 1% by weight of the total composition.
In particular, the pharmaceutical composition comprising 3 to 5% by weight of the total composition of Form I olanzapine, lactose anhydrous, mannitol, hydroxyl propyl cellulose, sodium starch Glycolate and magnesium stearate.
In a preferred embodiment of the invention, the pharmaceutical composition comprises
3 to 5% of Form I olanzapine,
88 to 38% of lactose anhydrous,
5% of mannitol,
2.5% of hydroxyl propyl cellulose,
1% of sodium starch glycolate and
1% of magnesium stearate.
Tablets can be made from the final dosage Form of the composition. The tablet may either be a film coated tablet or an orodispersible. The term 'coated olanzapine' as used herein refers to olanzapine powder coated by at least one excipient. The coating can be achieved by conventional technique. Protective coating of the tablets is, in essence, not necessary. If desired, a tablet may be film- coated to improve its appearance and handling using conventional film-coating materials and techniques. This technique comprises mixing suitable film forming
polymer with water to form dispersion and spraying the dispersion over the compressed tablets using suitable tablet coating machine.
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, preferably 1 to 30 mg and most preferably 1 to 20 mg per day may be used. The preferred weight of the tablets is 50 to 1000 mg, most preferably 100 to 500 mg.
In the state of art it is stressed that due to the potent nature of olanzapine, consistent dose uniformity is imperative and that such uniformity is hardly obtained by direct compression. Dose uniformity (i.e., homothetic blend formulations) is imperative, because the same blend can be compressed at different tablet weights to achieve tablets of different strength. In this way the manufacturing process time and cost is reduced and also the process becomes less tedious and simplified. Owing to all such advantages of development of homothetic blend for film coated tablets (herein after called as FCT) of strengths 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg and orodispersible tablets (hereafter called as ODT) of strengths 5 mg, 10 mg, 15 mg and 20 mg respectively it was a challenge to the present inventors to formulate a homothetic blend for 6 strengths of FCT range and 4 strength of ODT range. During this development the tablet attributes/parameters were never compromised.
The present inventors surprisingly observed that homothetic blend could be possible only by improving the flow properties of active ingredient by co sifting it by excipients especially sodium starch glycolate. The bulk density of this blend was found to 0.672 g/ml. This bulk density was found to matching with the cosifting blend of lactose anhydrous and Hydroxy Propyl Cellulose which was 0.610 g/ml.
Sodium starch glycolate has been conventionally know to exhibit the property of a super disintegrant, stabilizer, dissolution aid for tablets/capsules/pellets and/or suspending vehicle. The property of sodium starch glycolate to improve the flow property of the poorly flow active materials, found by the present inventors, is novel and is not be obvious to a person skilled in the art. This property helped in achieving a homogenous formulation.
In another embodiment of the invention there is provided a process for the preparation of a stable, scalable homogenous solid oral pharmaceutical composition comprising olanzapine, preferably Form I olanzapine that is stable to discoloration, degradation and has good dose uniformity. The process involves
(a) Co-sifting olanzapine, mannitol and sodium starch glycolate ;
(b) Separately sifting lactose and hydroxy propyl cellulose;
(c) Mixing the material of step (a) and (b);
(d) Lubricating the blend of step (c) and ;
(e) Compressing the blend of step (d) into tablets.
In particular, the process comprises the following steps:
STEP 1 : Dispense all excipients in double lined clear polythene bags and
Olanzapine (Form 1) in clear double lined polythene bags.
STEP 2: Co - sift Olanzapine, Sodium Starch Glycolate and Mannitol through
BSS Sieve no. 36 [425 micron size] and collect in double lined polythene bags.
STEP 3: Co - sift Lactose Anhydrous & Hydroxy Propyl Cellulose and pass through BSS Sieve no. 36 [425 micron size] and collect in the same double lined polythene bags containing sifted materials of Step 2.
STEP 4: Sift Magnesium Stearate through BSS Sieve no. 60 [250 micron size] and collect in double lined polythene bags.
STEP 5: Charge Step 3 materials in 50 L capacity Intermediate bulk container
[IBC] and fit in bin blender and blend for 25 min at 18 ± 1 rpm.
STEP 6 Add material of Step No. 4 to materials of Step 5 present
STEP 7 Blend the Step 6 materials for 3 min at 18±1 rpm.
STEP 8 Compress the Step 7 lubricated blend on a tablet press.
STEP 9 Coat the Step 8 core tablets using film coating dispersion
STEP 10: Pack the tablets of step 8 in Alu / Alu blister pack.
The following examples, without limiting the scope of the claimed invention, illustrate the vital role of the drug to excipient ratio for the stabilization of the composition.
EXAMPLES
The stability of the composition is determined by the generation of the potential degradants formed during the stability studies of the drug product. The potential degradants like N-oxide and deaminated oxidative impurity formed was found to be controlled in the composition wherein the olanzapine concentration in the said composition was 3 to 5 % by weight of total composition. In addition it was studied that the discoloration of the olanzapine with concentration between 3-5 % by weight of total composition were found to be negligible in comparison to the drug product with 2.5 %.
The experiments been carried to stabilize the formulation reveals that the drug to excipient ratio is very critical and important in developing a stable dosage form, meeting the quality standards of reference product.
Example No. 1 - Analysis of impurities in a composition containing 2.5% by weight of the total composition of olanzapine by a stability indicating related substances method:
Raw Materials % w/w mg per tablet
Olanzapine Form 1 2.50 2.50
Lactose anhydrous 88.00 88.00
Mannitol 5.00 5.00
Hydroxy Propyl Cellulose 2.50 2.50
Sodium starch glycolate 1.00 1.00
Magnesium stearate 1.00 1.00
Tablet wt. . 100% 100 mg
Procedure :
Olanzapine, mannitol, lactose anhydrous, hydroxy propyl cellulose, sodium starch glycolate and magnesium stearate were sifter through suitable mesh and compressed into tablets and charged for open exposure stress degradation studies and for 1 month and in finished alu/alu pack at accelerated stability conditions. Samples were withdrawn at definite time intervals and subjected for analysis of impurities by a stability indicating related substances method. The results of individual and total impurities are tabulated here underwith.
Table No. 1: Open Exposure stress degradation at 40°C 75% RH (relative humidity)
Olanzapine film coated tablets 10 mg
Batch No. OLA- 10/33
Details: 2.5% by weight of total composition of olanzapine
Relative retention time (RRT) Initial 15 days 30 days
0.33 (N-Oxide impurity) 0.03% 0.07% 0.08
Below
0.4 (Desmethyl Impurity) 0.01% 0.03%
detection limit
0.60 (Amide Impurity) 0.02% 0.09% 0.14
Below
0.63 0.02% 0.01%
detection limit
Total Impurities 0.13% 0.27% ~
Table no. 2:
* Since impurities at 2na month were observed to be high, therefore 3r and 6U month sample were not analyzed.
Example No. 2 - Analysis of impurities in a composition containing 3.57% by weight of the total composition of olanzapine by a stability indicating related substances method:
Raw Materials % w/w mg per tablet
Olanzapine Form 1 3.57 2.50
Lactose anhydrous 58.00 58.00
Mannitol 5.00 5.00
Hydroxy propyl Cellulose 2.50 2.50
Sodium starch glycolate 1.00 1.00
Magnesium stearate 1.00 1.00
Tablet wt. 100% 70 mg
Procedure :
Olanzapine, mannitol, lactose anhydrous, hydroxy propyl cellulose, sodium starch glycolate and magnesium stearate were sifter through suitable mesh and compressed into tablets and charged for open exposure stress degradation studies and for 1 month and in finished alu/alu pack at accelerated stability conditions. Samples were withdrawn at definite time intervals and subjected for analysis of impurities by a stability indicating related substances method. The results of individual and total impurities are tabulated here underwith.
Table No. 3 : Open Exposure stress degradation at 40°C 75% RH
Table No. 4:
Period/ Condition Related Substances
Details: 3.75% by weight of
total composition of Amide Impurity [ %] Total olanzapine (at RRT~ 0.6) Impurities [ %]
Batch No. OLA- 10/51
Initial 0.07 0.31
1 Month at 40°C & 75 % RH 0.10 0.36
3 Month at 40°C & 75 % RH 0.14 --
Example 3 - Analysis of impurities in a composition containing 5% by weight of the total composition of olanzapine by a stability indicating related substances method:
Procedure:
Olanzapine, Mannitol, lactose anhydrous, hydroxy Propyl cellulose, sodium starch glycolate and magnesium stearate were sifter through suitable mesh and compressed into tablets and charged for open exposure stress degradation studies for 1 month and in finished alu/alu pack at accelerated stability conditions. Samples were withdrawn at definite time intervals and subjected for analysis of impurities by a stability indicating related substances method. The results of individual and total impurities are tabulated here under with.
Table No. 5: Open Exposure stress degradation at 40°C 75% RH
Table No. 6
i) Olanzapine film coated tablets 10 mg
Batch No. 298002 At 40°C & 75% RH At 25°C & 60% RH
Amide Amide
Total Total Impurity Impurity
Period/ Condition Impurities Impurities
[ %] [ %]
[ %] [ %] (at RRT 0.6) (at RRT 0.6)
Specification limits
0.5% N/AP 0.5% N/AP (as per ICH Norms)
Initial 0.03 0.21 0.030 0.214
3 Month 0.22 0.63 0.082 0.409
6 Month 0.315 0.709 0.096 0.421
9 Month 0.131 0.446
12 Month 0.171 0.475
18 Month 0.181 0.503
24 Month 0.232 0.536
ii) Olanzapine Orodispersible tablets 10 mg
Example 4 - Analysis of the dose uniformity of the composition:
The pharmaceutical composition is produced according to the method of the present invention and analyzed for its dose uniformity.
Samples from Blend Uniformity Results (% Label claim) 10 different (Acceptance criteria: Between 90 - 110%, locations of RSD: NMT 5.0%)
blend Batch No. 298001
Blending time: 03 Blending time: 05
Minutes Minutes
1 98.9 98.1
2 106.1 99.2
3 102.4 97.5
4 100.7 97.7
5 101.4 99.4
6 103.6 98.8
7 101.3 96.9
8 100.8 100.0
9 98.3 96.2
10 101.9 98.9
Mean 101.5 98.3
RSD 2.19 1.20
The above example illustrates that drug to excipient ratio plays a vital role in the stabilization of the composition. The degradation and discoloration of the olanzapine with concentration between 3-5 % by weight of total composition were found to be negligible in comparison to the drug product with 2.5 %. Further, as illustrated above, a homothetic blend of the composition was obtained by using sodium starch glycolate.
Each of the patents, patent applications mentioned herein above are incorporated herein by reference. The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.
Claims
1. A stable, scalable, homogenous solid oral pharmaceutical composition comprising olanzapine or one of its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients wherein the olanzapine constitute about 3 to 5% by weight of the total composition.
2. The pharmaceutical composition as claimed in claim 1, wherein the said olanzapine is Form I olanzapine.
3. The composition as claimed in claim 1 or 2, wherein the pharmaceutically acceptable excipients are selected from the group consisting of a diluent, glidant/lubricant, binder and mixtures thereof.
4. The pharmaceutical composition as claimed in claims 1 to 3, wherein said diluent is lactose anhydrous and mannitol
5. The pharmaceutical composition as claimed in claims 1 to 3, wherein said glidant/lubricant is magnesium stearate
6. The pharmaceutical composition as claimed in claims 1 to 3, wherein said binder is hydroxy propyl cellulose.
7. The pharmaceutical composition as claimed in claims 1 to 3, wherein said bulk density modifier is sodium starch glycolate.
8. The pharmaceutical composition as claimed in claims 1 to 7, comprising
3 to 5% of Form I olanzapine,
88 to 38% of lactose anhydrous,
5% of mannitol,
2.5% of hydroxyl propyl cellulose,
1% of sodium starch glycolate and
1% of magnesium stearate.
9. The pharmaceutical composition as claimed in claims 1 to 8, wherein said composition is a tablet.
10. The pharmaceutical composition as claimed in claims 1 to 9, wherein said tablet is a film coated tablet.
1 1. The pharmaceutical composition as claimed in claim 10, wherein in said tablet has weight of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg and 400 mg.
12. A process for the preparation of a stable oral pharmaceutical composition comprising olanzapine Form I, which comprises the steps of:
(a) Co-sifting olanzapine, mannitol and sodium starch glycolate;
(b) Separately sifting lactose and hydroxy propyl cellulose;
(c) Mixing the material of step (a) and (b);
(d) Lubricating the blend of step (c) and ;
(e) Compressing the blend of step (d) into tablets.
13. Use of sodium starch glycolate as an excipient in the preparation of a pharmaceutical composition comprising olanzapine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1379MU2011 | 2011-05-04 | ||
| IN1379/MUM/2011 | 2011-05-04 |
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| Publication Number | Publication Date |
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| WO2012153347A2 true WO2012153347A2 (en) | 2012-11-15 |
| WO2012153347A3 WO2012153347A3 (en) | 2013-01-03 |
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| PCT/IN2012/000322 WO2012153347A2 (en) | 2011-05-04 | 2012-05-02 | Oral pharmaceutical composition of olanzapine form 1 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014218472A (en) * | 2013-05-10 | 2014-11-20 | エルメッド エーザイ株式会社 | Tablet containing olanzapine or salt thereof |
| US9937153B2 (en) | 2013-08-30 | 2018-04-10 | Merck Sharp & Dohme Ltd. | Oral pharmaceutical formulation of omarigliptin |
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| US5229382A (en) | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
| EP0733635A1 (en) | 1995-03-24 | 1996-09-25 | Eli Lilly And Company | Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation |
| EP0733367A1 (en) | 1995-03-24 | 1996-09-25 | Eli Lilly And Company | Oral olanzapine formulation |
| EP0830858A1 (en) | 1996-09-24 | 1998-03-25 | Eli Lilly And Company | Formulation comprising coated olanzapine particles |
| WO2004035027A1 (en) | 2002-10-18 | 2004-04-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical formulation of olanzapine |
| WO2005000940A1 (en) | 2003-06-11 | 2005-01-06 | E.I. Dupont De Nemours And Company | Sulfonated aliphatic-aromatic copolyesters and shaped articles produced therefrom |
| WO2007134845A2 (en) | 2006-05-18 | 2007-11-29 | Synthon B.V. | Olanzapine pharmaceutical composition |
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| WO2006087629A2 (en) * | 2005-02-21 | 2006-08-24 | Aurobindo Pharma Limited | Rapidly disintegrating composition of olanzapine |
| WO2007049304A2 (en) * | 2005-10-27 | 2007-05-03 | Jubilant Organosys Limited | Stable coated pharmaceutical formulation of olanzapine and process for preparing the same |
| DE602006014030D1 (en) * | 2006-07-05 | 2010-06-10 | Bilim Ilac Sanayii Ve Ticaret | STABLE OLANZAPINE FORMULATION WITH ANTIOXIDANTS |
| US20080138409A1 (en) * | 2006-09-29 | 2008-06-12 | Osinga Niels J | Olanzapine pharmaceutical composition |
| US20120058185A1 (en) * | 2009-05-22 | 2012-03-08 | Pattanayak Durgaprasad | Stable pharmaceutical compositions of olanzapine and process for their preparation |
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| EP0454436A1 (en) | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
| US5229382A (en) | 1990-04-25 | 1993-07-20 | Lilly Industries Limited | 2-methyl-thieno-benzodiazepine |
| EP0733635A1 (en) | 1995-03-24 | 1996-09-25 | Eli Lilly And Company | Crystal forms of a thieno(2,3-B)(1,5) benzodiazepine derivative and process for their preparation |
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| WO2005000940A1 (en) | 2003-06-11 | 2005-01-06 | E.I. Dupont De Nemours And Company | Sulfonated aliphatic-aromatic copolyesters and shaped articles produced therefrom |
| WO2007134845A2 (en) | 2006-05-18 | 2007-11-29 | Synthon B.V. | Olanzapine pharmaceutical composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014218472A (en) * | 2013-05-10 | 2014-11-20 | エルメッド エーザイ株式会社 | Tablet containing olanzapine or salt thereof |
| US9937153B2 (en) | 2013-08-30 | 2018-04-10 | Merck Sharp & Dohme Ltd. | Oral pharmaceutical formulation of omarigliptin |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012153347A3 (en) | 2013-01-03 |
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