CN1660074A - 含有依他普仑的晶体组合物 - Google Patents
含有依他普仑的晶体组合物 Download PDFInfo
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- CN1660074A CN1660074A CN2004100941660A CN200410094166A CN1660074A CN 1660074 A CN1660074 A CN 1660074A CN 2004100941660 A CN2004100941660 A CN 2004100941660A CN 200410094166 A CN200410094166 A CN 200410094166A CN 1660074 A CN1660074 A CN 1660074A
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- 229960004341 escitalopram Drugs 0.000 title claims description 25
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 title claims description 25
- 239000000203 mixture Substances 0.000 title claims description 19
- 239000002245 particle Substances 0.000 claims abstract description 47
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000007892 solid unit dosage form Substances 0.000 claims description 32
- 238000001816 cooling Methods 0.000 claims description 25
- 239000013078 crystal Substances 0.000 claims description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
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- 239000000314 lubricant Substances 0.000 claims description 8
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 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 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 235000011010 calcium phosphates Nutrition 0.000 claims description 4
- 235000013539 calcium stearate Nutrition 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
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- 238000000926 separation method Methods 0.000 claims description 4
- 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 claims description 4
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
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- 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 claims description 2
- 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 2
- 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 claims description 2
- 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004368 Modified starch Substances 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 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
- 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 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000019426 modified starch Nutrition 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 235000000346 sugar Nutrition 0.000 claims description 2
- 239000001993 wax Substances 0.000 claims description 2
- 229940054157 lexapro Drugs 0.000 claims 7
- 239000003513 alkali Substances 0.000 claims 3
- 230000014759 maintenance of location Effects 0.000 claims 2
- 239000008119 colloidal silica Substances 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 239000010413 mother solution Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 229960005086 escitalopram oxalate Drugs 0.000 abstract description 35
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 13
- 229960001653 citalopram Drugs 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 238000007907 direct compression Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 10
- 238000005469 granulation Methods 0.000 description 9
- 230000003179 granulation Effects 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229960000584 citalopram hydrobromide Drugs 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000011049 filling Methods 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 150000003891 oxalate salts Chemical class 0.000 description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
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- 238000007909 melt granulation Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 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
- 108010010803 Gelatin Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
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- 238000003825 pressing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
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- 150000008163 sugars Chemical class 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本申请公开了粒径为至少40μm的依他普仑草酸盐晶体颗粒。本申请还公开了制备所述晶体颗粒的方法以及包含所述晶体颗粒的药物组合物。
Description
本申请是申请日为2004年1月30日国家申请号为02815031.7的中国专利申请的分案申请。
本发明涉及化合物依他普仑(INN名称)的草酸盐的晶体制剂，其中依他普仑是众所周知的抗抑郁药物西酞普兰的S-对映体，即(S)-1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃甲腈草酸盐的晶体制剂。
技术背景
西酞普兰是具有下述结构的众所周知的抗抑郁药物：
其是选择性的中枢活性血清素(5-羟基色胺；5-HT)再摄取抑制剂，因此具有抗抑郁活性。
西酞普兰最早公开在相当于US 4,136,193的DE 2,657,013中。该专利出版物描述了通过一种方法来制备西酞普兰，并概要描述了可用于制备西酞普兰的另一种方法。所制得的西酞普兰是分别作为草酸盐、氢溴酸盐和盐酸盐以晶体形式分离出来的。另外，西酞普兰碱是作为油状物获得的(B.P.175℃/0.03mmHg)。该出版物还概要描述了含有西酞普兰盐的片剂的制备。西酞普兰分别以氢溴酸盐和盐酸盐的形式在市售。
US专利4,943,590中公开了依他普仑、其药理活性以及依他普仑草酸盐晶体。其中还概要描述了制备依他普仑的药物制剂的方法。
西酞普兰已作为片剂在很多国家中市售，这样的片剂是通过将西酞普兰氢溴酸盐颗粒、乳糖和其它赋形剂压缩来制得的。
公认的是，制备具有可再现组成的片剂需要所有干燥的组分都具有良好的流动性。当活性组分具有良好的流动性时，片剂可通过将组分直接压缩来制得。然而，在很多情况下，活性物质的粒径很小，活性物质是粘聚性的，或者具有不良的流动性。
此外，与具有较大粒径的赋形剂混和的具有小粒径的活性物质在制片过程中一般会分离或分层。
小粒径和不良流动性的问题一般是通过增大活性物质的粒径来解决的，增大活性物质的粒径一般是通过将单独或者与填充剂和/或其它常规片剂组分合并在一起的活性组分制粒来实现的。
一种这样的治疗方法是“湿法”制粒方法。使用该方法，将干燥固体(活性组分、填充剂、粘合剂等)混和，用水或另一种润湿剂(例如醇)润湿，将润湿的固体形成附聚物或颗粒。继续进行湿聚集直至已获得所需的均匀粒径，将粒化产物干燥。
“湿法”制粒的一个替代方法是“熔化”制粒，其也称为“热塑”制粒方法，其中是使用低熔点固体作为制粒剂。首先将干燥的固体混和，加热直至粘合剂熔化。因为粘合剂液化并散布在颗粒的表面上，微粒将彼此粘结并形成颗粒。在冷却时，粘合剂固化，形成干燥的颗粒产物。
湿法制粒以及熔化制粒都是能量加强的设备操作，需要复杂且昂贵的装置以及技术人员。
然而，如果活性组分具有合适的流动性，则可以不用制粒步骤，并且片剂可通过是低成本制备方法的直接压缩来制得。
用于制备西酞普兰氢溴酸盐的方法使得产物具有约2-20μm的小粒径，象具有小粒径的其它微粒产物一样，其具有非常不良的流动性。因此，在制片期间为了适当地配送西酞普兰氢溴酸盐的量，有人认为需要制备具有较大粒径和改善的流动性的西酞普兰氢溴酸盐。
市售西酞普兰片剂是用粒化的西酞普兰氢溴酸盐与各种赋形剂制得的。
我们已经发现，依他普仑具有显著不同于西酞普兰外消旋体的溶解度和成盐性质。例如，迄今为止已知的唯一药用结晶盐是草酸盐，而西酞普兰外消旋体也形成氢溴酸盐和盐酸盐结晶。
按照US专利4,943,590中概要描述的方法通过从丙酮中结晶而制得的依他普仑草酸盐产物象上述西酞普兰氢溴酸盐产物一样具有约2-20μm的非常小的粒径，这也导致类似的不良流动性。
由于直接压片比涉及制粒的方法要简单且成本低得多，因此希望获得较大的依他普仑或其可药用加成盐晶体。
经过广泛的实验室和工业规模研究，已经发现了制备较大的依他普仑草酸盐晶体颗粒，即粒径与填充剂相差不大的依他普仑草酸盐晶体颗粒的新的且有创造性的结晶方法。所述颗粒可用于制备直接压缩的片剂。使用这种较大颗粒也可以实现在胶囊中的精确剂量配送。
发明目的
本发明的目的是提供适用于直接压缩的大的依他普仑草酸盐晶体颗粒。
本发明的第二个目的是提供制备大的依他普仑草酸盐晶体颗粒的方法。
本发明的第三个目的是提供含有大的依他普仑草酸盐晶体颗粒的新的药物单位剂型，其中所述单位剂型可以是片剂，优选可通过直接压缩制得的片剂，或胶囊。
发明概述
本发明特别包括单独或组合的下列方面：
中值粒径为至少40μm，且适用于固体单位剂型的依他普仑草酸盐晶体颗粒。
制备中值粒径为至少40μm，且适用于固体单位剂型的依他普仑草酸盐晶体颗粒的方法，其中所述方法包括将依他普仑草酸盐在适当溶剂系统中的溶液从第一个温度逐渐冷却至第二个温度，同时保持控制的冷却特性，并且在冷却期间给结晶系统提供晶种至少一次，所述提供晶种是通过加入依他普仑草酸盐晶体来进行的，然后在第二个温度保持一定时间，通过常规固体/液体分离技术将所述晶体分离出来。
通过将依他普仑碱或其可药用盐与可药用赋形剂的混合物直接压缩，或者通过将所述混合物填充在硬明胶胶囊中而制得的包含依他普仑的固体单位剂型。
将依他普仑、填充剂和其它可药用赋形剂直接压缩成片剂具有不使用制粒和干燥步骤这一很大优点。此外，因为不用制粒步骤，所以不再需要加入粘合剂。
本文所用的“依他普仑草酸盐”是指由依他普仑、草酸和任选的水构成的任何加成盐。这样的盐的实例是依他普仑的草酸氢盐，即由一个依他普仑分子/个草酸分子构成的盐，以及依他普仑的草酸盐，即由两个依他普仑分子/个草酸分子构成的盐。
本文所用的“晶体颗粒”是指单晶、聚集体和附聚物的任何组合。
本文所用的“直接压缩”是指固体单位剂型是通过将活性组分与赋形剂的简单混合物压缩而制得的，不用将活性组分进行中间的制粒加工来使其包埋到较大颗粒内和改善其流动性。
本文所用的“粘合剂”是指在湿法和熔化制粒加工中使用的，在粒化产物中作为粘合剂起作用的物质。
本文所用的“粒径分布”是指如在Sympatec Helos装置中以1巴的分散压通过激光衍射确定的相等球直径的总体积粒径分布。“中值粒径”是指所述粒径分布的中值。
本文所用的“回流温度”是指溶剂或溶剂系统在常压下回流的温度。
本文所用的“冷却特性”是指随着时间变化的结晶系统的温度。
本文所用的“冷却速度”是指每单位时间所下降的温度。
因此，在一个本发明实施方案中，依他普仑草酸盐晶体颗粒具有至少40μm，优选为50-200μm的中值粒径。
用于直接压缩的依他普仑草酸盐晶体的流动性、分离性和分层性以及由此溶解度取决于中值粒径和粒径分布。
在另一个本发明实施方案中，中值粒径为至少40μm，优选为50-200μm，并且适用于固体单位剂型的依他普仑草酸盐晶体颗粒是从依他普仑草酸盐在适当溶剂系统内的溶液中结晶出来的。所述溶剂系统可包含一种或多种醇和任选的水，溶剂系统优选为乙醇。优选地，在50℃-溶剂系统回流温度下，优选在60℃-溶剂系统回流温度下，更优选在在70℃-溶剂系统回流温度下，将依他普仑草酸盐溶解在溶剂系统中，适当地，在回流温度下将依他普仑草酸盐溶解。依他普仑的可药用盐和溶剂的用量优选相当于溶剂∶溶质重量比为0.05∶1-0.6∶1，更优选为0.1∶1-0.5∶1，最优选为0.2∶1-0.4∶1。将依他普仑草酸盐的溶液逐渐冷却至晶体可从母液中分离出来的温度，该温度是0-20℃，优选为0-15℃，更优选为7-15℃，同时保持控制的冷却特性，使初始冷却期间的冷却速度不超过0.6℃/分钟，优选将冷却速度保持在0.2-0.4℃/分钟，并且所述冷却期间延长至结晶系统的温度在60℃以下，优选在50℃以下，更优选在40℃以下，对于整个冷却，将冷却速度适当地保持在该范围内。在冷却期间，通过加入依他普仑草酸盐晶体来给结晶系统提供晶种至少一次，以防止依他普仑草酸盐过度超饱和以及由此所致的自发结晶成小的晶体颗粒。在冷却期间，优选反复加入晶种以保证依他普仑草酸盐晶体的恒定存在，适当地，以半连续方式向结晶系统中加入晶种直至结晶已开始。将结晶系统在第二个温度下保持至少1小时，优选4-24小时，更优选6-12小时以进行晶体生长。在所述保持时间之后，使用常规分离技术例如过滤将依他普仑晶体颗粒从母液中分离出来。
在一个本发明实施方案中，本发明涉及由中值粒径为至少40μm，优选为50-200μm的大的依他普仑草酸盐晶体颗粒与可药用赋形剂的混合物制得的片剂。所述片剂优选是通过直接压缩制得的。
在另一个实施方案中，本发明涉及通过将中值粒径为至少40μm，优选为50-200μm的大的依他普仑草酸盐晶体颗粒与可药用赋形剂的混合物填充到硬明胶胶囊中而制得的胶囊。
本发明的固体单位剂型优选不含有粘合剂。
本发明的固体单位剂型可含有1-60％ w/w按依他普仑碱计的活性组分，优选4--40％ w/w按依他普仑碱计的活性组分，更优选6-10％ w/w按依他普仑碱计的活性组分。适当地，本发明的固体单位剂型含有8％ w/w按依他普仑碱计的活性组分。
本发明的固体单位剂型可含有选自下列的填充剂：乳糖，或其它糖例如山梨醇、甘露醇、葡萄糖和蔗糖、磷酸钙(含水和无水的磷酸氢钙、磷酸钙)、淀粉、改性淀粉、微晶纤维素、硫酸钙和/或碳酸钙。在优选的实施方案中，本发明的固体单位剂型不含有乳糖。
填充剂适当地为微晶纤维素例如由Penwest Pharmaceuticals生产的ProSolv SMCC90或由FMC Corporation生产的Avicel PH 200。
除了活性组分和填充剂以外，固体药物单位剂型可包含各种其它赋形剂例如崩解剂和任选少量润滑剂、着色剂和甜味剂。
依据本发明使用的润滑剂可适当地为一种或多种选自硬脂酸金属盐(硬脂酸镁、硬脂酸钙、硬脂酸钠)、硬脂酸、蜡、氢化植物油、滑石粉和胶态二氧化硅的那些。
润滑剂优选为一种或多种选自滑石粉、硬脂酸镁或硬脂酸钙的那些。适当地，润滑剂为滑石粉与硬脂酸镁的组合物。硬脂酸镁在固体单位剂型中的重量百分比优选为0.4％-2％，更优选为0.7％-1.4％。
崩解剂包括羟乙酸淀粉钠、交联羧甲基纤维素、聚维酮、低取代的羟丙基纤维素、改性玉米淀粉、预凝胶化的淀粉和天然淀粉。崩解剂适当地为交联羧甲基纤维素例如由FMC生产的Ac-Di-Sol。
可任选将本发明的固体药物单位剂型包衣。包衣适当地为基于常规包衣混合物例如由Colorcon生产的Opadry OY-S-28849的膜包衣。
本发明的固体药物单位剂型可通过常规方法，使用具有强制进料能力的压片机来制得。
本发明填充的硬明胶胶囊可通过常规方法，使用适于粉末填充的胶囊填充机来制得。
在下面通过实施例来举例说明本发明。然而，这些实施例仅是为了举例说明本发明，而不是限制本发明。
实施例1
将通过把依他普仑的乙醇溶液与草酸的乙醇溶液混合来沉淀出依他普仑草酸盐粗产物而获得的含有约35kg依他普仑草酸盐的湿的。通过将该结晶混合物过滤，用乙醇洗涤，将滤饼悬浮在322L乙醇中。通过加热至回流将该材料溶解，通过蒸馏除去150L乙醇。冷却，在80-40℃的温度间隔内以0.2-0.5℃/分钟的冷却速度将该混合物冷却。在冷却期间，在75、65和60℃向该混合物中加入依他普仑草酸盐晶体(每次10g)。将该结晶混合物在15℃保持10小时，然后分离出依他普仑草酸盐晶体。通过将该结晶混合物过滤，用乙醇洗涤，将滤饼干燥而获得了纯化的依他普仑草酸盐(27.7kg，产率为58.2％)。所得依他普仑草酸盐的粒径分布如表1所示。
表1：依他普仑草酸盐晶体和ProSolv SCMC90的粒径分布(SympatecHelos)。
| 量(％) | 实施例1(μm) | ProSolv SCMC90(μm) |
| 90 | 455 | 291 |
| 50 | 163 | 130 |
| 10 | 13 | 37 |
实施例2
通过将大的依他普仑草酸盐晶体颗粒直接压缩而制得的片剂
片剂组分：
片剂核芯
依他普仑草酸盐 2554g (10.2％ w/w)
滑石粉 1400g (5.6％ w/w)
ProSolv SMCC90 19896g (79.6％ w/w)
Ac-Di-Sol 900g (3.6％)
硬脂酸镁 250g (1.0％ w/w)
膜包衣
Opadry OY-S-28849，白625g(为核芯重量的2.5％ w/w)
将得自实施例1的依他普仑草酸盐晶体颗粒经由710μm筛网过筛，并在100litre Bohle PTM 200混和器中以6rpm混和15分钟。加入ProSolv SMCC90和Ac-Di-Sol，继续混和15分钟。将硬脂酸镁经由710μm筛网过筛，加入，并继续混和3分钟。
在装配有长椭圆形、凸起的、带刻痕的5.5×8mm冲头的KorschPH230压片机上将25kg所得混合物压片(125,000片/小时)。将片剂核芯重量设置为125mg。名义产量为200,000片。运转压片机直至混合物水平正好在强制进料器上面，即尽可能地继续压片以在最后量的混合物中确定可能的分离趋势。所制得的片剂具有令人满意的技术特征。
Claims (27)
1.依他普仑草酸盐晶体颗粒，其特征在于，所述晶体的中值粒径大于20μm。
2.制备权利要求1的依他普仑草酸盐晶体颗粒的方法，其特征在于，所述方法包括将依他普仑草酸盐在适当溶剂系统中的溶液从第一个温度逐渐冷却至第二个温度，同时保持控制的冷却特性，并且在冷却期间给结晶系统提供晶种至少一次，所述提供晶种是通过加入依他普仑草酸盐晶体来进行的，然后在所述第二个温度保持一定时间。
3.权利要求2的方法，其特征在于，所述晶体的中值粒径大于20μm。
4.权利要求2-3任一项的方法，其特征在于，所述溶剂系统包含一种或多种醇和任选水。
5.权利要求4的方法，其特征在于，所述溶剂是乙醇。
6.权利要求2-5任一项的方法，其特征在于，溶质：溶剂的重量比为0.05∶1-0.6∶1，优选为0.1∶1-0.5∶1，更优选为0.2∶1-0.4∶1。
7.权利要求2-6任一项的方法，其特征在于，所述第一个温度为50℃-溶剂系统的回流温度，优选为60℃-回流温度，更优选为70℃-回流温度。
8.权利要求2-7任一项的方法，其特征在于，所述第二个温度为0-20℃，优选为0-15℃，更优选为7-15℃。
9.权利要求2-8任一项的方法，其特征在于，所述控制的冷却特性包括其中冷却温度保持在固定范围内的初始冷却期间。
10.权利要求9的方法，其特征在于，所述初始冷却期间包括直至温度低于60℃，优选低于50℃，更优选低于40℃的期间。
11.权利要求9-10任一项的方法，其特征在于，将所述冷却速度保持在0-0.6℃/分钟，优选0.2-0.4℃/分钟的范围内。
12.权利要求2-11任一项的方法，其特征在于，所述提供晶种在初始冷却期间进行两次或更多次。
13.权利要求2-12任一项的方法，其特征在于，所述保持时间为至少1小时，优选4-24小时，更优选为6-12小时。
14.权利要求2-13任一项的方法，其特征在于，经过所述保持时间之后，通过常规固体/液体分离技术，优选通过过滤将晶体颗粒从母液中分离出来。
15.固体单位剂型，其中包含权利要求1任一项的依他普仑草酸盐晶体颗粒。
16.权利要求15的固体单位剂型，其特征在于，所述固体单位剂型是通过将依他普仑草酸盐与可药用赋形剂的混合物直接压缩而制得的片剂。
17.权利要求16的固体单位剂型，其特征在于，所述固体单位剂型是包衣的。
18.权利要求15的固体单位剂型，其特征在于，所述固体单位剂型是通过将依他普仑草酸盐与可药用赋形剂的混合物填充到硬明胶胶囊中而制得的。
19.权利要求15-18任一项的固体单位剂型，其特征在于，所述固体单位剂型不含有粘合剂。
20.权利要求15-19任一项的固体单位剂型，其特征在于，所述固体单位剂型含有1-30％w/w按依他普仑碱计的活性组分，优选4--20％w/w按依他普仑碱计的活性组分，更优选6-10％w/w按依他普仑碱计的活性组分。
21.权利要求15-20任一项的固体单位剂型，其特征在于，器含有选自下列的填充剂：乳糖，糖，优选山梨醇、甘露醇、葡萄糖和/或蔗糖，磷酸钙，优选含水和/或无水的磷酸氢钙、磷酸钙，淀粉、改性淀粉、微晶纤维素、硫酸钙和/或碳酸钙。
22.权利要求21的固体单位剂型，其特征在于，所述填充剂是微晶纤维素，例如ProSolv SMCC90或Avicel PH 200。
23.权利要求15-22任一项的固体单位剂型，其特征在于，所述固体单位剂型含有选自硬脂酸金属盐(硬脂酸镁、硬脂酸钙、硬脂酸钠)、硬脂酸、蜡、氢化植物油、滑石粉和胶态二氧化硅的润滑剂。
24.权利要求23的固体单位剂型，其特征在于，所述润滑剂是一种或多种选自滑石粉、硬脂酸镁和硬脂酸钙的润滑剂。
25.权利要求24的固体单位剂型，其特征在于，所述润滑剂是滑石粉与硬脂酸镁的组合物。
26.权利要求25的固体单位剂型，其特征在于，按所述固体单位剂型的重量为100％计，所述硬脂酸镁的重量百分比为0.4％-2％，优选为0.7％-1.4％。
27.权利要求15-26任一项的固体单位剂型，其特征在于，所述固体单位剂型基本上不含有乳糖。
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|---|---|---|---|---|
| CN106389374A (zh) * | 2015-08-03 | 2017-02-15 | 深圳信立泰药业股份有限公司 | 一种含有lcz696的药物组合物及其制备方法 |
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| TWI339651B (en) * | 2004-02-12 | 2011-04-01 | Lundbeck & Co As H | Method for the separation of intermediates which may be used for the preparation of escitalopram |
| CA2558198A1 (en) * | 2004-03-05 | 2005-09-15 | H. Lundbeck A/S | Crystalline composition containing escitalopram oxalate |
| US20050196453A1 (en) * | 2004-03-05 | 2005-09-08 | H. Lundbeck A/S | Crystalline composition containing escitalopram |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106389374A (zh) * | 2015-08-03 | 2017-02-15 | 深圳信立泰药业股份有限公司 | 一种含有lcz696的药物组合物及其制备方法 |
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