JP4415056B2 - エスシタロプラムの結晶質塩基、およびエスシタロプラム塩基を含む口腔内分散性錠剤 - Google Patents
エスシタロプラムの結晶質塩基、およびエスシタロプラム塩基を含む口腔内分散性錠剤 Download PDFInfo
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- JP4415056B2 JP4415056B2 JP2008260742A JP2008260742A JP4415056B2 JP 4415056 B2 JP4415056 B2 JP 4415056B2 JP 2008260742 A JP2008260742 A JP 2008260742A JP 2008260742 A JP2008260742 A JP 2008260742A JP 4415056 B2 JP4415056 B2 JP 4415056B2
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- Prior art keywords
- escitalopram
- active pharmaceutical
- pharmaceutical ingredient
- dispersible tablet
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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 127
- 229960004341 escitalopram Drugs 0.000 title claims description 124
- 239000007919 dispersible tablet Substances 0.000 title claims description 42
- 239000003826 tablet Substances 0.000 claims description 84
- 239000000203 mixture Substances 0.000 claims description 62
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 33
- 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 32
- 229930195725 Mannitol Natural products 0.000 claims description 28
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- 238000002844 melting Methods 0.000 claims description 26
- 230000008018 melting Effects 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
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- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 20
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
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- 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
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- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 claims description 4
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- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims description 2
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- 229960004587 carisoprodol Drugs 0.000 claims description 2
- OFZCIYFFPZCNJE-UHFFFAOYSA-N carisoprodol Chemical compound NC(=O)OCC(C)(CCC)COC(=O)NC(C)C OFZCIYFFPZCNJE-UHFFFAOYSA-N 0.000 claims description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 2
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- 150000004676 glycans Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 description 68
- 239000002585 base Substances 0.000 description 60
- 239000012458 free base Substances 0.000 description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 39
- 239000004606 Fillers/Extenders Substances 0.000 description 38
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 32
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- 150000003839 salts Chemical class 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 19
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 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 description 16
- 238000007906 compression Methods 0.000 description 16
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- WIHMBLDNRMIGDW-BDQAORGHSA-N escitalopram hydrobromide Chemical compound Br.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WIHMBLDNRMIGDW-BDQAORGHSA-N 0.000 description 16
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- 239000012535 impurity Substances 0.000 description 14
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- 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
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- 229960001653 citalopram Drugs 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PTJADDMMFYXMMG-UHFFFAOYSA-N Demethylcitalopram Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCNC)C1=CC=C(F)C=C1 PTJADDMMFYXMMG-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 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 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N alpha-methacrylic acid Natural products CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- CXOWYMLTGOFURZ-UHFFFAOYSA-N azanylidynechromium Chemical compound [Cr]#N CXOWYMLTGOFURZ-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 229960000673 dextrose monohydrate Drugs 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
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- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
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- 238000011049 filling Methods 0.000 description 1
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- 239000006260 foam Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000010884 ion-beam technique Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本発明は、式(I):
a)水溶性増量剤および活性医薬成分を、活性医薬成分の融点以上、該融点周辺または該融点よりわずかに下の温度で混合し、それによって活性医薬成分を水溶性増量剤上に吸着させること、
b)引き続いて、40℃以下の温度に冷却すること、
c)活性医薬成分および水溶性増量剤の混合物を、1種またはそれ以上の崩壊剤、および場合によりその他の賦形剤と混合し、混合物を少なくとも22 Nの硬度を有する錠剤に圧縮すること、
を含む、上記のような口腔内分散性錠剤の製造方法に関する。
1つの実施態様において、本発明は、固体形態にあり、好ましくは結晶質エスシタロプラム遊離塩基を含む固体形態にあり、さらに好ましくは少なくとも90%が結晶質である固体形態にあり、さらに一層好ましくは少なくとも95%が結晶質である固体形態にあり、最も好ましくは少なくとも98%が結晶質である固体形態にあるエスシタロプラム遊離塩基に関する。特に、本発明は結晶質エスシタロプラム遊離塩基に関する。
a)水溶性増量剤および活性医薬成分を、活性医薬成分の融点以上、該融点周辺または該融点よりわずかに下の温度で混合し、それによって活性医薬成分を水溶性増量剤上に吸着させること;
b)引き続いて、40℃以下、特に35℃以下、とりわけ30℃以下の温度に冷却すること;
c)活性医薬成分および水溶性増量剤の混合物を、1種またはそれ以上の崩壊剤、および場合によりその他の賦形剤と混合し、混合物を少なくとも22 Nの硬度を有する錠剤に圧縮すること、
を含む、前記製造方法に関する。
704 gのエスシタロプラムシュウ酸塩を、機械的なスターラーおよび等圧滴下漏斗を備えた6Lの三頚フラスコに入れた。3 Lの水を添加し、引き続いて600 mLのジエチルエーテルを添加した。27%(w/w)アンモニア水溶液の添加によりpHを9〜9.5に調節し、混合物を0.5時間撹拌した。相を分離し、水性相を300 mLのジエチルエーテルでもう一度抽出した。合わせた有機相を300 mLの水で洗浄し、MgSO4で乾燥し、ろ過し、そして40℃において減圧下で蒸発させることにより、淡褐色の油状物を得た。
収量:542.5 g(98.4 %)。
エスシタロプラムヒドロブロミド塩の沈殿:
12 kgの2-プロパノールに溶解した、淡褐色の油状物としての3 kgのエスシタロプラム遊離塩基(HPLCによる純度:99.16%(面積%))を、機械的撹拌、還流冷却器、スクラバー、ガス注入口および温度計を有する20 Lのサーモスタット制御の反応器に仕込んだ。溶液を40℃に加熱し、pHが3〜4になるまで溶液全体にわたってHBrガスのバブリングを行った。この反応は発熱性であり、反応器中の温度を40〜43℃に維持した。少量の種結晶(エスシタロプラムヒドロブロミド、100〜200 mg)を添加すると、結晶化が10分以内に開始した。その後、混合物をゆっくりと5時間かけて10℃に冷却し、この温度をさらに12時間維持した。結晶をろ過し、フィルター上で1Lの2-プロパノールを用いて3回洗浄し、60℃における減圧下で恒量まで乾燥した。
収量:3.49 kg(93 %)
HPLCによる生成物純度:99.86 %(面積%)。
650 gのエスシタロプラムヒドロブロミド(HPLCによる純度(ヒドロブロミド塩):面積%により99.86 %)を、機械的なスターラーおよび等圧滴下漏斗を備えた4 Lの三頚フラスコに入れた。2 Lの水を添加し、引き続いて1 Lのジエチルエーテルを添加した。27%(w/w)アンモニア水溶液の添加によりpHを9〜9.5に調節し、混合物を0.5時間撹拌した。相を分離し、水性相を500 mLのジエチルエーテルでもう一度抽出した。合わせた有機相を300 mLの水で洗浄し、MgSO4で乾燥し、ろ過し、そして40℃において減圧下で蒸発させることにより、淡褐色の油状物を得た。
収量:520 g(100%)。
エスシタロプラム遊離塩基を、機械的なスターラー、還流冷却器、N2イン/アウトおよび温度計を備えた2 Lのサーモスタット制御の反応器に移した。50 mLの酢酸エチルを添加し、引き続いて1.3 Lのヘプタンを添加した。混合物を40℃に加熱することにより、均一な溶液が形成された。この後に、12時間かけて-5℃にゆっくりと冷却し始め、温度が約20℃になったら、混合物に少量のエスシタロプラムシュウ酸塩(10〜20 mg)を用いてシード添加を行った。約0.5時間後に、遊離塩基の結晶化が開始した。その後、混合物を-5℃で5時間撹拌し、結晶をろ過し、フィルター上で150 mLのヘプタンを用いて2回洗浄し、25℃における減圧下で恒量まで乾燥した。
収量:432 g(83 %)
HPLCによる生成物純度:99.95 %(面積%)
融点(DSC、オンセット):46.6℃。
淡褐色油状物としてのエスシタロプラム遊離塩基520 g(純度:99.25 %;HPLC)を、機械的なスターラー、還流冷却器、N2イン/アウトおよび温度計を備えた2 Lのサーモスタット制御の反応器に入れた。50 mLの酢酸エチルを添加し、混合物を35℃に加熱してすぐに1.3 Lのヘプタンを添加した。溶液が均一になったら、12時間かけて-5℃にゆっくりと冷却を始めた。温度が約20℃になったら、少量(10〜20 mg)の種結晶(エスシタロプラム塩基)を添加した。結晶化が10℃付近で開始した。混合物を-5℃でさらに5〜7時間撹拌し、その後、結晶をろ過により除去した。結晶をフィルター上で150 mLのヘプタンを用いて2回洗浄し、25℃における減圧下で恒量まで乾燥した。
収量:485 g(93.3 %)
HPLCによる生成物純度:99.58 %(面積%)
融点(DSC、オンセット):45.8℃。
エタノールにおけるエスシタロプラム(遊離塩基、油状物)のストック溶液を使用した。エタノールを減圧化で除去し、得られた油状物400 gをフラスコに計り入れ、以下のものを添加した:シタロプラムの5-アミドアナログ((R,S)-1-(3-ジメチルアミノ-プロピル)-1-(4-フルオロ-フェニル)-1,3-ジヒドロ-イソベンゾフラン-5-カルボン酸アミド)を2 g、シタロプラムの5-ブロモアナログ((R,S)-{3-[5-ブロモ-1-(4-フルオロ-フェニル)-1,3-ジヒドロ-イソベンゾフラン-1-イル]-プロピル}-ジメチル-アミン)を2 g、およびシタロプラムのデスメチルアナログ((R,S)-1-(4-フルオロ-フェニル)-1-(3-メチルアミノ-プロピル)-1,3-ジヒドロ-イソベンゾフラン-5-カルボニトリル)を2 g。得られた混合物(S0)を酢酸エチルに溶解して1000 mLにし、等量に4分割して、それぞれを別々に蒸発させることによって油状物を得た。
100 gの遊離塩基を、40℃で10 mLの酢酸エチルおよび240 mLのヘプタンに溶解した。混合物を室温に冷却し、混合物に結晶質エスシタロプラム遊離塩基を用いてシード添加を行った。その後、混合物を約0℃に冷却し、約2時間撹拌し、結晶をろ過し、フィルター上でヘプタンを用いて洗浄し、そして25℃における減圧下で恒量まで乾燥した。
100 gの遊離塩基を250 mLの2-プロパノールに溶解した。2-プロパノール中の臭化水素(無水)を3.5〜4のpHが得られるまで添加し、2-プロパノールを用いて体積を400 mLに調節した。結晶化が10分以内に開始した。その後、混合物を室温に冷却し、約2時間撹拌した。結晶をろ過し、フィルター上で2-プロパノールを用いて洗浄し、60℃における減圧下で恒量まで乾燥した。
100 gのエスシタロプラムヒドロブロミドを70℃で500 mLの2-プロパノールに溶解した。混合物を室温に冷却した。結晶をろ過し、フィルター上で2-プロパノールを用いて洗浄し、60℃における減圧下で恒量まで乾燥した。
100 gの遊離塩基を250 mLの2-プロパノールに溶解した。1当量のシュウ酸二水和物を250 mLの温めた2-プロパノールに溶解し、40℃でエスシタロプラム塩基の溶液に添加した。40℃で10分間撹拌した後に結晶化が開始した。その後、混合物を室温に冷却し、約2時間撹拌した。結晶をろ過し、フィルター上で2-プロパノールを用いて洗浄し、60℃における減圧下で恒量まで乾燥した。
100 gのエスシタロプラムシュウ酸塩を還流下で1250 mLのエタノールに溶解した。混合物を室温に冷却した。結晶をろ過し、フィルター上でエタノールを用いて洗浄し、60℃における減圧下で恒量まで乾燥した。
100 gのエスシタロプラムヒドロブロミドまたはシュウ酸塩を水に溶解または懸濁し、酢酸エチルを添加した。27%(w/w)アンモニア水溶液の添加によりpHを9〜9.5に調節し、混合物を0.5時間撹拌した。相を分離し、水性相を酢酸エチルでもう一度抽出した。合わせた有機相を水で洗浄し、MgSO4で乾燥し、ろ過し、そして40℃において減圧下で蒸発させることにより、淡褐色の油状物を得た。
エスシタロプラムN-オキシド(HPLC-面積%による0.45%)を含むエスシタロプラム塩基(51.3グラム、純度98.60%(HPLC-面積%))を、室温でジエチルエーテル(250 mL)に溶解した。粗製エスシタロプラムを溶解させたほぼ直後に、沈殿物が形成し始めた。懸濁液を20℃で3時間撹拌した。沈殿物(0.77グラム)をろ過し、LC-MSを用いて、約2/1の比率にあるエスシタロプラム塩基およびエスシタロプラムN-オキシドの混合物であることを同定した。ろ液にはエスシタロプラム塩基(50.5グラム、純度99.0%(HPLC-面積%))が含まれていた。ろ液におけるエスシタロプラムN-オキシドの量を測定したところ、エスシタロプラム塩基に対して0.07%(HPLC-面積%)であった。
<製剤化実施例(口腔内分散性錠剤)>
<実施例7>
Claims (11)
- 少なくとも22Nの硬度および120秒未満の口腔内崩壊時間を有し、そして、活性医薬成分であって、水溶性増量剤および活性医薬成分を活性医薬成分の融点以上、該融点周辺または該融点よりわずかに下の温度で混合することによって水溶性増量剤上に吸着した活性医薬成分、1種またはそれ以上の崩壊剤、および場合により追加的な水溶性増量剤を含む口腔内分散性錠剤であって、前記活性医薬成分が40〜100℃の範囲の融点を有する、前記の口腔内分散性錠剤。
- 活性医薬成分が40〜90℃の範囲の融点を有することを特徴とする、請求項1記載の口腔内分散性錠剤。
- 活性医薬成分がエスシタロプラム、エトスクシミド、トリメタジオン、クロラムブシル、ジスルフィラム、フェノフィブラート、グアイフェネシン、ロムスチン、カリソプロドールおよびペルフェナジンからなる群から選択されることを特徴とする、請求項1または2のいずれか1つに記載の口腔内分散性錠剤。
- 活性医薬成分がエスシタロプラムであることを特徴とする、請求項3記載の口腔内分散性錠剤。
- 水溶性増量剤がモノサッカライド、ジサッカライド、糖アルコールおよびポリサッカライドからなる群から選択されることを特徴とする、請求項1〜4のいずれか1つに記載の口腔内分散性錠剤。
- 水溶性増量剤がマンニトール、ソルビトール、グルコース、マンノースおよびラクトースからなる群から選択されることを特徴とする、請求項5記載の口腔内分散性錠剤。
- 少なくとも22 Nの硬度を有することを特徴とする、請求項1〜6のいずれか1つに記載の口腔内分散性錠剤。
- 60秒未満の口腔内崩壊時間を有することを特徴とする、請求項1〜7のいずれか1つに記載の口腔内分散性錠剤。
- 崩壊剤が微結晶性セルロース、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、クロスポビドンおよびポビドンからなる群から選択されることを特徴とする、請求項1〜8のいずれか1つに記載の口腔内分散性錠剤。
- 1%未満の摩損度を有することを特徴とする、請求項1〜9のいずれか1つに記載の口腔内分散性錠剤。
- 以下:
a)水溶性増量剤および活性医薬成分を、活性医薬成分の融点以上、該融点周辺または該融点よりわずかに下の温度で混合し、それによって活性医薬成分を水溶性増量剤上に吸着させること;
b)引き続いて、40℃以下の温度に冷却すること;
c)活性医薬成分および水溶性増量剤の混合物を、1種またはそれ以上の崩壊剤、および場合によりその他の賦形剤と混合すること;
d)混合物を少なくとも22 Nの硬度を有する錠剤に圧縮すること、
を含む、請求項1〜10のいずれか1つに記載の口腔内分散性錠剤の製造方法。
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