CN1960716A - 口服制剂及其制造方法 - Google Patents
口服制剂及其制造方法 Download PDFInfo
- Publication number
- CN1960716A CN1960716A CNA2005800180183A CN200580018018A CN1960716A CN 1960716 A CN1960716 A CN 1960716A CN A2005800180183 A CNA2005800180183 A CN A2005800180183A CN 200580018018 A CN200580018018 A CN 200580018018A CN 1960716 A CN1960716 A CN 1960716A
- Authority
- CN
- China
- Prior art keywords
- oral formulations
- complex
- coating
- composition
- medicine
- 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
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 66
- 239000011248 coating agent Substances 0.000 claims abstract description 50
- 238000000576 coating method Methods 0.000 claims abstract description 50
- 239000003814 drug Substances 0.000 claims abstract description 34
- 235000019640 taste Nutrition 0.000 claims abstract description 29
- 238000002844 melting Methods 0.000 claims abstract description 16
- 230000008018 melting Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000009472 formulation Methods 0.000 claims description 25
- 229920002521 macromolecule Polymers 0.000 claims description 18
- 239000006188 syrup Substances 0.000 claims description 17
- 235000020357 syrup Nutrition 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- -1 silicon anhydride Chemical class 0.000 claims description 14
- 239000012528 membrane Substances 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 230000004206 stomach function Effects 0.000 claims description 9
- 229960002626 clarithromycin Drugs 0.000 claims description 8
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 8
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229940068968 polysorbate 80 Drugs 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 150000002484 inorganic compounds Chemical class 0.000 claims description 4
- 229910010272 inorganic material Inorganic materials 0.000 claims description 4
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 4
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical group [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229920003159 Eudragit® RS 100 Polymers 0.000 claims 1
- 229920003160 Eudragit® RS PO Polymers 0.000 claims 1
- 229920003134 Eudragit® polymer Polymers 0.000 claims 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 6
- 239000008187 granular material Substances 0.000 abstract description 4
- 230000000873 masking effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 2
- 239000008199 coating composition Substances 0.000 abstract 1
- 239000002131 composite material Substances 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 235000014113 dietary fatty acids Nutrition 0.000 description 12
- 239000000194 fatty acid Substances 0.000 description 12
- 229930195729 fatty acid Natural products 0.000 description 12
- 239000007921 spray Substances 0.000 description 11
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 239000007788 liquid Substances 0.000 description 8
- 238000005507 spraying Methods 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 229920003149 Eudragit® E 100 Polymers 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 235000021355 Stearic acid Nutrition 0.000 description 6
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 6
- 239000008117 stearic acid Substances 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- 101100120289 Drosophila melanogaster Flo1 gene Proteins 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229940075507 glyceryl monostearate Drugs 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229920003157 Eudragit® RL 30 D Polymers 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 235000013361 beverage Nutrition 0.000 description 3
- 239000004203 carnauba wax Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000000346 nonvolatile oil Substances 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- 239000007931 coated granule Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 238000005453 pelletization Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-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
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000256846 Apis cerana Species 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 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
- 229920002472 Starch Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 1
- 229960000648 digitoxin Drugs 0.000 description 1
- 229940120889 dipyrone Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000012182 japan wax Substances 0.000 description 1
- 229960004144 josamycin Drugs 0.000 description 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229950007634 kitasamycin Drugs 0.000 description 1
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 229960002757 midecamycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种口服制剂及其制造方法,该口服制剂通过在加热至熔点以上熔融的低熔点物质中分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒得到复合体,以含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物对该复合体进行涂敷而制成。本发明的口服制剂,在含有呈现不愉快味道的药物的微小颗粒形态等中,即使在酸性条件下,也可以维持对药物的不愉快味道的掩蔽和溶出性。
Description
技术领域
本发明涉及口服制剂及其制造方法,更详细地涉及在对呈现不愉快味道药物的掩蔽和溶出性(release profile)的控制方面优异的口服制剂及其制造方法。
背景技术
目前,报告了多项以呈现不愉快味道药物等的掩蔽和溶出性的控制为目的,用于在药剂上进行薄膜包衣(filmcoating)等包衣的技术。
例如,报告了在由非活性材料的极微颗粒组成的颗粒上设置酮洛芬等的药剂层,再在该药剂层上设置硬脂酸和乙基纤维素或石蜡和甲基丙烯酸共聚物的包衣膜,具有4~22小时或比其更长的有效性的组合物(专利文献1)。
此外,报告了干糖浆剂,其特征在于,含有在由分散有易溶于水的、具有不愉快味道药物的蜡状物质构成的微小球状颗粒上,包覆由(a)硬脂酸和表面活性剂;(b)硬脂酸、表面活性剂和胃溶性高分子或肠溶性高分子;或(c)硬化油和胃溶性高分子或肠溶性高分子中的任一个构成的包衣膜形成的包衣颗粒(专利文献2)。
还报告了由包衣散剂和包衣颗粒剂构成的味道掩蔽医药制剂,其特征在于,在含有不愉快味道的药物的核颗粒上包覆由低熔点物质和低分子量水溶性物质构成的包衣膜而形成(专利文献3)。
此外,还报告了混合含有药剂的缓释性散剂和含有甜味剂的安慰剂散剂的散剂(专利文献4)。
另一方面,本申请人也报告了用于进行对呈现不愉快味道药物的掩蔽和溶出性的控制的、由分散、溶解有上述药物和胃溶性高分子化合物的低熔点物质等构成的微小颗粒的技术(专利文献5~7)。
但是,作为使幼儿服用药品的剂型之一,已知有干糖浆剂。该干糖浆剂悬浮或溶解在水中以供服用,在幼儿不想服用的情况下,也可以加入幼儿喜欢的其它饮料中以供服用。上述微小颗粒等,在水等中溶解形成饮料时没有任何问题,但在果汁等酸性饮料中溶解饮用的情况下,在微小颗粒中含有的药物立刻溶出,产生不愉快的味道,反而使服用变的困难。
专利文献1:日本专利第2518882号
专利文献2:日本专利第3247511号
专利文献3:日本专利特开平11-349473号
专利文献4:日本专利特开2001-270821号
专利文献5:日本专利第3265680号
专利文献6:日本专利第2973751号
专利文献7:日本专利特开2000-169364号
发明内容
因此,本发明的目的在于提供在酸性条件下也能够保证在上述微小颗粒等中的药物的掩蔽和溶出性的技术。
本发明人等为了解决上述课题而进行潜心研究,结果发现,在加热至熔点以上熔融的低熔点物质中分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒得到复合体,以含有规定的重量比的不溶性高分子化合物和崩解剂的包衣用组合物包覆上述得到的复合体,由此,口服制剂中的药物在酸性条件下也不会溶出,能够充分地进行不愉快味道的掩蔽,由此完成了本发明。
即,本发明提供一种口服制剂,通过在加热至熔点以上熔融的低熔点物质中分散或熔融呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒而得到复合体,由含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物包覆该复合体而制成。
此外,本发明提供一种口服制剂的制造方法,其特征在于,通过在加热到熔点以上熔融的低熔点物质中分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒得到复合体后,以含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物对该复合体进行涂敷,接着,在35~45℃下进行固化(curing),在该复合体上形成包衣膜。
本发明的口服制剂是即使在酸性条件下,药物的不愉快味道的掩蔽和溶出性也优异的制剂。
并且,在本发明的口服制剂的制造方法中使用的包衣膜用组合物,包衣膜形成温度低,因此在本发明的口服制剂中,能够以各种低熔点物质作为复合体基剂使用。
具体实施方式
本发明的口服制剂是在加热到熔点以上熔融的低熔点物质中,分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒而得到复合体(以下简称为“复合体”),以含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物(以下,简称为“包衣用组合物”)包覆该复合体而制成。
在本发明中,作为呈现不愉快味道的药物,只要是呈现不愉快味道的药物就没有特别的限制,例如,可以列举红霉素、克拉霉素、吉他霉素、交沙霉素、麦迪霉素、罗红霉素、阿奇霉素等的大环内酯系抗生素;青霉素衍生物、头孢菌素衍生物等的β-内酰胺系抗生素;四环素等的四环素系抗生素;氯丙嗪、碳酸锂等的精神神经用剂;洋地黄毒苷等的强心剂;斯尔比林(sulpyrine)等的解热剂、西咪替丁等的抗溃疡剂。在这些呈现不愉快味道的药剂中,大环内酯系抗生素,特别是克拉霉素不愉快味道的程度显著,因此本发明口服制剂的效果优异。这些呈现不愉快味道的药物在复合体中的配合量,可以根据各药物的给药量确定。
此外,作为在复合体中使用的胃溶性高分子化合物,可以列举具有能够在胃液中溶解的性质的高分子,例如,可以列举甲基丙烯酸氨基烷基酯共聚物E、聚乙烯醇缩乙醛二乙基氨基乙酸酯(AEA)或这些的混合物。这些胃溶性高分子化合物,例如,以EUDRAGIT E100(Rohm Pharma GmbH生产)等商品名销售。这些胃溶性高分子化合物在复合体中的配合量为1~60质量%,优选为2~40质量%。
作为复合体基剂使用的低熔点物质,是能够作为药品添加剂使用的、熔点为40~120℃、优选为45~100℃的物质。作为这样的低熔点物质,可以列举石蜡、微晶蜡、纯地蜡等的烃类;硬化油、可可油脂等的油脂类;肉豆蔻酸、棕榈酸、硬脂酸等的脂肪酸类;十六烷醇、硬脂醇等的高级醇;聚乙二醇6000、聚乙二醇4000等的多元醇、日本蜡(Japan tallow)、巴西棕榈蜡(carnauba wax)、蜜蜡等的蜡等;甘油脂肪酸酯、丙二醇脂肪酸酯、山梨糖醇酐脂肪酸酯、蔗糖脂肪酸酯等的脂肪酸酯类或这些的混合物等。在这些低熔点物质中,优选甘油脂肪酸酯、硬脂醇、硬脂酸、硬化油、聚乙二醇6000、聚乙二醇4000等的聚乙二醇类、巴西棕榈蜡、石蜡、蔗糖脂肪酸酯或这些的混合物。这里,所谓甘油脂肪酸酯指的是甘油和脂肪酸酯结合的物质,优选在1个甘油中带1个或3个脂肪酸的单酸甘油酯或甘油三酸酯。并且,构成酯的脂肪酸,可以列举二十二烷酸、硬脂酸、油酸、棕榈酸、十四烷酸、月桂酸。这些低熔点物质在复合体中的配合量没有特别的限制,优选为2~98质量%左右。
上述复合体优选由例如以下说明的喷雾凝固造粒制造,通过在复合体的制造中使用喷雾凝固造粒,能够良好地掩蔽药物的不愉快味道,得到微细、生物利用度优异的复合体。
由该喷雾凝固造粒进行的制造,具体的如下进行。首先,在加热到熔点以上熔融的低熔点物质中,溶解或分散胃溶性高分子化合物。接着,在其中分散呈现不愉快味道的药物,以预先设定的喷雾条件,通过喷雾凝固造粒,得到复合体。其中,这里所谓的喷雾凝固造粒,一般被归于称为熔融造粒法的造粒法之一,是喷雾液体或悬浊液、使产生的液滴冷却、得到球状或粒状的固体颗粒的方法。该方法具有不使用有机溶剂的特征,并且与作为熔融造粒法的代表性例子的喷雾干燥在进行冷却这方面不同。由该喷雾凝固造粒制造的复合体的粒径没有特别限制,优选为10~1000μm、特别优选为50~400μm。
如上所述制造的复合体,接着由包衣用组合物包覆。在该包衣用组合物中使用的不溶性高分子化合物是在酸性溶液中不溶解的化合物,例如,可以使用乙基纤维素等的pH非依赖型高分子等。
在这些不溶性高分子化合物中,优选甲基丙烯酸氨基烷基酯共聚物RS,这是丙烯酸乙酯与甲基丙烯酸乙酯和甲基丙烯酸乙基三甲基氯化铵(chlorotrimethylammoniumethyl methacrylate)的共聚物,以EudragitRL30D(Rohm Pharma GmbH生产)等的商品名销售。
另一方面,在包衣用组合物中使用的崩解剂,是即便溶解或分散也难以提高液体粘度的物质,例如,可以使用淀粉、羧甲基纤维素、低取代度羟丙基纤维素等。
在这些崩解剂中,优选羧甲基纤维素钠(CMC-Na),该物质以Cellogen PR-S(第一工业制药生产)等的商品名销售。
在本发明中使用的包衣用组合物,可以以重量比80∶20~99∶1、优选以重量比90∶10~97∶3混合上述不溶性高分子化合物和崩解剂而得到。该包衣用组合物在35~45℃、优选38~42℃的固化温度固化,形成包衣膜。
并且,在上述包衣用组合物中,作为增塑剂优选添加聚山梨醇酯80(polysorbate 80)等的非离子性表面活性剂。该非离子性表面活性剂在包衣用组合物中优选配合10~30质量%左右。
在上述包衣用组合物中,也能够添加轻质硅酸酐等作为防凝聚剂。其配合量优选为1~20质量%左右。
使用上述复合体和上述包衣用组合物的本发明口服制剂的制造,例如,可以如下进行。即,例如,如上所述对每1g复合体以0.1~2g、优选以0.5~1g的包衣用组合物包覆由喷雾凝固造粒而造粒的复合体,接着,在35~45℃、优选在38~42℃下进行固化,在复合体上形成包衣膜。
上述涂敷,例如,可以使用Wurster型涂敷机等装置,在给气温度40℃左右的条件下进行。并且,固化使用箱型干燥机等装置,进行5~50小时左右。
本发明的口服制剂能够如上所述制造,在以包衣用组合物包覆复合体后、固化前,优选再使用选自氧化镁、滑石、轻质硅酸酐中的1种以上的无机化合物对包衣用组合物进行处理。通过这些无机化合物进行处理,在固化后口服制剂之间隔着包衣膜而不会粘附,能够提高生产率。这种情况下,无机化合物优选在包衣膜组合物上被均匀地分散,其用量为每1g复合体0.005~0.03g左右。
由此得到的本发明口服制剂,能够通过通常的方法,直接或根据需要混合公知的添加剂,例如赋型剂、崩解剂、粘合剂、润滑剂、抗氧化剂、涂层剂、着色剂、矫正剂、表面活性剂、增塑剂、香料等,制成为颗粒剂、散剂、胶囊剂、片剂、干糖浆剂等。在本发明中,在这些制剂中优选干糖浆剂。该干糖浆剂是在液体中的分散性特别理想的制剂。
实施例
以下,列举实施例和试验例、详细地说明本发明,但并不是对本发明的任何限定。
实施例1
干糖浆制剂的制造(1):
以120℃熔融、分散180g克拉霉素、360g单硬脂酸甘油酯和60g的Eudragit E100(Rohm Pharma GmbH生产),以喷雾干燥机CL-12(大川原化工机生产)进行喷雾凝固造粒,得到复合体(粒径100μm)。使用Wurster型涂敷机GPCG-1(Glatt/Powrex生产),以由600g(固体组分200g)Eudragit RL30D(Rohm Pharma GmbH生产)、18g的CMC-Na、72g聚山梨醇酯80和700g纯净水配制的涂敷液,对333g该复合体进行涂敷。接着,在该涂敷后的复合体中添加10g轻质硅酸酐、混合,在箱型干燥机中,在40℃下进行10小时固化,得到口服组合物。
再使用在190g纯净水中溶解10g羟丙基纤维素的粘合液,与316.5g该口服组合物、40g玉米淀粉、133.5g的D-甘露醇一起,以流动层造粒干燥机FLO-1(Freund Corporation生产)进行流动层造粒,并干燥,得到10%的干糖浆制剂。
实施例2
干糖浆制剂的制造(2):
以120℃熔融、分散180g克拉霉素、360g单硬脂酸甘油酯和60g的Eudragit E100(Rohm Pharma GmbH生产),以喷雾干燥机CL-12(大川原化工机生产)进行喷雾凝固造粒,得到复合体(粒径120μm)。使用Wurster型涂敷机GPCG-1(Glatt/Powrex生产),以由600g(固体组分200g)Eudragit RL30D(Rohm Pharma GmbH生产)、18g的CMC-Na、72g聚山梨醇酯80和700g纯净水配制的涂敷液对333g该复合体进行涂敷。接着,在该涂敷后的复合体中添加10g滑石、进行混合,在箱型干燥机中,在40℃下进行10小时固化,得到口服组合物。
再使用在190g纯净水中溶解有10g羟丙基纤维素的粘合液,与316.5g该口服组合物、40g玉米淀粉、133.5g的D-甘露醇一起,以流动层造粒干燥机FLO-1(Freund Corporation生产)进行流动层造粒和干燥,得到10%的干糖浆制剂。
实施例3
干糖浆制剂的制造(3):
以120℃熔融、分散180g克拉霉素、360g单硬脂酸甘油酯和60g的Eudragit E100(Rohm Pharma GmbH生产),以喷雾干燥机CL-12(大川原化工机生产)进行喷雾凝固造粒,得到复合体(粒径100μm)。使用Wurster型涂敷机GPCG-1(Glatt/Powrex生产),以由600g(固体组分200g)Eudragit RL30D(Rohm Pharma GmbH生产)、9g的CMC-Na、72g聚山梨醇酯80和700g纯净水配制的涂敷液对333g该复合体进行涂敷。接着,在该涂敷后的复合体中添加10g氧化镁、进行混合,在箱型干燥机中,在40℃下进行10小时固化,得到口服组合物。
再使用在190g纯净水中溶解有10g羟丙基纤维素的粘合液,与312g该口服组合物、40g玉米淀粉、138g的D-甘露醇一起,以流动层造粒干燥机FLO-1(Freund Corporation生产)进行流动层造粒和干燥,得到10%的干糖浆制剂。
实施例4
干糖浆制剂的制造(4):
以120℃熔融、分散180g克拉霉素、360g单硬脂酸甘油酯和60g的Eudragit E100(Rohm Pharma GmbH生产),以喷雾干燥机CL-12(大川原化工机生产)进行喷雾凝固造粒、得到复合体(粒径100μm)。使用Wurster型涂敷机GPCG-1(Glatt/Powrex生产)、以由480g(固体组分160g)Eudragit RL30D(Rohm Pharma GmbH生产)、14g的CMC-Na、58g聚山梨醇酯80和560g纯净水配制的涂敷液对333g该复合体进行涂敷。接着,在该涂敷后的复合体中添加10g轻质硅酸酐、进行混合,在箱型干燥机中,在40℃下进行10小时固化,得到口服组合物。
再使用在190g纯净水中溶解有10g羟丙基纤维素的粘合液,与287.5g该口服组合物、40g玉米淀粉、162.5g的D-甘露醇一起,以流动层造粒干燥机FLO-1(Freund Corporation生产)进行流动层造粒和干燥,得到10%的干糖浆制剂。
比较例1
比较干糖浆制剂的制造
以120℃熔融、分散180g克拉霉素、360g单硬脂酸甘油酯和60g的Eudragit E100(Rohm Pharma GmbH生产),以喷雾干燥机CL-12(大川原化工机生产)进行喷雾凝固造粒,得到复合体(粒径100μm)。使用在190g纯净水中溶解有10g羟丙基纤维素的粘合液、与166.5g该复合体、65g玉米淀粉、258.5g的D-甘露醇一起,以流动层造粒干燥机FLO-1(Freund Corporation生产)进行流动层造粒和干燥,得到10%的干糖浆制剂。
试验例1
苦味的感官检验
如下操作,对实施例1~4和比较例1的制剂进行苦味的感官检测。首先,在50mL的pH为4的水溶液中投入1g制剂,以调药勺搅拌。从投入制剂时计算时间,在10秒、60秒、120秒、180秒、240秒后以移液管采样约2mL、放入口中数秒钟,确认味道后吐出,用水漱口,准备下次测量。并且,试验液经常以调药勺搅拌。感官评价按照下述的标准,其结果示于表1。
<感官评价基准>
(评价)(内容)
○:不苦
△:不苦、但味道有变化
×:苦
表1
时间(秒) | 10 | 60 | 120 | 180 | 240 |
实施例1 | ○ | ○ | ○ | △ | △ |
实施例2 | ○ | ○ | ○ | ○ | △ |
实施例3 | ○ | ○ | ○ | ○ | ○ |
实施例4 | ○ | ○ | △ | △ | × |
比较例1 | × | × | × | × | × |
试验例2
分散性的试验
对实施例1和比较例1的制剂进行对水的分散性的试验。在50mL水中投入1g制剂,以调药勺连续搅拌。从投入制剂时计算时间,以目测确认在10秒、20秒、30秒、60秒后的分散性。分散性评价按照下述的标准,其结果示于表2。
<分散性评价基准>
(评价)(内容)
○:均匀的分散
×:不分散、浮起
表2
时间(秒) | 10 | 20 | 30 | 60 |
实施例1 | ○ | ○ | ○ | ○ |
比较例1 | × | × | × | × |
工业实用性
本发明的口服制剂,因为即使在酸性条件下也可以维持对药物的不愉快味道的掩蔽和溶出性,所以,能够作为不会被饮用条件影响的优异制剂被广泛地利用。
Claims (10)
1.一种口服制剂,其特征在于,在加热至熔点以上熔融的低熔点物质中分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒得到复合体,以含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物包覆该复合体而形成。
2.如权利要求1所述的口服制剂,其特征在于,不溶性高分子化合物为甲基丙烯酸氨基烷基酯共聚物RS。
3.如权利要求1所述的口服制剂,其特征在于,崩解剂是羧甲基纤维素钠。
4.如权利要求1~3中的任一项所述的口服制剂,其特征在于,包衣用组合物还含有聚山梨醇酯80。
5.如权利要求1所述的口服制剂,其特征在于,复合体的粒径为10~1000μm。
6.如权利要求1所述的口服制剂,其特征在于,呈现不愉快味道的药物是大环内酯系抗生素。
7.如权利要求6所述的口服制剂,其特征在于,大环内酯系抗生素为克拉霉素。
8.如权利要求1~7中任一项所述的口服制剂,其特征在于,为干糖浆剂。
9.一种口服制剂的制造方法,其特征在于,在加热到熔点以上而熔融的低熔点物质中分散或溶解呈现不愉快味道的药物和胃溶性高分子化合物,将其造粒形成复合体后,以含有重量比为80∶20~99∶1的不溶性高分子化合物和崩解剂的包衣用组合物对该复合体进行涂敷,接着,在35~45℃下进行固化,在该复合体上形成包衣膜。
10.如权利要求9所述的口服制剂的制造方法,其特征在于,在固化前,以选自氧化镁、滑石、轻质硅酸酐中的一种以上的无机化合物对包衣用组合物进行处理。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP165654/2004 | 2004-06-03 | ||
JP2004165654 | 2004-06-03 | ||
PCT/JP2005/009509 WO2005117845A1 (ja) | 2004-06-03 | 2005-05-25 | 経口製剤およびその製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1960716A true CN1960716A (zh) | 2007-05-09 |
CN1960716B CN1960716B (zh) | 2011-02-09 |
Family
ID=35462711
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800180183A Expired - Fee Related CN1960716B (zh) | 2004-06-03 | 2005-05-25 | 口服制剂及其制造方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US8420115B2 (zh) |
EP (1) | EP1757277A4 (zh) |
JP (1) | JP4779970B2 (zh) |
KR (1) | KR101078576B1 (zh) |
CN (1) | CN1960716B (zh) |
AU (1) | AU2005249305B2 (zh) |
CA (1) | CA2569514C (zh) |
HK (1) | HK1100424A1 (zh) |
RU (1) | RU2376013C2 (zh) |
WO (1) | WO2005117845A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106511317A (zh) * | 2016-12-13 | 2017-03-22 | 浙江中同科技有限公司 | 一种掩味克拉霉素颗粒的制备方法 |
CN115209876A (zh) * | 2020-03-11 | 2022-10-18 | 泽井制药株式会社 | 颗粒和使用该颗粒的制剂 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5141115B2 (ja) * | 2006-07-11 | 2013-02-13 | 大正製薬株式会社 | 不快味を呈する薬物含有製剤粒子 |
FR3027802B1 (fr) * | 2014-10-31 | 2018-03-02 | Ethypharm | Granules de principe actif a double masquage de gout, leur procede de preparation et comprimes orodispersibles les contenant |
JP6711875B2 (ja) * | 2018-08-29 | 2020-06-17 | 日本食品化工株式会社 | マクロライド化合物の苦味抑制剤 |
KR102661150B1 (ko) | 2022-01-26 | 2024-04-26 | 양영미 | 부정 인증 차단 방법 및 이를 실행하는 인증 웹 서버 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5758631A (en) | 1980-09-24 | 1982-04-08 | Toyo Jozo Co Ltd | Coating composition |
IT1200217B (it) | 1986-09-30 | 1989-01-05 | Valducci Roberto | Membrana per uso farmaceutico ed industriale |
JP2833292B2 (ja) | 1991-10-11 | 1998-12-09 | 三菱化学株式会社 | 塩酸ビフェメランドライシロップ剤 |
JP2973751B2 (ja) | 1991-12-04 | 1999-11-08 | 大正製薬株式会社 | 矯味経口組成物の製造方法 |
JPH05163163A (ja) | 1991-12-13 | 1993-06-29 | Shin Etsu Chem Co Ltd | 有核製剤 |
US5599556A (en) * | 1991-12-31 | 1997-02-04 | Abbott Laboratories | Prolamine coatings for taste masking |
JP3265680B2 (ja) | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | 経口製剤用組成物 |
JP3247511B2 (ja) * | 1993-09-07 | 2002-01-15 | 山之内製薬株式会社 | 医薬用組成物 |
EP0826376B1 (en) * | 1995-05-02 | 2007-01-24 | Taisho Pharmaceutical Co. Ltd | Composition for oral administration |
US6245351B1 (en) | 1996-03-07 | 2001-06-12 | Takeda Chemical Industries, Ltd. | Controlled-release composition |
DE19809719A1 (de) | 1998-03-06 | 1999-09-09 | Roehm Gmbh | Wäßrige Dispersion geeignet zur Herstellung von Überzugs- und Bindemitteln für feste orale Arzneiformen |
JP3466921B2 (ja) | 1998-06-03 | 2003-11-17 | 大塚製薬株式会社 | 味マスキング医薬製剤 |
JP2000169364A (ja) * | 1998-09-30 | 2000-06-20 | Taisho Pharmaceut Co Ltd | 経口製剤用粒子 |
AU5997999A (en) | 1998-09-30 | 2000-04-17 | Taisho Pharmaceutical Co., Ltd. | Grains for oral preparations |
JP2001270821A (ja) | 2000-03-23 | 2001-10-02 | Eisai Co Ltd | 服用感が優れた散剤 |
JP3934383B2 (ja) * | 2001-10-11 | 2007-06-20 | アルフレッサファーマ株式会社 | 経口投与用製剤 |
-
2005
- 2005-05-25 KR KR1020077000025A patent/KR101078576B1/ko not_active IP Right Cessation
- 2005-05-25 WO PCT/JP2005/009509 patent/WO2005117845A1/ja active Application Filing
- 2005-05-25 CN CN2005800180183A patent/CN1960716B/zh not_active Expired - Fee Related
- 2005-05-25 US US11/628,062 patent/US8420115B2/en not_active Expired - Fee Related
- 2005-05-25 EP EP20050743784 patent/EP1757277A4/en not_active Withdrawn
- 2005-05-25 AU AU2005249305A patent/AU2005249305B2/en not_active Ceased
- 2005-05-25 CA CA2569514A patent/CA2569514C/en not_active Expired - Fee Related
- 2005-05-25 JP JP2006514074A patent/JP4779970B2/ja active Active
- 2005-05-25 RU RU2006147222/15A patent/RU2376013C2/ru not_active IP Right Cessation
-
2007
- 2007-07-30 HK HK07108288.7A patent/HK1100424A1/xx not_active IP Right Cessation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106511317A (zh) * | 2016-12-13 | 2017-03-22 | 浙江中同科技有限公司 | 一种掩味克拉霉素颗粒的制备方法 |
CN115209876A (zh) * | 2020-03-11 | 2022-10-18 | 泽井制药株式会社 | 颗粒和使用该颗粒的制剂 |
EP4119129A4 (en) * | 2020-03-11 | 2024-01-24 | Sawai Pharmaceutical Co., Ltd. | GRANULES AND THEIR USE |
Also Published As
Publication number | Publication date |
---|---|
RU2006147222A (ru) | 2008-07-20 |
CA2569514A1 (en) | 2005-12-15 |
EP1757277A4 (en) | 2012-11-21 |
US8420115B2 (en) | 2013-04-16 |
KR101078576B1 (ko) | 2011-11-01 |
JP4779970B2 (ja) | 2011-09-28 |
AU2005249305B2 (en) | 2010-05-20 |
CA2569514C (en) | 2013-01-08 |
WO2005117845A1 (ja) | 2005-12-15 |
HK1100424A1 (en) | 2007-09-21 |
AU2005249305A1 (en) | 2005-12-15 |
JPWO2005117845A1 (ja) | 2008-04-03 |
CN1960716B (zh) | 2011-02-09 |
KR20070030879A (ko) | 2007-03-16 |
RU2376013C2 (ru) | 2009-12-20 |
EP1757277A1 (en) | 2007-02-28 |
US20080031965A1 (en) | 2008-02-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100833633B1 (ko) | 산에 불안정한 활성 화합물을 포함하는 신규 제제 및 투여형태 | |
RU2147231C1 (ru) | Кишечные гранулы дульоксетина | |
US6264989B1 (en) | Spherical single-substance particles, medicines and foodstuffs containing the particles, and method of production thereof | |
CN1040061C (zh) | 控释药物制剂的制备方法 | |
US5614222A (en) | Stable aqueous drug suspensions and methods for preparation thereof | |
FI119720B (fi) | Pitkävaikutteisten rakeisten valmisteiden valmistusmenetelmä | |
JP2538134B2 (ja) | 徐放性製剤およびその製造法 | |
KR20010042547A (ko) | 소수성 폴리머로 코팅된 코어를 갖는 습윤성 마이크로캡슐 | |
CN1960716A (zh) | 口服制剂及其制造方法 | |
CN1479611A (zh) | 包含酸不稳定活性成分的糊剂形式的药物制剂 | |
KR20080074083A (ko) | 난용성 약물을 포함하는 의약용 고형 제제와 그의 제조방법 | |
WO1991019486A1 (en) | Stable aqueous drug suspensions | |
JPH0533095B2 (zh) | ||
JP2000169364A (ja) | 経口製剤用粒子 | |
WO2000018372A1 (fr) | Granules pour preparations orales | |
JPS6259207A (ja) | 薬物が、非晶化及び/又は結晶化状態で分散する微細球状粒体の簡易な製造法 | |
JP2006131548A (ja) | 粒子の製造方法 | |
JPH11209306A (ja) | 高薬物含有率徐放製剤の製法 | |
Guan | Preparation and Coating of 5-ASA Pellets with a Novel Rotating Fluidized Bed |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1100424 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1100424 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110209 Termination date: 20170525 |
|
CF01 | Termination of patent right due to non-payment of annual fee |