WO2013100878A1 - Pharmaceutical formulations comprising aripiprazole - Google Patents
Pharmaceutical formulations comprising aripiprazole Download PDFInfo
- Publication number
- WO2013100878A1 WO2013100878A1 PCT/TR2012/000234 TR2012000234W WO2013100878A1 WO 2013100878 A1 WO2013100878 A1 WO 2013100878A1 TR 2012000234 W TR2012000234 W TR 2012000234W WO 2013100878 A1 WO2013100878 A1 WO 2013100878A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- range
- aripiprazole
- pharmaceutical formulation
- diluent
- formulation
- Prior art date
Links
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 43
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 5
- 208000020706 Autistic disease Diseases 0.000 claims abstract description 4
- 208000020925 Bipolar disease Diseases 0.000 claims abstract description 4
- 206010022998 Irritability Diseases 0.000 claims abstract description 4
- 208000024714 major depressive disease Diseases 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 83
- 238000009472 formulation Methods 0.000 claims description 52
- 239000003085 diluting agent Substances 0.000 claims description 44
- 239000007884 disintegrant Substances 0.000 claims description 24
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 18
- 239000013543 active substance Substances 0.000 claims description 15
- 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 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 11
- 239000003086 colorant Substances 0.000 claims description 11
- 229960000913 crospovidone Drugs 0.000 claims description 11
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 11
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 11
- 235000010447 xylitol Nutrition 0.000 claims description 11
- 239000000811 xylitol Substances 0.000 claims description 11
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 11
- 229960002675 xylitol Drugs 0.000 claims description 11
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 9
- 235000013355 food flavoring agent Nutrition 0.000 claims description 9
- 235000003599 food sweetener Nutrition 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 9
- 239000003765 sweetening agent Substances 0.000 claims description 9
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 229940069328 povidone Drugs 0.000 claims description 7
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 6
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 4
- 239000005995 Aluminium silicate Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 235000012211 aluminium silicate Nutrition 0.000 claims description 4
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 235000001055 magnesium Nutrition 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000010981 methylcellulose Nutrition 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 claims description 2
- 244000223760 Cinnamomum zeylanicum Species 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims description 2
- 244000131522 Citrus pyriformis Species 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims description 2
- 239000005770 Eugenol Substances 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 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 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960005164 acesulfame Drugs 0.000 claims description 2
- -1 anetol Chemical compound 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 235000021466 carotenoid Nutrition 0.000 claims description 2
- 150000001747 carotenoids Chemical class 0.000 claims description 2
- 229930002875 chlorophyll Natural products 0.000 claims description 2
- 235000019804 chlorophyll Nutrition 0.000 claims description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 2
- 229960005233 cineole Drugs 0.000 claims description 2
- 235000017803 cinnamon Nutrition 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229960002217 eugenol Drugs 0.000 claims description 2
- 229960002737 fructose Drugs 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 229940091250 magnesium supplement Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 229940041616 menthol Drugs 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229960001047 methyl salicylate Drugs 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000002020 sage Nutrition 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 239000007916 tablet composition Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 26
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003908 quality control method Methods 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
- A61K9/0012—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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/2013—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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to pharmaceutical formulations comprising aripiprazole so as to be used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder.
- Aripiprazole was firstly disclosed in the application numbered EP367141. In said document, it was explained that aripiprazole is effective in the treatment of schizophrenia.
- Aripiprazole is available in the form of 1 mg/ml oral solution and 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets on the market.
- the excipients and their amounts used in the preparation of the formulations are important for the formulations comprising aripiprazole to be in desired weight and size and to have the optimum physical properties. Failure of the obtained tablets to reach the desired mass due to use of low doses of aripiprazole as active agent in the preparation of formulations comprising aripiprazole leads to the result that the final product does not have the desired tablet weight and size.
- the inventors have observed that the substances in the formulation are easily combined, weight uniformity is obtained by providing smooth flow and an effective treatment is obtained with the tablet forms having desired physical properties in the case that the formulations comprising aripiprazole and formulated in the form of orodispersible tablet comprise diluent in the range of 55 to 90% and have a ratio of diluent: disintegrant in the range of 1 :1 to 20:1.
- the present invention relates to pharmaceutical formulations comprising aripiprazole.
- the inventors have observed that the substances in the formulation are easily combined, weight uniformity is obtained by providing smooth flow, and an effective treatment is obtained with the tablet forms having desired physical properties; in the case that the formulations comprising aripiprazole and formulated in the form of orodispersible tablet comprise diluent in the range of 55 to 90% and have a ratio of diluent: disintegrant in the range of 1 :1 to 20:1.
- the first constituent of the invention is formulations comprising aripiprazole and formulated in the form of orodispersible tablet, characterized in that said formulation comprises diluent in the range of 55 to 90% and has a ratio of diluent: disintegrant in the range of 1 : 1 to 20: 1.
- the ratio of diluent: disintegrant is preferably in the range of 3:1 to 5:1 by weight.
- the diluent used according to the invention was selected from a group comprising D- mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.
- a pharmaceutical composition comprising aripiprazole, characterized in that the diluent used is selected from a group comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose and combinations thereof.
- a pharmaceutical composition comprising aripiprazole, characterized in that the diluent used is more preferably a mixture comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone and dibasic calcium phosphate anhydrose.
- Dissolution rate of the pharmaceutical composition comprising aripiprazole formulated in orodispersible tablet form is a considerably important parameter for the bioavailability of the drug and the effectiveness of the treatment. Accordingly, the inventors have observed that the weight of each diluent agent used in the diluent mixture has an influence on the dissolution rate of the obtained tablet form.
- the obtained aripiprazol tablet forms can dissolve more rapidly and a high bioavailability can be obtained.
- the present invention relates to the pharmaceutical composition
- aripiprazol formulated in the form of orodispersible tablet form wherein said composition comprises a diluent mixture comprising D-mannitol in the range of 40-80%), xylitol in the range of 1-15%, microcrystalline cellulose in the range of 5-30%, crospovidone in the range of 3-15% and dibasic calcium phosphate anhydrous in the range of 1-20% in proportion to the total weight of the mixture.
- the ratio of aripiprazol active agent to the diluent mixture by weight also has an effect on the solubility and the dispersion rate of the orodispersible aripiprazol tablet in the mouth. It has been seen that when the ratio of aripiprazol to the diluent mixture is in the range of 1 :15 to 5:1, preferably 1 :12 to 1 :1, more preferably 1:10 to 1 :2 by weight, a high solubility and rapid dispersion can be obtained.
- the present invention relates to the pharmaceutical compositions comprising aripiprazol formulated in the form of orodispersible tablet form wherein the ratio of aripiprazol active agent to the diluent mixture is in the range of 1 :15 to 5:1, preferably 1 :12 to 1 : 1 , more preferably 1 : 10 to 1 :2 by weight.
- the disintegrant used within the scope of the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
- a pharmaceutical composition comprising aripiprazole, characterized in that said composition preferably comprises povidone as disintegrant.
- the formulations of the invention can comprise at least one pharmaceutically acceptable excipient in addition to the active agent aripiprazole, diluent and disintegrant.
- the pharmaceutically acceptable excipients to be used in addition to aripiprazole, diluent and disintegrant in the present invention can be selected from a group comprising lubricant, binder, coloring agent, sweetener and flavoring agent.
- the lubricant that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
- the binder that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methylcellulose, povidone.
- the sweetener that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising acesulfame, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
- the flavoring agent that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising menthol, menthane, anetol, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry or combinations thereof.
- the coloring agent that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising carotenoids, chlorophyll and yellow iron oxide or combinations thereof.
- a pharmaceutical formulation comprising aripiprazole according to a preferred embodiment of the invention, characterized in that the coloring agent used in it is preferably yellow iron oxide.
- aripiprazole in the formulations of the invention comprising aripiprazole, diluent and disintegrant, aripiprazole can be in the range of 0.1 to 75%, preferably in the range of 2 to 60%, more preferably in the range of 3 to 50% by weight.
- aripiprazole active agent is an important criteria for obtaining homogeneous and highly dispersible tablet formulations comprising aripiprazole.
- the inventors have studied on the dispersion rate of the formulation by using aripiprazole having different average particle size. Based on the study, they have observed that when aripiprazol having average particle size in the range of 50-350 ⁇ , preferably 75- 300 ⁇ and more preferably 100- 250 ⁇ is used as active agent, the obtained aripiprazole tablets can disperse more rapidly and homogeneously.
- the present invention relates to pharmaceutical compositions comprising aripiprazol formulated in the form of orodispersible tablet form wherein aripiprazol having average particle size in the range of 50-350 ⁇ , preferably 75-300 ⁇ and more preferably 100- 250 ⁇ is used as active agent.
- the formulations prepared according to the present invention can comprise diluent in the range of 10 to 99%, preferably in the range of 30 to 95%, more preferably in the range of 55 to 90% in proportion to the total weight of the unit dosage form.
- the formulations prepared according to the present invention can comprise disintegrant in the range of 1 to 20%, sweetener in the range of 0.1 to 15%», flavoring agent in the range of 0.1 to 10%, lubricant in the range of 0.1 to 5%, coloring agent in the range of 0.1 to 10% in proportion to the total weight of the unit dosage form.
- disintegrant in the range of 1 to 20%
- sweetener in the range of 0.1 to 15%
- flavoring agent in the range of 0.1 to 10%
- lubricant in the range of 0.1 to 5%
- coloring agent in the range of 0.1 to 10% in proportion to the total weight of the unit dosage form.
- Another characteristic of the present invention is that compacting is performed twice during the production of the formulations and the obtained orodispersible aripiprazole tablets have the property of fast dispersibility.
- the production method for the preparation of pharmaceutical formulations of the invention comprises the following steps:
- the pharmaceutical formulation of the invention can be used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder.
- aripiprazole, diluent, coloring agent, flavoring agent, sweetener and povidone are mixed together and sieved.
- Lubricant is added into this mixture and mixed again.
- the obtained mixture is taken into the compacting machine, compacted, sieved; and the same process is applied again.
- the mixture sieved again after the 2 nd compacting process is compressed into tablets.
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Abstract
The present invention relates to pharmaceutical formulations comprising aripiprazole to be used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder.
Description
PHARMACEUTICAL FORMULATIONS COMPRISING ARIPIPRAZOLE
The present invention relates to pharmaceutical formulations comprising aripiprazole so as to be used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder. Aripiprazole was firstly disclosed in the application numbered EP367141. In said document, it was explained that aripiprazole is effective in the treatment of schizophrenia.
Aripiprazole is available in the form of 1 mg/ml oral solution and 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets on the market. The excipients and their amounts used in the preparation of the formulations are important for the formulations comprising aripiprazole to be in desired weight and size and to have the optimum physical properties. Failure of the obtained tablets to reach the desired mass due to use of low doses of aripiprazole as active agent in the preparation of formulations comprising aripiprazole leads to the result that the final product does not have the desired tablet weight and size. Besides, there are also some difficulties experienced in combining the dry mixture of active agent and excipients in a desired form and providing a smooth flow of the mixture obtained by direct compacting while compressing the formulations comprising aripiprazole into tablets. Failure to enable smooth flow leads to failure to provide weight and dose uniformity in the tablets obtained. This case causes problems for the producer in the production and quality control phases; and also makes the patient unable to take same amounts of doses during the treatment due to the deficiency of weight and dose uniformity in the obtained dosage forms. As a result, these problems seen in the prior art leads to a decrease in the efficiency of the treatment.
As can be seen, there is still need for developing new approaches to obtain aripiprazole formulations with optimum physical characteristics in order to combine the active agent and
the excipients effectively in the formulations that can be prepared by direct compacting; and to obtain smooth flow and provide weight uniformity enabling the product in tablet form to be in desired weight and sizes.
Surprisingly, the inventors have observed that the substances in the formulation are easily combined, weight uniformity is obtained by providing smooth flow and an effective treatment is obtained with the tablet forms having desired physical properties in the case that the formulations comprising aripiprazole and formulated in the form of orodispersible tablet comprise diluent in the range of 55 to 90% and have a ratio of diluent: disintegrant in the range of 1 :1 to 20:1. Description of the Invention
The present invention relates to pharmaceutical formulations comprising aripiprazole. As a result of the studies conducted for this need, the inventors have observed that the substances in the formulation are easily combined, weight uniformity is obtained by providing smooth flow, and an effective treatment is obtained with the tablet forms having desired physical properties; in the case that the formulations comprising aripiprazole and formulated in the form of orodispersible tablet comprise diluent in the range of 55 to 90% and have a ratio of diluent: disintegrant in the range of 1 :1 to 20:1.
According to this, the first constituent of the invention is formulations comprising aripiprazole and formulated in the form of orodispersible tablet, characterized in that said formulation comprises diluent in the range of 55 to 90% and has a ratio of diluent: disintegrant in the range of 1 : 1 to 20: 1.
In a preferred embodiment of the invention, the ratio of diluent: disintegrant is preferably in the range of 3:1 to 5:1 by weight.
The diluent used according to the invention was selected from a group comprising D- mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.
According to a preferred embodiment of the invention, a pharmaceutical composition comprising aripiprazole, characterized in that the diluent used is selected from a group
comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose and combinations thereof.
According to a preferred embodiment of the invention, a pharmaceutical composition comprising aripiprazole, characterized in that the diluent used is more preferably a mixture comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone and dibasic calcium phosphate anhydrose.
Dissolution rate of the pharmaceutical composition comprising aripiprazole formulated in orodispersible tablet form is a considerably important parameter for the bioavailability of the drug and the effectiveness of the treatment. Accordingly, the inventors have observed that the weight of each diluent agent used in the diluent mixture has an influence on the dissolution rate of the obtained tablet form. They have seen that when the diluent mixture comprises D- mannitol in the range of 40-80%, xylitol in the range of 1-15%, microcrystalline cellulose in the range of 5-30%, crospovidone in the range of 3-15% and dibasic calcium phosphate anhydrous in the range of 1-20% in proportion to the total weight of the mixture, the obtained aripiprazol tablet forms can dissolve more rapidly and a high bioavailability can be obtained.
In another aspect, the present invention relates to the pharmaceutical composition comprising aripiprazol formulated in the form of orodispersible tablet form wherein said composition comprises a diluent mixture comprising D-mannitol in the range of 40-80%), xylitol in the range of 1-15%, microcrystalline cellulose in the range of 5-30%, crospovidone in the range of 3-15% and dibasic calcium phosphate anhydrous in the range of 1-20% in proportion to the total weight of the mixture.
The inventors have also observed that the ratio of aripiprazol active agent to the diluent mixture by weight also has an effect on the solubility and the dispersion rate of the orodispersible aripiprazol tablet in the mouth. It has been seen that when the ratio of aripiprazol to the diluent mixture is in the range of 1 :15 to 5:1, preferably 1 :12 to 1 :1, more preferably 1:10 to 1 :2 by weight, a high solubility and rapid dispersion can be obtained.
In another aspect, the present invention relates to the pharmaceutical compositions comprising aripiprazol formulated in the form of orodispersible tablet form wherein the ratio of aripiprazol active agent to the diluent mixture is in the range of 1 :15 to 5:1, preferably 1 :12 to 1 : 1 , more preferably 1 : 10 to 1 :2 by weight.
The disintegrant used within the scope of the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
According to a preferred embodiment of the invention, a pharmaceutical composition comprising aripiprazole, characterized in that said composition preferably comprises povidone as disintegrant.
The formulations of the invention can comprise at least one pharmaceutically acceptable excipient in addition to the active agent aripiprazole, diluent and disintegrant.
According to this, the pharmaceutically acceptable excipients to be used in addition to aripiprazole, diluent and disintegrant in the present invention can be selected from a group comprising lubricant, binder, coloring agent, sweetener and flavoring agent.
The lubricant that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
The binder that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methylcellulose, povidone.
The sweetener that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising acesulfame, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose. The flavoring agent that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising menthol, menthane, anetol, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry or combinations thereof.
The coloring agent that can be used in the formulations of the invention comprising aripiprazole, diluent and disintegrant can be selected from a group comprising carotenoids, chlorophyll and yellow iron oxide or combinations thereof.
A pharmaceutical formulation comprising aripiprazole according to a preferred embodiment of the invention, characterized in that the coloring agent used in it is preferably yellow iron oxide.
The % amount values given within the scope of the invention were calculated in proportion to the unit dosage weight.
In the formulations of the invention comprising aripiprazole, diluent and disintegrant, aripiprazole can be in the range of 0.1 to 75%, preferably in the range of 2 to 60%, more preferably in the range of 3 to 50% by weight.
It is known that the average particle size of aripiprazole active agent is an important criteria for obtaining homogeneous and highly dispersible tablet formulations comprising aripiprazole. The inventors have studied on the dispersion rate of the formulation by using aripiprazole having different average particle size. Based on the study, they have observed that when aripiprazol having average particle size in the range of 50-350 μπι, preferably 75- 300 μιη and more preferably 100- 250 μιη is used as active agent, the obtained aripiprazole tablets can disperse more rapidly and homogeneously.
In another aspect, the present invention relates to pharmaceutical compositions comprising aripiprazol formulated in the form of orodispersible tablet form wherein aripiprazol having average particle size in the range of 50-350 μιη, preferably 75-300 μηι and more preferably 100- 250 μιη is used as active agent.
The formulations prepared according to the present invention can comprise diluent in the range of 10 to 99%, preferably in the range of 30 to 95%, more preferably in the range of 55 to 90% in proportion to the total weight of the unit dosage form.
The formulations prepared according to the present invention can comprise disintegrant in the range of 1 to 20%, sweetener in the range of 0.1 to 15%», flavoring agent in the range of 0.1 to 10%, lubricant in the range of 0.1 to 5%, coloring agent in the range of 0.1 to 10% in proportion to the total weight of the unit dosage form.
One of the problems faced during the preparation of tablets comprising aripiprazole is that tablets do not disperse fast and effectively in the mouth after they are compressed. As a result of the studies conducted for this need, the inventors obtained aripiprazole tablets that can disperse faster and more effectively by the method of compacting twice.
According to this, another characteristic of the present invention is that compacting is performed twice during the production of the formulations and the obtained orodispersible aripiprazole tablets have the property of fast dispersibility.
The production method for the preparation of pharmaceutical formulations of the invention comprises the following steps:
• Mixing the active agent aripiprazole with diluent, disintegrant, coloring agent, sweetener and flavoring agent; and sieving this mixture
• Adding lubricant into the mixture and mixing it again
• Compacting the obtained mixture once and sieving it
• Compacting the mixture for the second time and sieving it again
• And compressing the final mixture obtained into tablets.
The pharmaceutical formulation of the invention can be used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder.
EXAMPLE: Formulation and process for preparation of orodispersible tablets comprising aripiprazole
To obtain the formulation to be used within the scope of said invention; aripiprazole, diluent, coloring agent, flavoring agent, sweetener and povidone are mixed together and sieved. Lubricant is added into this mixture and mixed again. The obtained mixture is taken into the compacting machine, compacted, sieved; and the same process is applied again. The mixture sieved again after the 2nd compacting process is compressed into tablets.
Claims
1. Orodispersible tablet formulation comprising aripiprazole, characterized in that said formulation comprises diluent in the range of 55 to 90% by weight and the ratio of diluent: disintegrant is in the range of 1 :1 to 20:1 by weight.
2. The pharmaceutical formulation comprising aripiprazole according to claim 1, characterized in that the ratio of diluent: disintegrant is in the range of 3:1 to 15:1 by weight.
3. The pharmaceutical formulation according to claims 1 and 2, characterized in that the diluent is selected from a group comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and combinations thereof.
4. The pharmaceutical formulation according to claim 3, characterized in that the diluent is selected from a group comprising D-mannitol, xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose and combinations thereof.
5. The pharmaceutical formulation according to claim 4, characterized in that the diluent is preferably a combination comprising xylitol, microcrystalline cellulose, crospovidone, dibasic calcium phosphate anhydrose.
6. The pharmaceutical formulation according to claims 1-5, characterized in that said formulation comprises a diluent mixture comprising D-mannitol in the range of 40- 80%, xylitol in the range of 1-15%, microcrystalline cellulose in the range of 5-30%, crospovidone in the range of 3-15% and dibasic calcium phosphate anhydrous in the range of 1 -20% in proportion to the total weight of the mixture.
7. The pharmaceutical formulation according to claims 1-6, characterized in that the ratio of aripiprazol active agent to the diluent mixture is in the range of 1 : 15 to 5: 1 ,
8. The pharmaceutical formulation according to claim 7, characterized in that the ratio of aripiprazol active agent to the diluent mixture is in the range of l :12 to 1 : 1.
9. The pharmaceutical formulation according to claim 8, characterized in that the ratio of aripiprazol active agent to the diluent mixture is in the range of 1 : 10 to 1 :2 by weight.
10. The pharmaceutical formulation according to claims 1 to 9, characterized in that the disintegrant is selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
11. The pharmaceutical formulation according to claim 10, characterized in that said formulation comprises povidone as disintegrant.
12. The pharmaceutical formulation according to claims 1 to 11, characterized in that said formulation comprises at least one pharmaceutically acceptable excipient in addition to aripiprazole, diluent and disintegrant.
13. The pharmaceutical formulation according to claim 12, characterized in that the pharmaceutically acceptable excipients that can be used in addition to aripiprazole, diluent and disintegrant are selected from a group comprising lubricant, binder, coloring agent, sweetener and flavoring agent.
14. The pharmaceutical formulation according to claim 13, characterized in that the lubricant is selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
15. The pharmaceutical formulation according to claim 13, characterized in that the binder is selected from a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methylcellulose, povidone.
16. The pharmaceutical formulation according to claim 13, characterized in that the sweetener is selected from a group comprising acesulfame, aspartame, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
17. The pharmaceutical formulation according to claim 13, characterized in that the flavoring agent is selected from a group comprising menthol, menthane, anetol, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, lemon, orange, strawberry, blackberry or combinations thereof.
18. The pharmaceutical formulation according to claim 13, characterized in that the coloring agent is selected from a group comprising carotenoids, chlorophyll and yellow iron oxide or a combination thereof.
19. The pharmaceutical formulation according to claim 18, characterized in that said formulation comprises yellow iron oxide as coloring agent.
20. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises aripiprazole in the range of 0.1 to 75% by weight.
21. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises aripiprazol having average particle size in the range of 50-350 μπι.
22. The pharmaceutical formulation comprising aripiprazole according to claim 21 , characterized in that said formulation comprises aripiprazol having average particle size in the range of 75-300 μπι.
23. The pharmaceutical formulation comprising aripiprazole according to claim 22, characterized in that said formulation comprises aripiprazol having average particle size in the range of 100- 250 μπι is used as active agent.
24. The formulation according to claim 23, characterized in that said formulation comprises aripiprazole in the range of 2 to 60% by weight.
25. The formulation according to claim 24, characterized in that said formulation comprises aripiprazole in the range of 3 to 50% by weight.
26. The formulation according to any one of the preceding claims, characterized in that said formulation comprises diluent in the range of 10 to 99% in proportion to the total weight of the unit dose amount.
27. The formulation according to claim 26, characterized in that said formulation comprises diluent in the range of 30 to 95% by weight.
28. The formulation according to claim 27, characterized in that said formulation comprises diluent in the range of 55 to 90% by weight.
29. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises disintegrant in the range of 1 to 20% by weight.
30. The formulation according to any one of the preceding claims, characterized in that said formulation comprises lubricant in the range of 1 to 20% by weight.
31. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises sweetener in the range of 0.1 to 15% by weight.
32. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises flavoring agent in the range of 0.1 to 10% by weight.
33. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, characterized in that said formulation comprises coloring agent in the range of 0.1 to 10%.
34. The process for preparation of the pharmaceutical formulation comprising aripiprazole according o any one of the preceding claims, characterized in that it is obtained by a method comprising the steps of:
• Mixing the active agent aripiprazole with diluent, disintegrant, coloring agent, sweetener and flavoring agent; and sieving this mixture
• Adding lubricant into the mixture and mixing it again
• Compacting the obtained mixture once and sieving it
• Compacting the mixture for the second time and sieving it again
• And compressing the final mixture obtained into tablets.
35. The pharmaceutical formulation comprising aripiprazole according to any one of the preceding claims, wherein said formulation is used in the treatment of irritability associated with schizophrenia, bipolar disorder, major depression and autistic disorder.
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| Application Number | Priority Date | Filing Date | Title |
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| TR2011/12993 | 2011-12-27 | ||
| TR201112993 | 2011-12-27 | ||
| TR201203834 | 2012-04-04 | ||
| TR2012/03834 | 2012-04-04 |
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| WO2013100878A1 true WO2013100878A1 (en) | 2013-07-04 |
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| PCT/TR2012/000234 WO2013100878A1 (en) | 2011-12-27 | 2012-12-27 | Pharmaceutical formulations comprising aripiprazole |
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| CN103860494A (en) * | 2014-01-24 | 2014-06-18 | 浙江美华鼎昌医药科技有限公司 | Aripiprazole tablet and preparation method of aripiprazole tablet |
| WO2014173515A1 (en) * | 2013-04-22 | 2014-10-30 | Pharmathen S.A. | Pharmaceutical composition comprising an atypical antipsychotic agent and method for the preparation thereof |
| WO2015067313A1 (en) | 2013-11-07 | 2015-05-14 | Synthon B.V. | Orodispersible pharmaceutical compositions comprising aripiprazole |
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| DE102010019416A1 (en) * | 2010-05-04 | 2011-11-10 | Stada Arzneimittel Ag | Orodispersible tablet comprising a triptan or an atypical neuroleptic |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014173515A1 (en) * | 2013-04-22 | 2014-10-30 | Pharmathen S.A. | Pharmaceutical composition comprising an atypical antipsychotic agent and method for the preparation thereof |
| WO2015067313A1 (en) | 2013-11-07 | 2015-05-14 | Synthon B.V. | Orodispersible pharmaceutical compositions comprising aripiprazole |
| CN103860494A (en) * | 2014-01-24 | 2014-06-18 | 浙江美华鼎昌医药科技有限公司 | Aripiprazole tablet and preparation method of aripiprazole tablet |
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