CN1228693A - 含有三唑类抗真菌化合物的口服组合物 - Google Patents
含有三唑类抗真菌化合物的口服组合物 Download PDFInfo
- Publication number
- CN1228693A CN1228693A CN97197432A CN97197432A CN1228693A CN 1228693 A CN1228693 A CN 1228693A CN 97197432 A CN97197432 A CN 97197432A CN 97197432 A CN97197432 A CN 97197432A CN 1228693 A CN1228693 A CN 1228693A
- Authority
- CN
- China
- Prior art keywords
- compositions
- beadlet
- antifungal compound
- weight
- surfactant
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 68
- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 56
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 title claims abstract description 48
- 150000003852 triazoles Chemical class 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 239000002775 capsule Substances 0.000 claims description 24
- 239000004094 surface-active agent Substances 0.000 claims description 22
- -1 hydroxypropyl Chemical group 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000004014 plasticizer Substances 0.000 claims description 8
- 239000013530 defoamer Substances 0.000 claims description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 5
- 229920001400 block copolymer Polymers 0.000 claims description 5
- 235000000346 sugar Nutrition 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000001294 propane Substances 0.000 claims description 4
- 239000003945 anionic surfactant Substances 0.000 claims description 3
- 239000007963 capsule composition Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- 239000011324 bead Substances 0.000 abstract description 5
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract 1
- 239000003429 antifungal agent Substances 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 239000000725 suspension Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 239000000194 fatty acid Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 150000004665 fatty acids Chemical class 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 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 7
- 239000008187 granular material Substances 0.000 description 7
- 239000000600 sorbitol Substances 0.000 description 7
- 241001597008 Nomeidae Species 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 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 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 229920001993 poloxamer 188 Polymers 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 240000008886 Ceratonia siliqua Species 0.000 description 2
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920002884 Laureth 4 Polymers 0.000 description 2
- 229920001363 Polidocanol Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical group 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 2
- 229960000201 isosorbide dinitrate Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229940051841 polyoxyethylene ether Drugs 0.000 description 2
- 229920000056 polyoxyethylene ether Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000009991 scouring Methods 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical class CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 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 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose 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
- 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
- 239000005639 Lauric acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229920002023 Pluronic® F 87 Polymers 0.000 description 1
- 229920002511 Poloxamer 237 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 241000195474 Sargassum Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000015125 Sterculia urens Nutrition 0.000 description 1
- 240000001058 Sterculia urens Species 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical group O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 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 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940061515 laureth-4 Drugs 0.000 description 1
- 229940062711 laureth-9 Drugs 0.000 description 1
- 229950006462 lauromacrogol 400 Drugs 0.000 description 1
- 229940053336 lauromacrogols Drugs 0.000 description 1
- 210000004932 little finger Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 229940041672 oral gel Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229940113171 polysorbate 85 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
含有下列物质的药用组合物:i)基本为惰性的珠粒;其中所述珠粒为用ii)包被的;ii)为(－)－(2R－顺式)－4－[4－[4－[4－[[5－(2,4－二氟苯基)－四氢－5－(1H－1,2,4－三唑－1－基甲基)呋喃－3－基]甲氧基]苯基]－1－哌嗪基]苯基]－2,4－二氢－2－[(S)－1－乙基－2(S)－羟基丙基]－3H－1,2,4－三唑－3－酮抗真菌剂;iii)粘合剂,以使所述抗真菌化合物粘附于所述珠粒上。该组合物能使具有极低水溶性的抗真菌化合物在哺乳动物例如人体中提高其生物利用度。
Description
本发明的背景
本发明涉及增加或提高新三唑类抗真菌化合物的生物利用度的组合物。
国际专利公开号WO 95/17407(1995年6月29日公开)提出了一类新的四氢呋喃/三唑类抗真菌化合物。发现其中的一个特殊化合物(2R-顺式)-4-[4-[4-[4-[[5-(2,4-二氟苯基)-四氢-5-(1H-1,2,4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-[(S)-1-乙基-2(S)-羟基丙基]-3H-1,2,4-三唑-3-酮(“抗真菌化合物”)在悬浮液中对机会性真菌例如曲霉菌、假丝酵母菌、隐球酵母菌及其它的机会性真菌具有有效的抗真菌活性。然而，发现固体组合物例如粉末剂或颗粒剂的抗真菌活性和/或生物利用度降低，推测是由于该化合物在水中的溶解度极低的缘故。因此需要提供在药用组合物中能增加或提高抗真菌活性和/或生物利用度的该抗真菌化合物。
本发明的简述
本发明涉及含有下列物质的药用组合物：
ⅰ)许多珠粒；其中所述珠粒为用ⅱ)包被的；ⅱ)下式的抗真菌剂：
和ⅲ)使所述抗真菌化合物粘附于所述珠粒上的粘合剂。
该药用组合物也可以含有其它的赋形剂例如ⅳ)表面活性剂，ⅴ)增塑剂，ⅵ)消泡剂和着色剂。该药用组合物也可以制成其它合适的释放体系或剂型，例如胶囊剂、片剂或复制珠粒。
也令人吃惊和出人意料地发现用适当的粘合剂对珠粒用抗真菌化合物进行包被可以增加或相当于悬浮液中的抗真菌化合物的生物利用度。由于已知的参考文献，例如Peter G.Welling(Pharmacokinetics,Processes and Mathematics,American Chemical Society,Washingtion DC,ACS Monograph 185,1986，第57页)提出溶液和悬浮液一般比胶囊剂或片剂产生更令人满意的生物利用度，所以这些结果实在令人吃惊和出乎意料。J.G.Naim(Remington’s Pharmaceutical Sciences,18版，1990,Mack Publishing Co.，第83章，第1519页)也提出由于药物在其溶解状态被吸收，因而常常发现口服剂型的吸收速率按下列顺序降低：水溶液＞含水悬浮液＞胶囊或片剂。
本发明具有可以提供在药用组合物中的抗真菌化合物的优点，该药用组合物可以方便地配制成固体或“干”释放体系或剂型，例如胶囊剂、片剂或具有有效抗真菌活性和/或生物利用度的松散珠粒。
本发明的详述
WO 95/17407(1995年6月29日公开)公开具有下式的抗真菌化合物、其酯和醚或药学上可接受的盐：其中R1为由一个或两个羟基部分取代的直链或支链(C3-C8)烷基。在WO 95/17407的实施例24和32中提出上述化合物的特别优选的化合物为抗真菌化合物(-)-(2R-顺式)-4-[4-[4-[4-[[5-(2,4-二氟苯基)-四氢-5-(1H-1,2,4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-[(S)-1-乙基-2(S)-羟基丙基]-3H-1,2,4-三唑-3-酮(“抗真菌化合物”)，分子式为：C37H42F2N9O4；分子量：700.8；m.p.164-165℃,[a]D 25-29℃±3°(c=1.0,CHCl3)，其结构为：
抗真菌化合物的微粉化颗粒可以在抗真菌化合物生产的最后步骤获得，或在常规结晶步骤后用常规的微粉化技术获得。
当使用微粉化技术时，可以通过常规的技术例如用球形磨、超声方法或优选用流能磨擦磨例如由Platomer Products(Newton,Pennsylvania 18940)得到的trost流能磨，将抗真菌化合物微粉化至所需颗粒大小。当使用流能磨擦磨时，所需颗粒大小可以通过改变向所述磨中送抗真菌化合物的速率获得。
约99％的微粉化抗真菌颗粒长度小于或等于100μm，其中95％小于或等于90μm。优选约99％的微粉化抗真菌颗粒长度小于或等于50μm，其中95％小于或等于40μm。更优选约99％的微粉化抗真菌颗粒长度小于或等于20μm，其中95％小于或等于10μm。
所述组合物中使用的抗真菌化合物的量为有效控制目的微生物或真菌的量。此量可以为所述组合物重量的约2％-约50％、更优选为约6％-约40％、最优选为约5-约33％(重量)。特定剂型，如胶囊剂、片剂等中组合物的量为每剂型含有约10-约300mg抗真菌化合物、优选约50-约200mg。
通过将抗真菌化合物溶于或悬浮于含有粘合剂的适当的溶剂体系中，并任选含有一种或多种成分例如表面活性剂、增塑剂、消泡剂和/或着色剂，然后用所述溶液或悬浮液包被大小珠粒可以制备本发明的组合物。
本发明的药用组合物可以制成任何适当的剂型，例如胶囊剂、片剂或复制的松散珠粒。如用适当的缓冲剂(cushioning agent)例如微晶纤维素并任选崩解剂、润滑剂、助流剂等可以将上述组合物压制成片剂。
用下列术语描述本发明的药用组合物、在制剂中使用的成分和评价其生物活性或生物利用度的方法。
珠粒或晶核为可区分的颗粒，优选为球状颗粒或球体，可以用作所述抗真菌化合物包被于其上的固体基质，并构成所述组合物或剂型的主要部分。珠粒可以由糖如乳糖、蔗糖、甘露醇或脱水山梨醇制备，其它的珠粒可以衍生自小麦、玉米和马铃薯制得的淀粉以及纤维素例如微晶纤维素。糖珠粒(非-pareil晶核)的来源为已知的Nu-pareil PG(Crompton和Knowles Ingredient Technology Corporation of Mahawsh的商品名，Nes Jersey)。微晶纤维素珠粒的来源为Celphere(FMCCorporation的商品名，Philadelphia,Pennsylvania)。可以使用不同目大小的珠粒，例如18/20目、25/30目和40/50目。目的大小指颗粒或珠粒的大小，其直径为约1.0mm-约0.297mm。优选珠粒大小或直径为在较窄的范围，例如约1.0-0.84mm(18/20目)，或为约0.71-0.59mm(25/30目)，或为约0.42-0.297mm(40/50目)。珠粒应为“惰性”的指珠粒本身几乎没有或无抗真菌有效性。组合物中珠粒的量为总组合物重量的约50-90％、优选约60-约80％、更优选约65-约75％(重量)。
粘合剂-指结合或“胶合”抗真菌化合物和其它的成分于所述珠粒上的物质，从而使所述珠粒被包被。适当的粘合剂包括糖，如蔗糖；得自小麦、玉米或马铃薯的淀粉；天然胶例如阿拉伯胶、明胶和西黄蓍胶；海藻的衍生物例如藻酸、藻酸钠和藻酸钙铵；纤维素物质例如甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素和羧甲基纤维素钠；聚乙烯吡咯烷酮(聚维酮)；蛋白水解物；甲基丙烯酸和其盐；无机化合物例如硅酸铝镁。用作粘合剂的商业可得制剂已知为Opadry粉(Coloron Corporation的商品名，West Point,Pennsylvania)。Opadar粉可以含有羟丙基甲基纤维素和增塑剂例如聚乙二醇和表面活性剂例如聚山梨醇酯80。组合物中粘合剂的量为组合物重量的约1-约10％、优选约2-约8％(重量)、更优选约3-约6％。
崩解剂-指加至所述组合物中以帮助其分解(崩解)并释放药物的物质。适当的崩解剂包括淀粉；“冷水可溶的”改良淀粉例如羧甲基淀粉钠；天然和合成胶例如蝗虫豆(locust bean)、卡拉牙胶、瓜尔胶、西黄蓍胶和琼脂；纤维素衍生物例如甲基纤维素和羧甲基纤维素钠；微晶纤维素和交联微晶纤维素例如交联羧甲基纤维素钠；藻酸盐例如藻酸和藻酸钠；粘土例如膨润土；和泡腾剂混合物。组合物中崩解剂的量为组合物重量的约2-约15％、更优选约4-约10％(重量)。
表面活性剂-指可以降低两个不相混溶的相之间的表面张力的化合物，而此现象是由于其分子中含有两个区，一个为自然亲水的，另一个为疏水的。
非离子表面活性剂-指缺少净离子电荷的表面活性剂，并且在含水介质中不分离为可觉察的程度。非离子表面活性剂的性质主要取决于其分子中的亲水和疏水基团。亲水基团包括氧亚乙基(-OCH2CH2-)和羟基。通过改变疏水分子例如脂肪酸中这些基团的数目，可以获得强疏水性且水不溶性化合物例如甘油单硬脂酸酯至强亲水性且水溶性化合物例如大粒凝胶(macrogol)等物质。这两种极端类型的化合物包括其中亲水和疏水部分更加平衡的物质，例如大粒凝胶酯和醚以及脱水山梨醇衍生物。适当的非离子表面活性剂可以在Martindale的The ExtraPharmacopoeia(28版，1982,The Pharmaceutical Press,Lotdon,GreatBritain，第370-379页)发现。此类非离子表面活性剂可以包括环氧乙烷和环氧丙烷嵌段共聚物、甘油和脂肪酸的甘油酯以及它们的衍生物、脂肪酸的聚氧乙烯酯(大粒凝胶酯)、脂肪酸的聚氧乙烯醚和它们的衍生物(大粒凝胶醚)、聚乙烯醇和脱水山梨醇酯。优选，所述非离子表面活性剂为环氧乙烷和环氧丙烷的嵌段共聚物。
适当的环氧乙烷和环氧丙烷的嵌段共聚物在类别上称为“泊咯沙姆”，包括由下面化学结构代表的物质：
其中a为约10-约110的整数、优选约12-101；更优选约12-80；且
b为约20-约60的整数、更优选约20-约56；也优选约20-27。最优选，a为80,b为27，也称为PluronicF68的表面活性剂(BASF Corporation,Mount Olive,New Jersey,USA)。PluronicF68的表面活性剂也已知为泊咯沙姆188。该表面活性剂的平均分子量为8400，在20℃时为固体，在77℃时粘度(Brookfield)为1000cps。其它适当的环氧乙烷和环氧丙烷的嵌段共聚物包括Pluronic F87，也已知为泊咯沙姆237，其中a为64,b为37；Pluronic F127，也已知为泊咯沙姆407，其中a为101,b为56。
适当的甘油和脂肪酸的甘油酯及其衍生物包括甘油基单油酸酯和类似的水溶性衍生物；
适当的脂肪酸的聚氧乙烯酯(大粒凝胶酯)包括聚氧乙烯蓖麻油和氢化蓖麻油衍生物；
适当的脂肪酸的聚氧乙烯醚及其衍生物(大粒凝胶醚)包括Cetomacrogel 1000、Lauromacrogols(不同链长的大粒凝胶的十二烷基醚系列)如Laureth 4、Laureth 9和Lauromacrogol 400。
适当的脱水山梨醇酯(脱水山梨醇中的一个或多个羟基与脂肪酸例如硬脂酸、棕榈酸、油酸或月桂酸形成的酯)，包括例如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65、聚山梨醇酯80、聚山梨醇酯85、山梨醇单月桂酸酯、山梨醇单油酸酯、山梨醇单棕榈酸酯、山梨醇单硬脂酸酯、山梨醇倍半油酸酯、山梨醇三油酸酯和山梨醇三硬脂酸酯。
组合物中表面活性剂的量为组合物总量的约0.5-约25％、优选为约5-约15％(重量)。
阴离子表面活性剂-指具有净阴离子电荷的表面活性剂，且在水溶性介质中可以游离为可检测的程度。任选，本发明的组合物中也可以含有阴离子表面活性剂，例如十二烷基硫酸钠，其量可以为组合物总量的约1-约10％、更优选约3-约8％(重量)。
增塑剂-指使粘合剂柔软的物质。适当的增塑剂包括丙二醇、甘油、邻苯二甲酸二乙酯、癸二酸二丁酯、柠檬酸三乙酯、氢化甘油酯、聚乙二醇、聚环氧乙烷、甘油三乙酸酯等。组合物中增塑剂的量可以为约1-2至约5％(重量)。
消泡剂也称为抗泡沫剂，为用于减少由于机械搅拌或通气产生的泡沫、含氮物质或其它在加工中可能干扰的其它物质。其实例包括金属盐，例如氯化钠；C6-C12醇例如辛醇；磺化油；硅酮醚例如二甲基硅酮；有机磷酸酯等。组合物中消泡剂的量可以为约0.05-约5％(重量)、优选约0.1-2％(重量)。
助流剂(Glidents)-防止结块，提高颗粒流动特性以使流动流畅且均匀的物质。适当的助流剂包括二氧化硅和滑石粉。组合物中助流剂的量可以为组合物重量的约0.1％-约5％(重量)、优选约0.5-约2％(重量)。
润滑剂-指加至剂型中通过减少磨擦或磨耗使片子、颗粒等在被压制后能够从模具或冲模中释放的物质。适当的润滑剂包括金属的硬脂酸盐，例如镁、钙或钾的硬脂酸盐；硬脂酸；高熔点蜡；以及水溶性润滑剂例如氯化钠、苯甲酸钠、乙酸钠、油酸钠、聚乙二醇和d’1-亮氨酸。润滑剂通常在压制前最后一个步骤加入，因为它们必须存在于颗粒的表面，颗粒与压片机部件之间。组合物中润滑剂的量可以为组合物重量的约0.2％-约5％(重量)、优选约0.5-约2％(重量)。
着色剂-为组合物或剂型提供颜色的赋形剂。此类赋形剂包括食用级颜料和吸附于适当的吸附剂例如粘土或氧化铝上的食用级颜料。组合物中着色剂的量可以为组合物重量的约0.1％-约5％(重量)、优选约0.1-约1％(重量)。
剂型-制成释放体系例如含有非活性成分的片剂、胶囊剂、口服凝胶、复制粉末剂或悬浮液的含有抗真菌化合物的组合物。
胶囊剂-指由甲基纤维素、聚乙烯醇或变性明胶或淀粉制备的用于保存或容纳含有所述活性抗真菌化合物的组合物的特殊容器或外壳。硬壳胶囊一般由相对高胶凝力的骨和猪皮明胶的混合物制备。胶囊本身可以含有少量的颜料、遮光剂、增塑剂和防腐剂。
片剂-指含有所述活性成分(抗真菌化合物)和适当稀释剂的压制或模制固体剂型。通过将混合物或由湿法制粒、干法制粒获得的颗粒压制、压缩或压制含有包被的活性珠粒的混合物可以制备片剂。
用于复制的珠粒指可以悬浮于水、汁或果酱如苹果酱中的松散、包被的珠粒。
生物利用度-指与标准或对照相比所述活性药物成分或治疗部分从给药的剂型中被吸收进入血液循环的速率和程度。
Cmax值指血浆中检测到的所述抗真菌化合物的最大浓度(“峰浓度”)。
AUC(0-72hr)值指指定时间内所述抗真菌化合物的血浆/血清浓度-时间曲线下的面积。
制备片剂的常规方法是已知的。此类方法包括干法，例如直接压片或对通过压缩产生的颗粒压片或湿法或其它特殊方法。
下列实施例描述含有抗真菌化合物的本发明的组合物，但是它们不应解释为限制本发明权利要求的范围。
实施例1．胶囊剂中的包被珠粒
成分 g/批 ％(wt)总量
微粉化抗真菌化合物 135 20.3
Opadry YS-1-7006 30 4.5
二甲基硅酮 1.42 0.2
纯净水，USP(蒸发) 700ml -
非-Pareil晶核(25/30目) 500 75
666.42 100％
实施例2．胶囊剂中的包被珠粒
成分 mg/批 ％(wt)总量
微粉化抗真菌化合物 75 11.0
Opadry YS-1-7006 30 4.4
Pluronic F68表面活性剂 75 11.0
二甲基硅酮 0.7 0.1
纯净水，USP(蒸发) 500ml -
非-Pareil晶核(25/30目) 500 73.5
680.7 100％
实施例1、2和5胶囊剂中包被珠粒的制备
将Opadry YS-l-7006、Pluronic F68或十二烷基硫酸钠溶于水中。搅拌下加入二甲基硅酮。搅拌下、缓慢加入所述抗真菌化合物直至形成均匀悬浮液。通过25目手动筛将悬浮液过筛。用流化床涂膜机将悬浮液包被于非Pareil晶核上。将包被的珠粒干燥过夜，测定包被珠粒以检测抗真菌化合物的量。将包被的珠粒填充入适当大小的胶囊中至所需的填充量。
对照实施例3的悬浮水溶液的制备
在4ml蒸馏水甲制备含有59.8mg Pluronic F68的悬浮液。向上述溶液中加入200mg抗真菌化合物，混合得到均匀的悬浮液。
对照实施例4的在胶囊中的粉末混合物的制备
成分 mg/胶囊 ％(wt)总量
微粉化抗真菌混合物 100.0 28.6
十二烷基硫酸钠表面活性剂 22.5 6.4
微晶纤维素 178.0 50.9
羟乙酸淀粉钠 45.0 12.8
硬脂酸镁 4.5 1.3
350 100
将抗真菌混合物、十二烷基硫酸钠(表面活性剂)、微晶纤维素和羟乙酸淀粉钠在混合机中混合10分钟。加入硬脂酸镁并混合5分钟形成均匀粉末。将所述粉末填充于适当大小的胶囊中得到所需的填充量。
生物利用度试验
以两个胶囊或悬浮液的形式给予狗200mg剂量的抗真菌化合物。在选定的时间收集血清样品，用配有紫外检测器的高压液相层析仪通过HPLC/UV检测方法进行分析。在下表中，Cmax和AUC(0-72hr)值为抗真菌化合物的生物利用度的指标。AUC值越大，在72小时内血浆中积聚的抗真菌化合物的总量越大。
| 生物利用度的指标 | 胶囊剂中包被的珠粒-实施例1 | 胶囊剂中包被的珠粒-实施例2 | 对照悬浮液-对照实施例3 | 胶囊剂中的粉末混合物-对照实施例4 |
| Cmax(ug/ml) | 1.43 | 1.37 | 1.21 | 0.95 |
| AUC(0-72hr)ug/hr/ml | 50.21 | 50.17 | 47.98 | 29.72 |
以上结果表明，与对照的实施例3的含水悬浮液比较，尤其是与对照的实施例4的胶囊中的粉末混合物比较，实施例1和2的胶囊显示出升高的生物利用度。
实施例5．胶囊剂中的包被珠粒
成分 g/批 ％(wt)总量
微粉化抗真菌化合物 75.0 11.80
Opadry YS-1-7006 30.0 4.72
十二烷基硫酸钠 30.0 4.72
二甲基硅酮 1.0 0.16
纯净水，USP(蒸发) 500ml -
非-Pareil Seeds(25/30目) 500 78.60
636.0 100％
Claims (19)
1．含有下列物质的药用组合物：ⅰ)许多珠粒；其中所述珠粒为用ⅱ)包被的；ⅱ)下式的抗真菌剂：
ⅲ)使所述抗真菌化合物粘附于所述珠粒上的粘合剂。
2．权利要求1的组合物，其中所述珠粒由糖、淀粉或微晶纤维素制备。
3．权利要求1的组合物，其中所述珠粒由糖制备。
4．权利要求1的组合物，其中所述珠粒目的大小为约18/20-45/50。
5．权利要求1的组合物，其中所述抗真菌化合物在所述组合物中的量为约5％-约33％(重量)。
6．权利要求1的组合物，其中所述粘合剂为羟丙基甲基纤维素。
7．权利要求1的组合物还包括ⅳ)表面活性剂。
8．权利要求7的组合物，其中所述表面活性剂为非离子表面活性剂。
9．权利要求7的组合物，其中所述表面活性剂为环氧乙烷和环氧丙烷的嵌段共聚物。
10．权利要求7的组合物，其中所述表面活性剂为阴离子表面活性剂。
11．权利要求10的组合物，其中所述阴离子表面活性剂为十二烷基硫酸钠。
12．权利要求7的组合物还包括ⅴ)增塑剂。
13．权利要求12的组合物，其中所述增塑剂为聚乙二醇。
14．权利要求13的组合物还包括ⅵ)消泡剂。
15．权利要求14的组合物，其中所述消泡剂为二甲基硅酮。
16．为胶囊剂型的权利要求1的组合物。
17．权利要求16的组合物，其中所述抗真菌化合物在胶囊中的量为约50-300mg。
18．权利要求16的组合物，其中所述抗真菌化合物在胶囊中的量为约50-200mg。
19．权利要求1的药用组合物还包括
约11-20％(重量)的抗真菌化合物；
约73-75％(重量)的珠粒；
约0.5-15％(重量)的表面活性剂；
约4.7-5％(重量)的为羟丙基甲基纤维素的粘合剂；和
约0.5-1.5％(重量)的消泡剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67243296A | 1996-06-28 | 1996-06-28 | |
| US08/672,432 | 1996-06-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1228693A true CN1228693A (zh) | 1999-09-15 |
Family
ID=24698529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97197432A Pending CN1228693A (zh) | 1996-06-28 | 1997-06-25 | 含有三唑类抗真菌化合物的口服组合物 |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0914100A1 (zh) |
| JP (1) | JP2000514059A (zh) |
| KR (1) | KR20000022294A (zh) |
| CN (1) | CN1228693A (zh) |
| AU (1) | AU731704B2 (zh) |
| BR (1) | BR9710069A (zh) |
| CA (1) | CA2258683C (zh) |
| CZ (1) | CZ421498A3 (zh) |
| HU (1) | HUP9903869A3 (zh) |
| IL (1) | IL127780A0 (zh) |
| NO (1) | NO986087L (zh) |
| NZ (1) | NZ333514A (zh) |
| PL (1) | PL330864A1 (zh) |
| SK (1) | SK177598A3 (zh) |
| TR (1) | TR199802718T2 (zh) |
| WO (1) | WO1998000116A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949278A (zh) * | 2016-03-30 | 2016-09-21 | 南京曼杰生物科技有限公司 | 一种取代的四氢呋喃水溶性衍生物及其应用 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI0969821T1 (en) * | 1997-03-26 | 2003-10-31 | Janssen Pharmaceutica N.V. | Pellets having a core coated with an antifungal and a polymer |
| WO1999063971A1 (en) * | 1998-06-11 | 1999-12-16 | Em Industries, Inc. | Micro-osmotic controlled drug delivery systems |
| TR200002217T2 (tr) * | 1998-07-17 | 2001-02-21 | Janssen Pharmaceutica N.V. | Bir mantar ilacı ve bir polimer ile kaplanmış bir çekirdeğe sahip taneler. |
| ES2157731B1 (es) * | 1998-07-21 | 2002-05-01 | Liconsa Liberacion Controlada | Preparacion farmaceutica oral de un compuesto de actividad antifungica y procedimiento para su preparacion. |
| US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| FR2795961B1 (fr) * | 1999-07-09 | 2004-05-28 | Ethypharm Lab Prod Ethiques | Composition pharmaceutique contenant du fenofibrate micronise, un tensioactif et un derive cellulosique liant et procede de preparation |
| US7863331B2 (en) | 1999-07-09 | 2011-01-04 | Ethypharm | Pharmaceutical composition containing fenofibrate and method for the preparation thereof |
| KR100694667B1 (ko) * | 1999-12-08 | 2007-03-14 | 동아제약주식회사 | 생체내이용률 향상과 개인간 및 개인내 흡수 편차를감소시킨 이트라코나졸 함유 항진균성 제제 |
| US6663897B2 (en) * | 2001-02-06 | 2003-12-16 | Dsm Ip Assets B.V. | Oral itraconazole formulations and methods of making the same |
| EP1842532A3 (en) * | 2001-02-06 | 2009-04-22 | Stiefel Laboratories, Inc. | Oral sparingly water-soluble antifungal formulations and methods of making the same |
| FR2842736B1 (fr) | 2002-07-26 | 2005-07-22 | Flamel Tech Sa | Formulation pharmaceutique orale sous forme d'une pluralite de microcapsules permettant la liberation prolongee de principe(s) actif(s) peu soluble(s) |
| ITMI20031096A1 (it) * | 2003-05-30 | 2004-11-30 | Eurand Spa | Microcapsule per coacervazione contenenti farmaco incorporato nel polimero di rivestimento |
| DE10355461A1 (de) | 2003-11-27 | 2005-06-23 | Bayer Healthcare Ag | Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung |
| US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
| US20180153904A1 (en) | 2010-11-30 | 2018-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
| US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
| US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
| US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
| WO2016033556A1 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS |
| US20170246187A1 (en) | 2014-08-28 | 2017-08-31 | Lipocine Inc. | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
| CA3078723A1 (en) | 2016-11-28 | 2018-05-31 | Nachiappan Chidambaram | Oral testosterone undecanoate therapy |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580578A (en) * | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
| PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
| CO4520281A1 (es) * | 1993-12-21 | 1997-10-15 | Schering Corp | Antifungicos de tetrahidrofurano |
-
1997
- 1997-06-25 WO PCT/US1997/010122 patent/WO1998000116A1/en not_active Application Discontinuation
- 1997-06-25 PL PL97330864A patent/PL330864A1/xx unknown
- 1997-06-25 CN CN97197432A patent/CN1228693A/zh active Pending
- 1997-06-25 SK SK1775-98A patent/SK177598A3/sk unknown
- 1997-06-25 BR BR9710069A patent/BR9710069A/pt not_active IP Right Cessation
- 1997-06-25 HU HU9903869A patent/HUP9903869A3/hu unknown
- 1997-06-25 IL IL12778097A patent/IL127780A0/xx unknown
- 1997-06-25 JP JP10504148A patent/JP2000514059A/ja not_active Ceased
- 1997-06-25 EP EP97929927A patent/EP0914100A1/en not_active Ceased
- 1997-06-25 TR TR1998/02718T patent/TR199802718T2/xx unknown
- 1997-06-25 NZ NZ333514A patent/NZ333514A/xx unknown
- 1997-06-25 CZ CZ984214A patent/CZ421498A3/cs unknown
- 1997-06-25 CA CA002258683A patent/CA2258683C/en not_active Expired - Fee Related
- 1997-06-25 KR KR1019980710716A patent/KR20000022294A/ko not_active Application Discontinuation
- 1997-06-25 AU AU33874/97A patent/AU731704B2/en not_active Ceased
-
1998
- 1998-12-23 NO NO986087A patent/NO986087L/no not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949278A (zh) * | 2016-03-30 | 2016-09-21 | 南京曼杰生物科技有限公司 | 一种取代的四氢呋喃水溶性衍生物及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998000116A1 (en) | 1998-01-08 |
| JP2000514059A (ja) | 2000-10-24 |
| BR9710069A (pt) | 1999-08-10 |
| TR199802718T2 (xx) | 1999-03-22 |
| AU3387497A (en) | 1998-01-21 |
| AU731704B2 (en) | 2001-04-05 |
| HUP9903869A3 (en) | 2000-07-28 |
| NZ333514A (en) | 2000-05-26 |
| CA2258683A1 (en) | 1998-01-08 |
| NO986087D0 (no) | 1998-12-23 |
| KR20000022294A (ko) | 2000-04-25 |
| CZ421498A3 (cs) | 1999-06-16 |
| NO986087L (no) | 1999-02-26 |
| PL330864A1 (en) | 1999-06-07 |
| SK177598A3 (en) | 1999-07-12 |
| EP0914100A1 (en) | 1999-05-12 |
| CA2258683C (en) | 2007-07-31 |
| IL127780A0 (en) | 1999-10-28 |
| HUP9903869A2 (hu) | 2000-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1228693A (zh) | 含有三唑类抗真菌化合物的口服组合物 | |
| US5846971A (en) | Oral antifungal composition | |
| US5834472A (en) | Antifungal composition with enhanced bioavailability | |
| CN1206984C (zh) | 具有外涂一种杀真菌剂和一种聚合物的核心的药丸 | |
| CN1025150C (zh) | 能延续释放的新药物制剂的制备方法 | |
| CN1525855A (zh) | 治疗与预防心脏病与循环系统疾病的日服一次疗法用口服的控释医药组合物 | |
| CN1499930A (zh) | 生物利用度提高的抗真菌组合物 | |
| AU6239496A (en) | Controlled release formulations for poorly soluble drugs | |
| CZ20022047A3 (cs) | Farmaceutické kompozice poskytující zvýšenou koncentraci léčiva | |
| CN1273194C (zh) | 水溶性差的活性物质的口服固溶体配方 | |
| JP2010509363A (ja) | 固体剤形の多相医薬組成物の製造方法 | |
| CN1449744A (zh) | 抗真菌制剂及其制造和使用方法 | |
| CN101848705A (zh) | 氯吡格雷组合物的制备方法 | |
| CN101057834A (zh) | 含有肠溶固体分散体的固体制剂 | |
| CN1210065C (zh) | 具有改善溶出性能的普仑司特的固体分散体系及其制备方法 | |
| CN1121860C (zh) | 提高生物利用度的抗真菌组合物 | |
| CN105078974A (zh) | 一种阿利沙坦酯固体分散体及药物组合物 | |
| CN1921839A (zh) | 加巴喷丁的稳定缓释口服剂型及其制备方法 | |
| CN1543943A (zh) | 口服水飞蓟素缓释制剂及其制备方法 | |
| JPWO2003072085A1 (ja) | 難水溶性薬物の吸収性を改善した固形状製剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |