CN1352560A - 齐普拉西酮悬浮液 - Google Patents
齐普拉西酮悬浮液 Download PDFInfo
- Publication number
- CN1352560A CN1352560A CN00808120A CN00808120A CN1352560A CN 1352560 A CN1352560 A CN 1352560A CN 00808120 A CN00808120 A CN 00808120A CN 00808120 A CN00808120 A CN 00808120A CN 1352560 A CN1352560 A CN 1352560A
- Authority
- CN
- China
- Prior art keywords
- ziprasidone
- compositions
- chloride
- polysorbate
- suspension
- 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.)
- Granted
Links
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960000607 ziprasidone Drugs 0.000 title claims abstract description 61
- 239000000725 suspension Substances 0.000 title description 44
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 229920000136 polysorbate Polymers 0.000 claims abstract description 25
- 229950008882 polysorbate Drugs 0.000 claims abstract description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000008119 colloidal silica Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 15
- -1 alkali metal salt Chemical class 0.000 claims description 9
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000006068 taste-masking agent Substances 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001514 alkali metal chloride Inorganic materials 0.000 claims description 3
- 229910001617 alkaline earth metal chloride Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 150000001447 alkali salts Chemical class 0.000 claims 2
- 239000002253 acid Substances 0.000 abstract description 2
- 239000007900 aqueous suspension Substances 0.000 abstract 1
- 239000012458 free base Substances 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 238000004062 sedimentation Methods 0.000 description 11
- 239000000796 flavoring agent Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 235000013355 food flavoring agent Nutrition 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000002156 mixing Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- ZCBZSCBNOOIHFP-UHFFFAOYSA-N ziprasidone hydrochloride hydrate Chemical compound [H+].O.[Cl-].C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 ZCBZSCBNOOIHFP-UHFFFAOYSA-N 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 235000019640 taste Nutrition 0.000 description 4
- 238000009736 wetting Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 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 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 230000007246 mechanism Effects 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000218645 Cedrus Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 244000183685 Citrus aurantium Species 0.000 description 1
- 235000007716 Citrus aurantium Nutrition 0.000 description 1
- 235000000228 Citrus myrtifolia Nutrition 0.000 description 1
- 235000016646 Citrus taiwanica Nutrition 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920002907 Guar gum Polymers 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
- 244000147568 Laurus nobilis Species 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 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
- 230000003213 activating effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
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- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
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- 239000000665 guar gum Substances 0.000 description 1
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- 229960002154 guar gum Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
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- 235000021017 pears Nutrition 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
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- 239000001117 sulphuric acid Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 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
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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Abstract
含有齐普拉西酮游离碱或难于润湿的药物上可接受的齐普拉西酮酸加合盐、聚山梨酯和胶态二氧化硅的组合物形成良好的水性悬浮液,该悬浮液具有有效贮存期限并且如果发生沉降时容易再悬浮。
Description
发明领域
本发明涉及一种口服悬浮液，它含有齐普拉西酮(ziprasidone)游离碱或药物上可接受的齐普拉西酮酸加合盐、聚山梨酯、胶态二氧化硅、增粘剂和水。在一个更具体的方面，本发明涉及这样一种味道被掩盖的悬浮液。本发明进一步涉及用这种制剂治疗精神病的方法。
发明背景
齐普拉西酮是具有以下结构的已知化合物：
该化合物公开在美国专利4,831,031和5,312,925(将它们全文并入本文作参考)中，可用作精神抑制药，所以特别适用作抗精神病药。它通常以盐酸加合盐、齐普拉西酮盐酸一水合物口服给药。盐酸盐的优点在于它是高渗透性(一种有利地影响生物利用率的因素)药物。然而，盐酸盐以及其它的齐普拉西酮酸加合盐确实具有较低的水溶解度(一种不利地影响生物利用率的因素)。
在制药领域，从制剂的角度来看，难于润湿的药物上可接受的化合物可能是成问题的。例如，齐普拉西酮盐酸盐，除了具有低溶解度之外，难于用水性介质润湿，于是，从试图形成水悬浮液的观点来看存在特殊的问题。在下文的讨论中，讨论了齐普拉西酮盐酸盐作为由难于润湿的齐普拉西酮游离碱和齐普拉西酮酸加合盐构成的组中的典型一员。然而，不能认为本发明局限于齐普拉西酮盐酸盐。
由于在润湿齐普拉西酮酸加合盐(例如齐普拉西酮盐酸盐)中的难度，如果没有借助于应用长时间高剪切混合，该物质就难于充分悬浮在水性介质中。常规实验室均化器如果不操作很长的时间一般就不能润湿齐普拉西酮盐酸盐。长混合时间几乎不可避免地导致起泡，并且仍然得到较差的结果，药物聚集体仍然明显存在，夹带在泡沫中。因而，齐普拉西酮盐酸盐趋于漂浮在水和其它水性介质表面，并且只能以被认为极端的物理措施(长时间高剪切混合)导致形成悬浮液。
一种备选混合方法包括：首先只在齐普拉西酮盐中加入少量水，接着研磨以润湿大块的药物。这使得物质充分润湿，于是它能悬浮在水中。然而，这种方法仍有缺点，即，难于按比例扩大。此外，一旦引起齐普拉西酮盐酸盐形成这种形式的水性悬浮液，另外的要求是防止或延迟迅速的再沉降，该现象对于齐普拉西酮盐酸盐来说较快地发生，通常在大约一小时之内，这取决于颗粒大小。对于药物悬浮液，由于悬浮液必须充分再悬浮以确保对患者施用足够剂量，沉降就会尤其成问题。
一种改善悬浮液的抗沉降性的方法是采用增粘剂，例如任何天然树胶或者纤维素，如羟丙基纤维素(HPC)或羟丙基甲基纤维素(HPMC)，以提高粘度，从而延迟悬浮液中润湿颗粒的再沉降速率。在齐普拉西酮盐酸盐的情况下，已经发现这种方法是成问题的，由于一旦添加增粘剂，当齐普拉西酮盐酸盐最终沉降时，它趋于形成位于底部并且极难破碎和再悬浮的薄块。温度的波动和震动(例如在通常的搬运和运输中发生的震动)会促进这样的结块。
再者，在齐普拉西酮酸加合盐的特定情形下，这样的盐通常显示极苦的味道，苦味程度随特定盐的溶解度升高而增加。糖(含或不含其它的甜味剂和/或调味剂时)通常不足以掩盖这种苦味。调节pH以形成较低溶解度(从而更少苦味)的游离碱，是减小苦味的一项选择。然而，如果不保持非常仔细和连续的控制，这样的调节会引起颗粒大小的变化。颗粒大小的实质性变化可能反过来不良地导致生物利用率的变化。
因此，含有齐普拉西酮游离碱或齐普拉西酮盐酸盐(或其它药物上可接受的齐普拉西酮加合盐)、维持改善的贮存期限(即，它在再沉降之前维持更长的悬浮时期)并且易于再悬浮的悬浮液应当代表对制药领域有价值的补充。在齐普拉西酮酸加合盐悬浮液的特定情形下，具有改善的味道的悬浮液会是进一步有价值的补充。
发明概述
现已明确的是，含有齐普拉西酮游离碱或难于润湿的药物上可接受的齐普拉西酮酸加合盐、聚山梨酯、增粘剂和胶态二氧化硅的干组分易于在水性介质中形成良好悬浮液。因此本发明一方面是一种物质组合物，它是含有齐普拉西酮游离碱或难于润湿的药物上可接受的齐普拉西酮酸加合盐、水、聚山梨酯、增粘剂和胶态二氧化硅的悬浮液。“难于润湿”表示当通过常规方法(例如实验室掺合机，在常规速度下掺合10分钟)混合时，齐普拉西酮药物上可接受的盐不容易在水中形成悬浮液。这样的盐自身在水中不会形成如下定义的“良好的悬浮液”。
此外，应该注意，本文采用的齐普拉西酮盐酸盐是例证本发明，不过应懂得，该例子的应用不能理解成限制性的。
按照润湿能力，不认为齐普拉西酮盐酸盐颗粒的粒径是特别重要的，不过，平均粒度通常小于或等于85μm。
本发明的预先构成的悬浮液显示良好的悬浮作用并且沉降时可再混合。“良好的悬浮作用”表示(1)在本发明的悬浮液中，室温(RT，通常25℃)下超过24小时、优选超过一周无可见的沉降，以及(2)当可见沉降确实发生时，通过简单的物理混合(例如轻度的手工搅拌或适当的手工摇动)易于引起再悬浮，无需高剪切混合。
本发明令人意外之处在于，聚山梨酯是在经过试验的一系列润湿剂中得到积极结果的唯一润湿剂。其它润湿剂(例如十二烷基硫酸钠)在获得充分润湿之前产生泡沫。这样的起泡是成问题的，因为，尽管一些颗粒似乎润湿了，但其它的盐颗粒夹带在泡沫中，并且还有其它的盐颗粒作为干物质位于水上部，结果不形成均匀的悬浮液。因此，在本发明中，聚山梨酯适用作在起泡水平以下允许完全润湿的试剂。
术语“聚山梨酯”是应用其技术上认可的含义，即，聚氧乙烯山梨糖醇酐脂肪酸酯，如药物赋形剂手册(Handbook Of PharmaceuticalExcipients)，Ainley Wade和Paul Weller编辑，ThePharmaceutical Press，London，1994中公开合定义的。适用的聚山梨酯包括聚山梨酯20、21、40、60、61、65、80、81、85和120。聚山梨酯80是优选的。
本文可采用的胶态二氧化硅在本领域是已知类型的(例如，可作为CAB-O-SIL商购的那种，注册商标为Cabot Corporation，Boston，MA)并且，尽管不希望受任何具体理论或机理的限制，确信起防结块剂作用。即，在本发明的悬浮液中，即使可能发生一定的再沉降，但再沉降的物质也不结块，这表明，尽管存在增粘剂，在胶态二氧化硅的存在下，再沉降物质也不会形成难于粉碎和再分散的结实物质。在胶态二氧化硅存在时，产生防结块性能，这样以致于通过前述简单的物理混合可进行再悬浮。因此，本发明的优点在于，聚山梨酯和胶态二氧化硅的组合实现良好的润湿，同时在发生沉降时具有易再悬浮性。
在本发明一个更具体的方面，提供了一种齐普拉西酮水性悬浮液，它含有悬浮于水性药物上可接受载体中的齐普拉西酮酸加合盐，所述载体含有碱金属(例如，钠、锂或钾)氯化物或碱土金属(例如，镁或钙)氯化物。业已确定，这些盐是非常有效的味道掩盖剂。尽管不希望受理论或陈述机理的限制，但认为这样的盐减小了溶解度，因此减小了悬浮液中齐普拉西酮盐的溶解量和/或浓度。然而，已溶齐普拉西酮在悬浮液剂型中浓度的减小并不是不利的，而在本发明中是有益的，由于悬浮的齐普拉西酮比溶解的齐普拉西酮化学上更稳定，从而改善了化学稳定性以及味道。
本发明进一步提供了一种治疗精神病的方法，它包括，给需要这种治疗的病人施用有效量的悬浮液，该悬浮液含有齐普拉西酮游离碱或药物上可接受的齐普拉西酮酸加合盐、聚山梨酯、增粘剂、胶态二氧化硅和水，所述悬浮液又是本文公开和描述的。
可应用呈任何活性晶态或无定形形式的齐普拉西酮盐酸盐，不过，晶态齐普拉西酮盐酸盐一水合物是优选的。详细说明
一般地，聚山梨酯的用量是至少能足够产生完全的润湿，即，意谓着药物在合理的时间内容易分散。采用的聚山梨酯用量(作为上限)不应等于或超过可产生泡沫的用量。
胶态二氧化硅用量至少为防结块量，即，一定的用量，以致在通常的运输和贮藏条件下不会形成结实的、难于再悬浮的块。有可能发生再沉降，通过轻度物理搅动(即搅拌或振动)容易使它重悬浮。胶态二氧化硅的上限是这样的量，即，高于它时，和增粘剂一起产生胶凝。发现具体级别的胶态二氧化硅并不是紧要的，只要它是药物上可接受的即可。
聚山梨酯和胶态二氧化硅两者的量是体系特定的，最优的量，这取决于药物形式(例如，游离碱对酸盐)，以及其它还可以用作悬浮液部分的赋形剂的用量和类型。通常，聚山梨酯的用量基于最终悬浮液重量是约0.01～约2.0wt％，更优选约0.05～约0.30wt％。胶态二氧化硅通常的用量基于悬浮液重量为0.05wt％～2.0wt％。
适合的增粘剂(本领域也称为“增稠剂”)也用作本发明的成分。这样的增粘剂起悬浮剂的作用，并包括例如，已知适于这种目的的水解胶体胶，它的实例包括：黄原胶、瓜尔豆胶、槐树豆胶、黄蓍胶等。选择性地，可以采用合成的悬浮剂，例如羧甲基纤维素钠、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素等。增粘剂通常的用量基于悬浮液的重量为约0.01wt％～约10wt％。在具体制剂中实际用量取决于准确的药剂和存在的其它赋形剂。
齐普拉西酮游离碱或酸加合盐可呈任何形式用于本发明，包括无水的或水合的。本文(包括实施例中)采用的齐普拉西酮盐酸盐是齐普拉西酮盐酸盐一水合物，为方便起见，通常简称为齐普拉西酮盐酸盐。本发明同样适用于其它齐普拉西酮酸加合盐，例如醋酸、乳酸、琥珀酸、马来酸、酒石酸、柠檬酸、葡糖酸、抗坏血酸、苯甲酸、肉桂酸、富马酸、硫酸、磷酸、氢溴酸、氢碘酸、氨基磺酸、磺酸(如甲磺酸、苯磺酸)和相关酸。
如前所述，在药物上可接受的齐普拉西酮酸加合盐的特定情形下在悬浮液中包括味道掩盖剂是有益的。这样的味道掩盖剂是碱金属氯化物和碱土金属氯化物，包括氯化钠、氯化锂、氯化钾、氯化镁和氯化钙。氯化钠是优选的。味道掩盖剂一般以味道掩盖量包含在悬浮液中，当它为氯化钠时，用量一般基于悬浮液重量为约0.5～约2.0wt％。至于其它的盐，可计算等摩尔量。
本发明的组合物是口服、预先组成的悬浮液，它含有作为必需成分的齐普拉西酮游离碱或齐普拉西酮酸加合盐，水，聚山梨酯，增粘剂和胶态二氧化硅。本发明的组合物也可含有其它常规药物上可接受的赋形剂，例如，调味剂、缓冲剂、pH调节剂、稀释剂、色料、防腐剂和甜味剂。一些赋形剂可起多种作用。
掺入本组合物中的香味剂可选自合成的香味油和增香的芳香剂和/或天然油，植物叶、花、果实等的提取物和它们的组合。这些可包括肉桂油、冬青油、薄荷油、丁香油、月桂油、茴香油、桉树油、百里香油、雪松叶油、肉豆蔻油、鼠尾草油、苦杏仁油和桂皮油。还有用作香味剂的是香草、柠檬油，包括柠檬、橙、葡萄、莱母酸橙和葡萄柚，以及果香香精，包括苹果、香焦、梨、桃、草莓、树莓、樱桃、李、菠萝、杏等。调味剂的量取决于一些因素，包括希望的感官性能作用。一般采用调味剂时，其含量基于悬浮液总重量为约0.01～约1.0wt％。
这种悬浮液可通过常规制药方法制备，采用常规设备(例如悬挂式搅拌器)通常以大约100-500RPM的速率混合各种成分。可以采用许多不同次序往搅拌器中添加成分。本发明典型的混合顺序(不过其它次序当然是可行的)是：(1)为了任何需要高于室温(rt)的温度以便溶解的成分而添加加热至70℃的水(如果不采用这样的成分，就不需要加热)；(2)冷却至rt(大约30℃)；接着，按下列顺序添加(并且假定每个成分均采用)：增粘剂、甜味剂、缓冲剂、聚山梨酯、味道掩盖剂(如果采用)、齐普拉西酮、胶态二氧化硅和香味剂。
通过如下非限制性实施例进一步例示和公开了本发明：实施例1
通过以下步骤制备悬浮液制剂：加热733.31g的水至70℃，接着添加1.36g对羟基苯甲酸甲酯和0.17g对羟基苯甲酸丙酯，同时用悬挂式搅拌器以约200rpm的搅拌速率搅拌。在对羟基苯甲酸酯完全溶解之后，温度降低至大约30℃。接着按顺序加入下列成分：2.78g黄原胶、333.90g木糖醇、1.13g无水柠檬酸、1.21g柠檬酸三钠二水合物、0.55g聚山梨酯80、11.13g NaCl、11.33g公称粒径为38μm的齐普拉西酮盐酸盐一水合物、11.13g胶态二氧化硅和5.0g樱桃香味剂。根据需要，应用氢氧化钠水溶液和盐酸调节pH至4.0。
实施例2
本实施例公开了制备齐普拉西酮游离碱悬浮液的方法。
向2升烧杯中加入重812.9g的水，采用悬挂式搅拌器以大约200rpm的速度搅拌。将水加热至70℃。一旦温度达到70℃，添加1.36g对羟基苯甲酸甲酯和0.17g对羟基苯甲酸丙酯。当对羟基苯甲酸酯完全溶解时，降低温底至40℃。向溶液中缓慢加入3.27g增粘剂[CARBOPOL树脂974P(Union Carbide Corporation，Danbury，CT)]，小心以避免产生大块物，必要时增大搅拌速度。保持搅拌直至增粘剂完全分散和/或溶解。向溶液中加入218g蔗糖。在蔗糖溶解之后，将温度降至30℃。向溶液中加入2.94g柠檬酸三钠盐。在溶液中添加0.544g聚山梨酯80。往溶液中缓慢加入11.325g齐普拉西酮游离碱。采用10％NaOH溶液调节制剂的pH至5.7。在pH平衡之后，添加1.09g胶态二氧化硅(CAB-O-SIL，CabotCorporation)。
实施例3
本实施例阐述了采用胶态二氧化硅作为防结块剂所得的结果(与其它用于同样目的的试剂比较)。
如实施例2制备含有相同成分(防结块剂除外)的齐普拉西酮游离碱悬浮液(齐普拉西酮公称粒径为38μm)，含有和不含以下列出的每种防结块剂。每种防结块剂加入60cc瓶的制剂中，接着在2000RPM离心20分钟以促进沉降，然后以大约每2秒一转的速度轻轻地旋转瓶而再悬浮沉降的固体。记录制剂变得完全均匀(视觉检察无固体粘着在瓶的底部)所需的时间。数据证实，采用胶态二氧化硅大为缩短了再悬浮制剂所需要的时间(下表的CSD)，在大约0.3％的含量大为缩短了再悬浮时间。
| 序号 | 防结块剂 | 制剂内含量(w/w％) | 再悬浮性 |
| 1 | 无 | ＞20分钟 | |
| 2 | MCC*，200μm** | 3.0 | ＞20分钟 |
| 3 | MCC，50μm | 1.0 | ＞20分钟 |
| 4 | SiO2 | 1.0 | ～2分钟 |
| 5 | CSD | 0.3 | ～1分钟 |
| 6 | 硬脂酸镁 | 0.2 | ＞20分钟 |
*MCC是微晶纤维素的缩写
**以微米计的粒径都是公称粒径
实施例4
测试不同表面活性剂在水中润湿齐普拉西酮HCl一水合物的能力：十二烷基硫酸钠(SLS)、MIGLYOL(Dynamit NobelAktiengesellschaft，Germany的注册商标)甘油三酯(810)和聚山梨酯80。在三份单独的100mL体积水中，以制备1％溶液的量添加上文列出的每种表面活性剂。添加过量的MIGLYOL(是由于其低溶解度)。在应用悬挂式搅拌器在200rpm搅拌时，向这三种表面活性剂溶液的每种中各加入1.132g齐普拉西酮(等于10mgA/ml)。记录观测到的润湿速率如下：
1)SLS ＞20分钟
2)MIGLYOL甘油三酯 ＞20分钟
3)聚山梨酯-80 ＜2分钟只有聚山梨酯80溶液在混合一夜后不显示任何可见的聚集体。
在不同浓度下进一步的聚山梨酯-80试验阐明了，低到0.05％的浓度可显著缩短药物润湿时间。
浓度(％) 药物润湿时间
0.05 4分钟
0.15 3.8分钟
0.25 3.5分钟
Claims (15)
1.一种组合物，它包含齐普拉西酮游离碱或药物上可接受的齐普拉西酮酸加合盐、水、聚山梨酯、增粘剂和胶态二氧化硅。
2.权利要求1的组合物，其中，所述齐普拉西酮酸加合盐是齐普拉西酮盐酸盐。
3.权利要求1的组合物，其中，所述聚山梨酯是聚山梨酯20、21、40、60、61、65、80、81、85或120。
4.权利要求3的组合物，其中，所述聚山梨酯是聚山梨酯80。
5.权利要求1的组合物，它进一步包含选自碱金属氯化物和碱土金属氯化物的味道掩盖剂。
6.权利要求5的组合物，其中，所述碱金属盐是氯化钠、氯化钾或氯化锂。
7.权利要求6的组合物，其中，所述碱金属盐是氯化钠。
8.权利要求5的组合物，其中，所述碱土金属盐是氯化镁或氯化钙。
9.一种组合物，它包含齐普拉西酮游离碱或齐普拉西酮盐酸盐、聚山梨酯、胶态二氧化硅、增粘剂和水。
10.权利要求9的组合物，其中，所述聚山梨酯是聚山梨酯20、21、40、60、61、65、80、81、85或120。
11.权利要求10的组合物，其中，所述聚山梨酯是聚山梨酯80。
12.权利要求9的组合物，它进一步包含选自碱金属氯化物和碱土金属氯化物的味道掩盖剂。
13.权利要求12的组合物，其中，所述碱金属盐是氯化钠、氯化钾或氯化锂。
14.权利要求13的组合物，其中，所述碱金属盐是氯化钠。
15.权利要求12的组合物，其中，所述碱土金属盐是氯化镁或氯化钙。
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| US7175855B1 (en) | 1999-05-27 | 2007-02-13 | Pfizer Inc. | Ziprasidone suspension |
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| CN100518827C (zh) | 2000-10-30 | 2009-07-29 | 欧罗赛铁克股份有限公司 | 控释氢可酮制剂 |
| JP4619658B2 (ja) * | 2002-03-12 | 2011-01-26 | 富山化学工業株式会社 | 快い味の経口懸濁液および方法 |
| BR0315663A (pt) * | 2002-10-25 | 2005-08-30 | Pfizer Prod Inc | Formulações de depósito de agentes ativos de aril-heterocìclicos na forma de uma suspensão |
| BR0315568A (pt) * | 2002-10-25 | 2005-08-23 | Pfizer Prod Inc | Formulações de depósito injetáveis |
| EP1418492B1 (en) | 2002-11-05 | 2017-09-20 | LG Electronics, Inc. | Touch screen mounting assembly for LCD monitor |
| EP1628973A2 (en) | 2003-10-24 | 2006-03-01 | Teva Pharmaceutical Industries Ltd. | Processes for preparation of ziprasidone |
| WO2005107719A2 (en) * | 2004-05-06 | 2005-11-17 | Sandoz Ag | Pharmaceutical composition comprising hydrophobic drug having improved solubility |
| US20070237828A1 (en) * | 2004-06-11 | 2007-10-11 | Dr. Reddy's Laboratories Limited | Ziprasidone Dosage Form |
| WO2006085168A2 (en) * | 2005-01-07 | 2006-08-17 | Ranbaxy Laboratories Limited | Solid oral dosage forms of ziprasidone containing colloidal silicone dioxide |
| EP1901722A4 (en) * | 2005-06-20 | 2011-06-15 | Elan Pharma Int Ltd | NANOTEHOUS COMPOSITIONS WITH CONTROLLED RELEASE FROM ARYL-HETEROCYCLIC COMPOUNDS |
| WO2007052289A2 (en) | 2005-07-22 | 2007-05-10 | Rubicon Research Pvt Ltd. | Novel dispersible tablet composition |
| KR20080076667A (ko) * | 2007-02-15 | 2008-08-20 | 주식회사 중외제약 | 요변성 약학 조성물 |
| JP4336380B1 (ja) * | 2008-11-06 | 2009-09-30 | 塩野義製薬株式会社 | 水懸濁性を向上させた細粒剤 |
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| US5312925A (en) * | 1992-09-01 | 1994-05-17 | Pfizer Inc. | Monohydrate of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one-hydrochloride |
| US6150366A (en) * | 1998-06-15 | 2000-11-21 | Pfizer Inc. | Ziprasidone formulations |
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