CN1294512A - 帕罗西汀组合物 - Google Patents
帕罗西汀组合物 Download PDFInfo
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- CN1294512A CN1294512A CN99804347A CN99804347A CN1294512A CN 1294512 A CN1294512 A CN 1294512A CN 99804347 A CN99804347 A CN 99804347A CN 99804347 A CN99804347 A CN 99804347A CN 1294512 A CN1294512 A CN 1294512A
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- Prior art keywords
- paroxetine
- solid carrier
- pharmaceutically acceptable
- solvent
- adsorbed
- Prior art date
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- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 70
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 title claims abstract description 50
- 229960002296 paroxetine Drugs 0.000 title claims abstract description 50
- 239000000203 mixture Substances 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 27
- 239000003513 alkali Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 241001597008 Nomeidae Species 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000000935 solvent evaporation Methods 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000012876 carrier material Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000001694 spray drying Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 239000002775 capsule Substances 0.000 abstract description 5
- 239000000843 powder Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- 229960005183 paroxetine hydrochloride Drugs 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
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- -1 potassium hydroxide paroxetine chemical compound Chemical class 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- 239000012458 free base Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 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 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
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- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 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
- 239000001828 Gelatine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 description 1
- 238000013019 agitation Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
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- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
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- 206010027599 migraine Diseases 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 238000011287 therapeutic dose Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 208000002271 trichotillomania Diseases 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
- A61K9/2004—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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
将帕罗西汀吸附在载体上,以形成用于填充胶囊或形成片剂的可自由流动粉末;并用于治疗抑郁症。
Description
本发明涉及药物活性化合物的新制剂，尤其是帕罗西汀新制剂。
US-A-3912743和US-A-4007196中描述了具有抗抑郁和抗帕金森氏病特性的药物产品。在其中所公开的化合物当中，特别重要的化合物是帕罗西汀，即4-(4’-氟苯基)-3-(3’，4’-亚甲二氧基苯氧基甲基)哌啶的(-)反式异构体。
在文献中，帕罗西汀通常是以酸加成盐、尤其是盐酸盐形式分离到的。帕罗西汀已被批准以盐酸盐形式在人中使用，并且已被建议用于治疗和预防特别是抑郁症、强迫观念与行为性障碍(OCD)以及恐慌症。
文献中已描述过作为结晶半水合物(参见Beecham Group的EP-A-0223403)和各种无水结晶(参见SmithKline Beecham的WO96／24595)形式的盐酸帕罗西汀。
迄今为止，帕罗西汀游离碱已经作为油状物在文献中公开过，该游离碱本身还没有被考虑用于治疗，更易于纯化和加工成剂型的结晶形式一直是优选的。
本发明是基于下述发现完成的，即当吸附到固体载体上或被固体载体吸收时，帕罗西汀例如帕罗西汀游离碱能有利地配制成药物组合物。
本发明提供了药物组合物，其中包含吸附到可药用固体载体上或被可药用固体载体吸收的帕罗西汀或其可药用衍生物，本发明还提供了所述组合物作为治疗剂的应用或在生产药物中的应用。
通过本发明，可获得在治疗中可直接使用(例如通过直接压制成片剂)或与其它混合组分一起使用的可自由流动粉末。
用于实施本发明的帕罗西汀优选为帕罗西汀游离碱，但是也可以是其可药用衍生物例如盐、尤其是盐酸盐。
通过将帕罗西汀溶液与合适的吸附或吸收材料混合，并将溶剂蒸发、例如通过喷雾干燥将溶剂蒸发，可方便地获得本发明组合物。合适的溶剂有甲苯、乙醇、丙酮、丙-2-醇、或乙酸乙酯、或任意其它适当溶剂或溶剂混合物，溶液中帕罗西汀浓度为1-20％、更优选为1-4％。
或者，可将通过把溶剂从溶液中除去而获得的油状物与固体吸附或吸收材料混合。
选作帕罗西汀载体的材料通常为适于形成片剂或作为明胶胶囊填充材料的赋形剂，例如环糊精(β和／或γ环糊精)、多孔硅酸盐、淀粉、乳糖或磷酸钙、二氧化硅、山梨醇、麦芽糖糊精、微晶纤维素或纤维素粉末、羧甲基纤维素钠或羧甲基纤维素钙、碳酸钙、高岭土、硅酸镁铝。此外，可溶性赋形剂例如硬脂酸镁可形成部分溶液相。
还具有味道掩饰作用的载体例如离子交换树脂是有利的。
帕罗西汀游离碱溶液可通过将碱例如三乙胺加到结晶帕罗西汀盐、尤其是盐酸盐或乙酸盐的溶液中来制得。或者该溶液可通过将非晶形盐酸帕罗西汀、或无水结晶或水合形式的盐酸帕罗西汀的溶液碱化而制得。
US 4007196的实施例2中描述了帕罗西汀游离碱及其马来酸盐的制备。其乙酸盐也可用作原料。EP-A-0223403中描述了形成盐的方法。
此外，可通过将碱例如氢氧化钾加到N-保护的帕罗西汀化合物例如N-苯氧基羰基帕罗西汀的溶液中来制得帕罗西汀游离碱溶液或油状物。
在配制包含吸附到固体载体上或被固体载体吸收的帕罗西汀的本发明组合物时，可使用或不使用用于片剂形成或用作胶囊填充粉末的常规赋形剂。
将帕罗西汀的用量调节为在单位剂量中含有治疗有效量的帕罗西汀。单位剂量优选含有10-100mg帕罗西汀(按帕罗西汀游离碱计)。帕罗西汀在单位剂量中的含量更优选为10mg、20mg、30mg、40mg或50mg。单位剂量中帕罗西汀的含量最优选为20mg。
本发明帕罗西汀产品的治疗应用包括治疗：酒精中毒、焦虑症、抑郁症、强迫观念与行为性障碍、恐慌症、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、厌食症、社交恐怖症、经前期综合征(PMS)、青春期抑郁症、拔毛发癖、精神抑郁症和药物滥用，这些病症在下文中称为“病症”。
因此，本发明还提供了：
用于治疗或预防所述病症的药物组合物，其中包含吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物，和任选含有的至少一种其它可药用赋形剂；
吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物在制备用于治疗或预防所述病症的药物中的应用；和
治疗所述病症的方法，其包括将治疗或预防有效量的吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物对患有一种或多种所述病症的患者给药。
通过下述实施例举例说明本发明。
实施例1：制备含有帕罗西汀游离碱的片剂预混物
在键控成粒机中以240r．p．m．的搅拌速度和3000r．p．m．的叶轮推进速度将磷酸氢二钙二水合物(408g)、羟丙基甲基纤维素(25g)和羟乙酸淀粉钠(25g)的混合物混合3分钟。以约4ml／分钟的速度用13．5分钟加入纯化水(57ml)，同时将键控成粒机的搅拌速度设置为240r．p．m．、叶轮推进速度设置为1500r．p．m．。将该混合物继续搅拌1分钟，把所得颗粒在热空气箱中于50℃干燥3小时。
将一部分上述制得的颗粒(50g)加到帕罗西汀游离碱(2．0g)的丙-2-醇(50ml)溶液中，把所得浆状物在搅拌下于50℃真空干燥。
该产物适于直接压制成含有10、20、或30mg帕罗西汀的片剂。
实施例2：制备固体负载形式的帕罗西汀游离碱
将N-苯氧基羰基帕罗西汀(50．0g)、氢氧化钾(45．0g)和甲苯(750ml)的搅拌混合物在氮气氛下加热回流3小时。将该混合物冷却至室温后，加入蒸馏水(500ml)，将该混合物搅拌30分钟。分离有机层，用硫酸镁干燥，浓缩至总体积为85ml。
将甲苯(100ml)加到帕罗西汀游离胺甲苯溶液(0．43g／ml)的等分试样(2．4ml)中，向该溶液中加入硅藻土(25．0g)，并将该混合物搅拌5分钟。把溶剂减压除去(55℃水浴)，获得了负载在硅藻土上的帕罗西汀游离胺，为可自由流动粉状固体(26．0g)。
该产物可与其它赋形剂混合并压制成片，或者直接装到胶囊壳中，以制得含有治疗剂量帕罗西汀的产品。
实施例3：将盐酸帕罗西汀溶液喷雾干燥到悬浮载体材料上
将无水盐酸帕罗西汀(60g)溶于无水乙醇(725ml)，用麦芽糖糊精DE4-6(506g)将该澄清溶液浆化。将该均匀悬浮液在NiroMobile Minor(TM)闭合循环喷雾干燥器中喷雾干燥，其中使用氮气作为工艺气体，旋转雾化器轮以27000r．p．m．的转速旋转(或者可使用并流或喷泉式双流喷嘴)，入口温度为96-104℃，出口温度为44-50℃，进料速度为4．1kg／小时。获得了平均粒径为84微米的白色可自由流动产物(490g)。
实施例4：制备含有盐酸帕罗西汀的片剂预混物
在键控成粒机中以240r．p．m．的搅拌速度和3000r．p．m．的叶轮推进速度将磷酸氢二钙二水合物(408g)、羟丙基甲基纤维素(25g)和羟乙酸淀粉钠(25g)的混合物混合3分钟。以约4ml／分钟的速度用13．5分钟加入纯化水(57ml)，同时将键控成粒机的搅拌速度设置为240r．p．m．、叶轮推进速度设置为1500r．p．m．。将该混合物继续搅拌1分钟，把所得颗粒在热空气箱中于50℃干燥3小时。
将盐酸帕罗西汀半水合物(2．0g)的乙醇(100ml)溶液加到上述制得的颗粒(50g)中，把所得浆状物在50℃真空干燥。
实施例5：制备含有盐酸帕罗西汀的片剂预混物
将盐酸帕罗西汀半水合物(2．0g)的乙醇(150ml)溶液加到硅藻土(50g)中，搅拌混合物，把所得浆状物在50℃真空干燥，获得了适于用作片剂或胶囊制剂组分的可自由流动粉状固体。
实施例6：制备含有盐酸帕罗西汀的片剂预混物
将N-苯氧基羰基帕罗西汀(50．0g)、氢氧化钾(45．0g)和甲苯(750ml)的搅拌混合物在氮气氛下加热回流3小时。将该混合物冷却至室温后，加入蒸馏水(500ml)，将该混合物搅拌30分钟。分离有机层，用硫酸镁干燥并过滤。将帕罗西汀游离胺的甲苯溶液[0．048g／ml]的等分试样(21．0ml)用30ml甲苯稀释并加热至60℃。加入浓盐酸(0．34ml)，将该混合物搅拌10分钟。加入如实施例4所述制得的片剂颗粒(25．0g)，将该混合物在60℃搅拌5分钟。在70℃将溶剂减压除去，获得了可自由流动粉状固体(26．0g)。
实施例7：制备含有盐酸帕罗西汀的片剂预混物
在60℃、搅拌下，将浓盐酸(0．34ml)加到乙酸帕罗西汀(1．18g)的甲苯(50ml)溶液中，将该混合物搅拌10分钟。加入如实施例4所述制得的片剂颗粒(25．0g)，将该混合物在60℃搅拌5分钟。在70℃将溶剂减压除去，获得了可自由流动粉状固体(26．0g)。
Claims (9)
1．吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物。
2．含有吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物的药物组合物。
3．吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物在制备用于治疗抑郁症的药物中的用途。
4．治疗抑郁症的方法，包括将有效量的吸附在固体载体上或被固体载体吸收的帕罗西汀或其可药用衍生物对抑郁症患者给药。
5．前述权利要求任一项的组合物、用途或方法，其中所述帕罗西汀呈其游离碱形式。
6．制备权利要求1、2或5的组合物的方法，包括将帕罗西汀或其可药用衍生物的溶液与吸附或吸收固体载体材料混合，并将溶剂蒸发。
7．根据权利要求6的方法，其中在溶剂蒸发前将载体材料悬浮在溶剂中。
8．根据权利要求6的方法，其中在溶剂蒸发前将载体材料溶解在溶剂中。
9．根据权利要求6或8任一项的方法，其中溶剂的蒸发是通过喷雾干燥进行的。
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| GBGB9806312.6A GB9806312D0 (en) | 1998-03-24 | 1998-03-24 | Novel formulations |
| GB9806312.6 | 1998-03-24 |
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| CN103961333A (zh) * | 2014-05-07 | 2014-08-06 | 浙江华海药业股份有限公司 | 甲磺酸帕罗西汀胶囊及其制备方法 |
| CN104027306A (zh) * | 2014-06-25 | 2014-09-10 | 万特制药(海南)有限公司 | 帕罗西汀口服混悬液及其制备方法 |
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| GB9914600D0 (en) * | 1999-06-22 | 1999-08-25 | Smithkline Beecham Plc | Novel,process |
| DK200100341A (da) * | 2001-03-02 | 2002-09-03 | Gea Farmaceutisk Fabrik As | Fremgangsmåde til fremstilling af farmaceutiske tabletter indeholdende paroxetinhydrochlorid-anhydrat |
| EP1643975A2 (en) * | 2003-07-02 | 2006-04-12 | Abbott Laboratories | Process for preparing formulations of lipid-regulating drugs |
| US8062664B2 (en) | 2003-11-12 | 2011-11-22 | Abbott Laboratories | Process for preparing formulations of lipid-regulating drugs |
| HU1000278D0 (en) * | 2010-05-28 | 2010-07-28 | Egis Gyogyszergyar Nyilvanosan | Novel pharmaceutical use uf silicic acid |
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| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| ES2058061T3 (es) * | 1985-10-25 | 1994-11-01 | Beecham Group Plc | Derivado de piperidina, su preparacion y su uso como medicamento. |
| AR001982A1 (es) * | 1995-02-06 | 1998-01-07 | Smithkline Beecham Plc | Clorhidrato de paroxetina anhidratado, y procedimiento para su preparacion |
| CA2206592A1 (en) * | 1996-05-30 | 1997-11-30 | Shu-Zhong Wang | Method of producing amorphous paroxetine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103961333A (zh) * | 2014-05-07 | 2014-08-06 | 浙江华海药业股份有限公司 | 甲磺酸帕罗西汀胶囊及其制备方法 |
| CN103961333B (zh) * | 2014-05-07 | 2020-02-21 | 浙江华海药业股份有限公司 | 甲磺酸帕罗西汀胶囊及其制备方法 |
| CN104027306A (zh) * | 2014-06-25 | 2014-09-10 | 万特制药(海南)有限公司 | 帕罗西汀口服混悬液及其制备方法 |
Also Published As
| Publication number | Publication date |
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| AU754765B2 (en) | 2002-11-21 |
| EP1063993A1 (en) | 2001-01-03 |
| NO313404B1 (no) | 2002-09-30 |
| IL138478A0 (en) | 2001-10-31 |
| CA2324612A1 (en) | 1999-09-30 |
| AU3045199A (en) | 1999-10-18 |
| BG104865A (en) | 2001-05-31 |
| TR200002750T2 (tr) | 2000-12-21 |
| ID26485A (id) | 2001-01-11 |
| CN1125639C (zh) | 2003-10-29 |
| WO1999048499A1 (en) | 1999-09-30 |
| NO20004740L (no) | 2000-10-03 |
| HUP0101326A2 (hu) | 2002-05-29 |
| JP2002507569A (ja) | 2002-03-12 |
| SK14102000A3 (sk) | 2001-03-12 |
| PL343095A1 (en) | 2001-07-30 |
| BR9908991A (pt) | 2000-12-12 |
| EA200000977A1 (ru) | 2001-02-26 |
| NZ506893A (en) | 2003-06-30 |
| AP2000001914A0 (en) | 2000-09-30 |
| HUP0101326A3 (en) | 2002-06-28 |
| EA003393B1 (ru) | 2003-04-24 |
| ZA200005697B (en) | 2001-10-02 |
| GB9806312D0 (en) | 1998-05-20 |
| NO20004740D0 (no) | 2000-09-22 |
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