CN1421206A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
- Publication number
- CN1421206A CN1421206A CN02152237A CN02152237A CN1421206A CN 1421206 A CN1421206 A CN 1421206A CN 02152237 A CN02152237 A CN 02152237A CN 02152237 A CN02152237 A CN 02152237A CN 1421206 A CN1421206 A CN 1421206A
- Authority
- CN
- China
- Prior art keywords
- compositions
- cefuroxime
- sweetener
- structure modifier
- coating
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 48
- 239000003765 sweetening agent Substances 0.000 claims abstract description 48
- 238000000576 coating method Methods 0.000 claims abstract description 42
- 150000002632 lipids Chemical class 0.000 claims abstract description 38
- 239000003607 modifier Substances 0.000 claims abstract description 38
- 235000019658 bitter taste Nutrition 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960001668 cefuroxime Drugs 0.000 claims description 74
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims description 74
- 239000011248 coating agent Substances 0.000 claims description 40
- 239000008187 granular material Substances 0.000 claims description 27
- 229920001285 xanthan gum Polymers 0.000 claims description 15
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 12
- 235000009508 confectionery Nutrition 0.000 claims description 12
- 229940085605 saccharin sodium Drugs 0.000 claims description 12
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 11
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 11
- 229960004998 acesulfame potassium Drugs 0.000 claims description 11
- 239000000619 acesulfame-K Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 230000002496 gastric effect Effects 0.000 claims description 6
- 239000000230 xanthan gum Substances 0.000 claims description 6
- 235000010493 xanthan gum Nutrition 0.000 claims description 6
- 229940082509 xanthan gum Drugs 0.000 claims description 6
- 239000001329 FEMA 3811 Substances 0.000 claims description 5
- VRKFBOPLJPXEAG-UHFFFAOYSA-N [Na].NS(=O)(=O)O.C1CCCCC1 Chemical compound [Na].NS(=O)(=O)O.C1CCCCC1 VRKFBOPLJPXEAG-UHFFFAOYSA-N 0.000 claims description 5
- ITVGXXMINPYUHD-CUVHLRMHSA-N neohesperidin dihydrochalcone Chemical compound C1=C(O)C(OC)=CC=C1CCC(=O)C(C(=C1)O)=C(O)C=C1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 ITVGXXMINPYUHD-CUVHLRMHSA-N 0.000 claims description 5
- 229940089953 neohesperidin dihydrochalcone Drugs 0.000 claims description 5
- 235000010434 neohesperidine DC Nutrition 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 239000000892 thaumatin Substances 0.000 claims description 4
- 235000010436 thaumatin Nutrition 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 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 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000010418 carrageenan Nutrition 0.000 claims description 2
- 239000000679 carrageenan Substances 0.000 claims description 2
- 229920001525 carrageenan Polymers 0.000 claims description 2
- 229940113118 carrageenan Drugs 0.000 claims description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 2
- 235000021096 natural sweeteners Nutrition 0.000 claims description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 5
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 abstract description 3
- 229960002620 cefuroxime axetil Drugs 0.000 abstract description 3
- 239000000725 suspension Substances 0.000 description 32
- 235000019640 taste Nutrition 0.000 description 18
- 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 14
- 229930006000 Sucrose Natural products 0.000 description 14
- 239000005720 sucrose Substances 0.000 description 14
- 235000021355 Stearic acid Nutrition 0.000 description 12
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 12
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 12
- 239000008117 stearic acid Substances 0.000 description 12
- 239000003651 drinking water Substances 0.000 description 11
- 235000020188 drinking water Nutrition 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 230000003115 biocidal effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000002562 thickening agent Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000004576 sand Substances 0.000 description 4
- 235000019605 sweet taste sensations Nutrition 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- -1 Zinacef ester Chemical class 0.000 description 3
- 239000007931 coated granule Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 229920003082 Povidone K 90 Polymers 0.000 description 2
- 239000008122 artificial sweetener Substances 0.000 description 2
- 235000021311 artificial sweeteners Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229940100692 oral suspension Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229940046284 zinacef Drugs 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 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
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 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
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 240000007707 Mentha arvensis Species 0.000 description 1
- 235000018978 Mentha arvensis Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940047496 ceftin Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008202 granule composition Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 229920013818 hydroxypropyl guar gum Polymers 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940127249 oral antibiotic Drugs 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 210000001779 taste bud Anatomy 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K9/14—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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- 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
Abstract
披露了一种组合物,包含颗粒状的头孢呋肟酯,所述颗粒用脂质或脂质混合物的完整包衣进行包衣,该包衣不溶于水中,其中该组合物进一步包含增甜剂体系和结构改性剂,所述增甜剂体系和结构改性剂用于掩蔽口服给药时头孢呋肟酯的苦味。
Description
技术领域
本发明涉及组合物,特别是涉及含有头孢氨呋肟(cefuroxime)的1-乙酰氧基乙酯,其批准的名称为头孢呋肟酯(cefuroxime axetil)的药物组合物。
背景技术
如英国专利说明书1453049中所披露的头孢氨呋肟是有价值的广谱抗生素,其特征在于对大范围的革兰氏阳性和革兰氏阴性微生物具有高活性,该性能通过该化合物对由大范围的革兰氏阴性微生物所产生的β-内酰胺酶的很高稳定性而得到增强。头孢氨呋肟及其盐主要是作为可注射的抗生素而起作用,因为胃肠道对它们的吸收能力很差。
如英国专利说明书1571683中所披露的那样,头孢氨呋肟的羧基酯化为1-乙酰氧基乙酯而得到头孢呋肟酯改善了口服给药的效率。1-乙酰氧基乙酯基的存在导致从胃肠道大量吸收该化合物,此时酯化基团通过存在于如血清和身体组织中的酶所水解,产生具有抗生素活性的酸。特别有利的是采用无定形形式的头孢呋肟酯,如英国专利说明书2127401中所披露的那样。
呈递口服抗生素的常规方式是颗粒的形式,所述颗粒可以以溶液或悬浮液的形式给药或与饮水(a draught of water)一起服用。作为如糖浆的颗粒的溶液或悬浮液对于孩子口服给药抗生素是特别方便的。但是,头孢呋肟酯具有极苦的味道,该味道是持久的且其不能通过向常规的颗粒剂中加入增甜剂和矫味剂而得到适当掩蔽。
另一个问题来自于结晶形式的和无定形的头孢呋肟酯与含水介质接触时形成凝胶物的趋势。该凝胶效应是温度依赖性的,但是在约37℃的温度下,即在口服的颗粒发生分解的生理温度下,确实发生该凝胶效应。当摄入后的头孢呋肟酯相当缓慢地扩散到周围的含水介质中时,组合物中所存在的头孢呋肟酯仍有可能发生凝胶的危险。这类凝胶形成导致头孢呋肟酯的溶解不好并因此导致从胃肠道的吸收不好,即,生物利用度低。在颗粒剂的情况下,希望使用小直径和大表面积的颗粒以避免这类凝胶。
在将头孢呋肟酯制成颗粒时,重要的是要避免在服药时,药物释放到该药物所悬浮的或服药时进入口中后的任何液体介质中。通过将头孢呋肟酯制成脂质包衣的颗粒可以将这类问题最小化。
GB 2204972披露了其中上述问题得以解决的颗粒剂。该专利披露了包含颗粒形式的头孢呋肟酯的组合物,该颗粒设置有脂质或脂质混合物的完整包衣,该包衣不溶于水中并用于掩蔽口服时头孢呋肟酯的苦味,但是在接触胃肠液体时该包衣分散或溶解。所配制的包衣的颗粒在接触胃肠流体时分解,使得其在胃肠道中迅速分散并分解。
WO94/25006披露了通过在低于发生明显的药物分解的温度下将药物与脂质混合而掩蔽颗粒状的苦味药物的味道的方法。向药物和脂质混合物中加入乳化剂和表面活性剂、聚合物溶液和稀释溶液以形成稳定的掩蔽味道的药物组合物。
WO00/076479披露了包含苦味活性物质如头孢呋肟酯和两种肠聚合物(enteric polymers)的掩蔽味道的组合物,所述肠聚合物即甲基丙烯酸共聚物和邻苯二甲酸酯聚合物,所述聚合物溶解于溶剂体系中,随后干燥以形成“固体溶液,,基质,其中药物以细分态保持在聚合物中,防止了苦味药物接触味蕾。
本申请人现在销售包含头孢呋肟酯的口服悬浮液组合物,颗粒上设置有脂质的完整包衣(integral coatings),在英国以商品名ZinnatTM销售,在美国以商品名CeftinTM销售。该口服悬浮液组合物除包含头孢呋肟酯外,还包含无活性的组分硬脂酸、tutti frutti矫味剂、粘结剂(Povidone K30)和作为本体增甜剂(bulk sweetener)的蔗糖。
尽管脂质包衣在一定程度上掩蔽了口服给药时头孢呋肟酯的苦味,但是头孢呋肟酯的苦味如此强以致于这些悬浮液和组合物仍具有苦味,并在给小孩给药时存在明显的问题。另外,悬浮液可能在口中有“砂状”(gritty)感,使它们比其他抗生素悬浮液的可口性差。这些因素可能影响患者的顺从性,因为,尤其是小孩中,一旦患者有所好转,不可口的抗生素容易被停止,而不是持续疗程直到预定的期间。鉴于上述问题,需要一种减少明显的苦味并改进口“感”的改进的头孢呋肟酯悬浮液。
本发明人令人惊奇地发现一种进一步改进用于形成悬浮液的头孢呋肟酯的味道的方法,结果是头孢呋肟酯的不好的苦味经证明更令人接受。有利的是,头孢呋肟酯悬浮剂在口中的整体“感觉”在低“砂状感”方面也得到改进并且更易于吞服。
发明内容
因此,本发明提供了一种包含颗粒状的头孢呋肟酯的组合物,所述颗粒上设置有脂质或脂质混合物的完整包衣,该包衣不溶于水中且在接触胃肠液体时该包衣分散或溶解,其特征在于:该组合物进一步包含增甜剂体系和结构改性剂(texture modifier),所述增甜剂体系和结构改性剂的用量足以掩蔽头孢呋肟酯的苦味。
更具体的是,本发明提供一种包含颗粒状的头孢呋肟酯、本体增甜剂和粘结剂的组合物,所述颗粒上设置有脂质或脂质混合物的完整包衣,该包衣不溶于水中且在接触胃肠液体时该包衣分散或溶解,其特征在于:该组合物进一步包含增甜剂体系和结构改性剂,所述增甜剂体系和结构改性剂的用量足以掩蔽头孢呋肟酯的苦味。
有利的是,现已经发现增甜剂体系和结构改性剂协同起作用以克服苦味并且还改进口“感”,从而有助于患者的顺从性。如上文所指出的那样,增甜剂体系通过在口中产生起始的甜味而克服苦味。但是,同时使用结构改性剂有助于提供更加乳状的(creamier)结构,改进了口“感”,此外减少了吞服药物时留在口中的脂质包衣的颗粒的数目,进一步降低了苦味效应。单独使用增甜剂或结构改性剂都不会在味道掩蔽和口“感”方面产生这类明显的改进。中请人已经发现,只有当结合增甜剂时才产生这些有益的效应,且当协同组合使用结构改性剂时,进一步改进了这些有益的效应。
具体实施方式
适用于包覆头孢呋肟酯颗粒的脂质或脂质的混合物以及制备头孢呋肟酯的脂质包衣的颗粒的方法描述在例如GB 2204792中,将所述文件引入本发明中作为参考。特别优选的脂质包衣是硬脂酸与棕榈酸的混合物,其中硬脂酸与棕榈酸的重量比例是3∶7至7∶3,更优选1∶1。
本发明的组合物可以包含结晶形式的头孢呋肟酯,呈结晶和无定形形式的混合物,更优选是无定形形式,例如GB 2127401中所述。
如GB 2204792中所述,头孢呋肟酯颗粒可以被具有包衣性能的物质底部包衣(undercoated),以便保护头孢呋肟酯,如果头孢呋肟酯可能对用于包衣的脂质具有化学敏感性时。如GB 2204792中所述,其中头孢呋肟酯以10-30%、例如约20%的浓度存在的底部包衣的颗粒可以方便地被脂质包衣。
GB 2204792中披露了用脂质或脂质的混合物包衣头孢呋肟酯颗粒的合适方法。该专利还披露了脂质包衣的颗粒的优选尺寸。当头孢呋肟酯被底部包衣时,脂质包衣优选占包衣的颗粒重量的20-80%,更优选为35-65%。
根据本发明的脂质包衣的颗粒优选包含5-90%、更优选5-50%、进一步优选5或10至30%重量的头孢呋肟酯。当头孢呋肟酯首先被底部包衣时,脂质包衣的颗粒最优选包含5-15%重量的头孢呋肟酯;当不采用底部包衣时,脂质包衣的颗粒最优选包含10-30%重量的头孢呋肟酯。
“增甜剂体系”意指除在下文所述的造粒过程期间所使用的并具体设计用于形成制剂的可接受程度的甜味的本体增甜剂外的增甜剂或增甜剂组合。本发明的增甜剂体系用于降低苦味。优选单独使用或以混合物的形式使用人工的或来自天然的增甜剂。合适的增甜剂包括但不限于:糖精、糖精钠、环己烷氨基磺酸钠、丁磺氨钾、奇甜蛋白、新橙皮苷二氢查耳酮和天冬甜精。
可供选择的是,增甜剂包括但不限于:糖精、糖精钠、环己烷氨基磺酸钠、丁磺氨钾、奇甜蛋白、新橙皮苷二氢查耳酮、甘草酸铵和天冬甜精。
增甜剂体系占最终颗粒组合物中的约0.1-10%、更优选约0.3-5%。当以混合物的形式使用两种增甜剂时,两种增甜剂的重量比范围为约1∶10至10∶1。
优选的增甜剂体系是丁磺氨钾和天冬甜精的混合物,其重量比优选为约1∶1。
组合物另外包含“结构改性剂”,其包含一种或多种增稠剂。除可能任选构成组合物部分的任何增稠剂或粘结剂外,加入结构改性剂,该结构改性剂构成本发明的基本特征。“结构改性剂”意指增稠剂或增稠剂的组合,其有助于改进口中的头孢呋肟酯制剂的结构以便产生所需的口“感”。
所用的结构改性剂通过悬浮脂质包衣的颗粒用于减少苦味,结果是减少了口中的接触、减少了砂状结构并使吞服更容易。合适的结构改性剂选自聚乙烯吡咯烷酮(povidone)如Povidone K30或Povidone K90、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、瓜尔胶和黄原胶。
可供选择的是,结构改性剂选自聚乙烯吡咯烷酮(povidone)如PovidoneK30或Povidone K90、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、瓜尔胶、藻酸盐、角叉藻聚糖和黄原胶。
优选的是,结构改性剂是黄原胶。
更优选的是,增甜剂体系是丁磺氨钾和天冬甜精的混合物且结构改性剂是黄原胶。
结构改性剂的存在量优选为改性剂与脂质包衣的颗粒的重量比为约1∶300至约1∶3000、更优选约1∶500至约1∶1500。结构改性剂占最终颗粒组合物重量的约0.01-5%、更优选约0.01-1%。
结构改性剂与增甜剂体系的重量比为约1∶1至约1∶1000、更优选约1∶10至约1∶100。
最终颗粒组合物中脂质包衣的颗粒:增甜剂体系:结构改性剂的重量比为约300∶10∶1至约3000∶100∶1、更优选为约500∶10∶1至约1500∶100∶1。
增甜剂/结构改性剂颗粒组合物还可任选包含其他赋形剂如悬浮剂和粘结剂、填料、增稠剂、矫味剂和本体增甜剂。
合适的悬浮剂和粘结剂包括但不限于:烷基纤维素如甲基纤维素、羟烷基纤维素如羟丙基纤维素和羟丙基甲基纤维素、羧甲基纤维素钠或其混合物、预凝胶化的(pregelatinised)玉米淀粉或聚乙烯吡咯烷酮。
合适的填料包括蔗糖、淀粉、乳糖和微晶纤维素。
适用于本发明中的本体增甜剂包括山梨醇、蔗糖或人工增甜剂如糖精钠或环己烷氨基磺酸钠。
可供选择的是,适用于本发明中的本体增甜剂包括山梨醇、甘露糖醇、麦芽糖醇(maltitol)、木糖醇、果糖、葡萄糖、蔗糖或人工增甜剂如糖精钠或环己烷氨基磺酸钠。
适用于本发明中的增稠剂包括但不限于卵磷脂或硬脂酸铝。
组合物中还可以附加地存在合适的矫味剂如薄荷(mint)、胡椒薄荷(peppermint)、草莓或tutti frutti。
在优选的实施方案中,使用聚乙烯吡咯烷酮(Povidone)的水溶液作为粘结剂将头孢呋肟酯的脂质包衣的颗粒与蔗糖一起造粒以形成颗粒。加入合适的矫味剂如tutti frutti并将组合物混合。可以在加入矫味剂之前、之后或同时采用常规的技术以干混物的形式将本发明的增甜剂和结构改性剂与成粒的颗粒一起混合以形成最终的颗粒组合物。可供选择的是,可以在造粒过程期间将增甜剂与结构改性剂与脂质包衣的颗粒共混。在混合过程中,重要的是确保增甜剂体系与结构改性剂与头孢呋肟酯的脂质包衣的颗粒均匀混合。
本发明的颗粒状产品可以用于口服给药的组合物中,且可以以用于给药的悬浮液的形式、在以悬浮液的形式给药之前用水或其他合适的载体构建的干产品形式、或用于直接给药然后用水或其他合适的液体冲洗的形式存在。
因此,另一方面,本发明提供了用于口服给药的药物组合物,包含本发明的组合物和一种或多种药物载体或赋形剂。
本发明的药物组合物,配制成用于口服给药的悬浮液形式,可以用合适量的水构建,用于口服给药头孢呋肟酯。通常以颗粒的形式存在以便给出包含头孢呋肟酯当量为125毫克至5克的多剂量(multidose)悬浮液或包含头孢呋肟酯当量为125毫克至500毫克的单剂量(multidose)悬浮液。
用于人类治疗的剂量范围对于成人来说为每天250-1000毫克头孢呋肟酯,对于小孩来说为每天80-500毫克头孢呋肟酯,尽管精确的剂量将特别取决于给药的频率。
用下文的实施例来进一步说明本发明,所述实施例不应当构成对本发明的限制。
实施例
实施例中所用的头孢呋肟酯是如GB 2127401中所述而制备的高纯度的喷雾干燥的无定形材料。将增甜剂体系和结构改性剂与头孢呋肟酯颗粒一起混合成干混物,确保它们均匀存在于混合物中。
实施例1
头孢呋肟酯悬浮液125mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.150g 3.55硬脂酸 0.852g 20.19Povidone 0.013g 0.31Tutti Frutti矫味剂 0.100g 2.37蔗糖 3.062g 72.56丁磺氨钾 0.021g 0.50天冬甜精 0.021g 0.50黄原胶 0.001g 0.02饮用水至 5mL
实施例2
头孢呋肟酯悬浮液125mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.150g 3.55硬脂酸 0.852g 20.19Povidone 0.013g 0.31Tutti Frutti矫味剂 0.100g 2.37蔗糖 3.062g 72.56糖精钠 0.021g 0.50天冬甜精 0.021g 0.50黄原胶 0.001g 0.02饮用水至 5mL
实施例3
头孢呋肟酯悬浮液125mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.150g 3.55硬脂酸 0.852g 20.19Povidone 0.013g 0.31Tutti Frutti矫味剂 0.100g 2.37蔗糖 3.062g 72.56糖精钠 0.021g 0.50丁磺氨钾 0.021g 0.50黄原胶 0.001g 0.02饮用水至 5mL
实施例4
头孢呋肟酯悬浮液125mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.150g 3.56硬脂酸 0.852g 20.24Povidone 0.013g 0.31Tutti Frutti矫味剂 0.100g 2.38蔗糖 3.062g 72.75新橙皮苷二氢查耳酮 0.010g 0.24糖精钠 0.021g 0.50黄原胶 0.001g 0.02饮用水至 5mL
实施例5
头孢呋肟酯悬浮液125mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.150g 3.57硬脂酸 0.852g 20.29Povidone 0.013g 0.31Tutti Frutti矫味剂 0.100g 2.38蔗糖 3.062g 72.92奇甜蛋白 0.010mg 2.38×10-4糖精钠 0.021g 0.50黄原胶 0.001g 0.02饮用水至 5mL
实施例6
头孢呋肟酯悬浮液250mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.300g 7.50硬脂酸 1.203g 30.09Povidone 0.012g 0.30Tutti Frutti矫味剂 0.102g 2.55蔗糖 2.289g 57.25丁磺氨钾 0.045g 1.13天冬甜精 0.045g 1.13黄原胶 0.002g 0.05饮用水至 5mL
实施例7
头孢呋肟酯悬浮液250mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.300g 7.50硬脂酸 1.203g 30.09Povidone 0.012g 0.30Tutti Frutti矫味剂 0.102g 2.55蔗糖 2.289g 57.25糖精钠 0.045g 1.13天冬甜精 0.045g 1.13黄原胶 0.002g 0.05饮用水至 5mL
实施例8
头孢呋肟酯悬浮液250mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.300g 7.50硬脂酸 1.203g 30.09Povidone 0.012g 0.30Tutti Frutti矫味剂 0.102g 2.55蔗糖 2.289g 57.25糖精钠 0.045g 1.13丁磺氨钾 0.045g 1.13黄原胶 0.002g 0.05饮用水至 5mL
实施例9
头孢呋肟酯悬浮液250mg/5ml组分 5mL剂量 %w/w头孢呋肟酯 0.300g 7.55硬脂酸 1.203g 30.28Povidone 0.012g 0.30Tutti Frutti矫味剂 0.102g 2.57蔗糖 2.289g 57.62新橙皮苷二氢查耳酮 0.020g 0.50糖精钠 0.045g 1.13黄原胶 0.002g 0.05饮用水至 5mL
结果
进行了味道评尝试验,其中5个志愿者根据下列种类评估用饮用水重构的实施例1的组合物的悬浮液:
起始味道:甜或苦
评尝后的味道:评尝后(aftertaste)口味存在或消失
口感:乳状或砂状
风味:令人愉快的或令人不愉快的
下文以列表的形式给出评尝试验结果:
味道种类 | 志愿者的反应 |
起始味道 | 所有志愿者感觉到制剂中的甜味 |
评尝后的味道 | 没有一个志愿者在评尝后感觉到制剂中存在苦味 |
口感 | 所有志愿者感觉到制剂中乳状的口感,但可能检测到一些颗粒 |
风味 | 所有志愿者感觉到制剂中令人愉快的Tutti Frutti风味 |
在一些健康的成人患者中进行进一步的评尝试验,将实施例1(125毫克/毫升)和实施例6(250毫克/5毫升)的组合物与除不存在增甜剂体系和结构改性剂外其余均相同的头孢呋肟酯组合物的悬浮液进行对比。以“新鲜的”形式,即新鲜构建的组合物的形式评估两种强度(strength)的组合物。
在优先性测试设计中,比较组合物的甜味、苦味、口感和整体优先性。下表中示出的结果给出了患者对125毫克/5毫升的剂型和250毫克/5毫升的剂型的优先性的百分比。
悬浮液 | 更甜 | 更苦 | 更好的口感 | 优先性 |
125毫克/5毫升的味道评尝试验 | ||||
悬浮液1a | 66% | 0% | 42% | 58% |
悬浮液2b | 17% | 67% | 16% | 17% |
相同 | 17% | 33% | 42% | 25% |
250毫克/5毫升的味道评尝试验 | ||||
悬浮液1a | 75% | 0% | 42% | 92% |
悬浮液2b | 0% | 100% | 25% | 8% |
相同 | 25% | 0% | 33% | 0% |
a悬浮液1:头孢呋肟酯的脂质包衣的颗粒加上增甜剂体系和结构改性剂
b悬浮液2:头孢呋肟酯的脂质包衣的颗粒
结果清楚地表明包含附加的增甜剂和结构改性剂的本发明的悬浮液在味道和口感方面是优选得多的组合物。
Claims (12)
1.一种组合物,包含颗粒状的头孢呋肟酯、本体增甜剂和粘结剂,所述颗粒上设置有脂质或脂质混合物的完整包衣,该包衣不溶于水中且在接触胃肠液体时该包衣分散或溶解,其特征在于:该组合物进一步包含增甜剂体系和结构改性剂,所述增甜剂体系和结构改性剂的用量足以掩蔽头孢呋肟酯的苦味。
2.权利要求1的组合物,其中增甜剂体系包含至少一种人工的或来自天然的增甜剂,所述增甜剂选自:糖精、糖精钠、环己烷氨基磺酸钠、丁磺氨钾、奇甜蛋白、新橙皮苷二氢查耳酮、甘草酸铵和天冬甜精。
3.权利要求1或2的组合物,其中增甜剂体系包含重量比为1∶10至10∶1的两种增甜剂的混合物。
4.前述权利要求中任一项的组合物,其中增甜剂是丁磺氨钾和天冬甜精。
5.权利要求4的组合物,其中丁磺氨钾和天冬甜精以重量比为1∶1存在。
6.前述权利要求中任一项的组合物,其中结构改性剂选自聚乙烯吡咯烷酮、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、瓜尔胶、藻酸盐、角叉藻聚糖和黄原胶。
7.权利要求6的组合物,其中结构改性剂是黄原胶。
8.前述权利要求中任一项的组合物,其中结构改性剂与增甜剂体系的重量比为约1∶1至约1∶1000。
9.前述权利要求中任一项的组合物,其中脂质包衣的颗粒:增甜剂体系:结构改性剂的重量比为约300∶10∶1至约3000∶100∶1。
10.一种用于口服给药的药物组合物,包含前述权利要求中任一项的组合物和一种或多种可药用的载体或赋形剂。
11.权利要求10的药物组合物,呈含水悬浮液的形式。
12.权利要求10的药物组合物,呈颗粒的形式。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01500277.7 | 2001-11-23 | ||
EP01500277 | 2001-11-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1421206A true CN1421206A (zh) | 2003-06-04 |
CN1297274C CN1297274C (zh) | 2007-01-31 |
Family
ID=8183502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB021522375A Expired - Lifetime CN1297274C (zh) | 2001-11-23 | 2002-11-21 | 药物组合物 |
Country Status (34)
Country | Link |
---|---|
US (1) | US20030161888A1 (zh) |
EP (1) | EP1446126B1 (zh) |
JP (1) | JP3497503B2 (zh) |
KR (1) | KR100979328B1 (zh) |
CN (1) | CN1297274C (zh) |
AT (1) | ATE473006T1 (zh) |
AU (2) | AU2002302147B2 (zh) |
BE (2) | BE1014078A6 (zh) |
BR (1) | BR0204767A (zh) |
CA (1) | CA2408198C (zh) |
CH (1) | CH693982A5 (zh) |
CO (1) | CO5580783A2 (zh) |
CY (1) | CY1110778T1 (zh) |
CZ (1) | CZ12993U1 (zh) |
DE (3) | DE60236952D1 (zh) |
DK (1) | DK1446126T3 (zh) |
ES (2) | ES2201932B2 (zh) |
FR (1) | FR2832635B1 (zh) |
GB (1) | GB2383536B (zh) |
GR (1) | GR1004522B (zh) |
HR (2) | HRP20020924A2 (zh) |
HU (1) | HUP0204026A3 (zh) |
IL (2) | IL161972A0 (zh) |
IT (1) | ITMI20022470A1 (zh) |
MX (1) | MXPA02011561A (zh) |
NO (1) | NO335273B1 (zh) |
NZ (1) | NZ533092A (zh) |
PL (1) | PL205325B1 (zh) |
PT (1) | PT1446126E (zh) |
RU (1) | RU2241460C2 (zh) |
SI (1) | SI1446126T1 (zh) |
TR (1) | TR200202559A2 (zh) |
WO (1) | WO2003043638A1 (zh) |
ZA (1) | ZA200209473B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100402035C (zh) * | 2005-07-07 | 2008-07-16 | 石药集团中奇制药技术(石家庄)有限公司 | 一种微囊化头孢呋辛酯的药物组合物 |
CN102440960A (zh) * | 2011-09-01 | 2012-05-09 | 山东鲁抗医药股份有限公司 | 一种头孢呋辛酯干混悬剂药物组合物及其制备方法 |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
WO2005107713A2 (en) | 2004-05-11 | 2005-11-17 | Egalet A/S | Swellable dosage form comprising gellan gum |
US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
CA2584957C (en) | 2004-10-21 | 2015-08-25 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
US20060105038A1 (en) * | 2004-11-12 | 2006-05-18 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions prepared by coacervation |
JP4972311B2 (ja) * | 2004-12-15 | 2012-07-11 | あすか製薬株式会社 | イソソルビドの苦味が軽減された経口製剤及びその製造方法 |
JP2012107060A (ja) * | 2004-12-15 | 2012-06-07 | Aska Pharmaceutical Co Ltd | イソソルビドの苦味が軽減された経口製剤及びその製造方法 |
DE102005019458A1 (de) * | 2005-04-25 | 2006-10-26 | Grünenthal GmbH | Darreichungsform mit verbesserter Freisetzung von Cefuroximaxetil |
US9161918B2 (en) | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
US8637076B2 (en) * | 2006-06-01 | 2014-01-28 | Cima Labs Inc. | Prednisolone salt formulations |
US20070281014A1 (en) * | 2006-06-01 | 2007-12-06 | Cima Labs, Inc. | Prednisolone salt formulations |
CN101756906B (zh) * | 2009-11-02 | 2011-11-16 | 严洁 | 盐酸头孢卡品酯颗粒的药物组合物及其制备方法 |
WO2011067667A2 (en) | 2009-12-02 | 2011-06-09 | Eurand Pharmaceuticals Limited | Fexofenadine microcapsules and compositions containing them |
AR079862A1 (es) * | 2010-01-08 | 2012-02-22 | Eurand Inc | Composicion de topiramato con sabor enmascarado, un comprimido desintegrable oralmente que comprende la misma y metodo de preparacion |
WO2011139254A2 (en) | 2010-05-04 | 2011-11-10 | Mahmut Bilgic | Pharmaceutical formulations compising cefuroxime axetil |
JP5853461B2 (ja) * | 2010-07-30 | 2016-02-09 | 大正製薬株式会社 | 内服液剤 |
EP2741750A1 (en) * | 2011-08-12 | 2014-06-18 | Dhanuka Laboratories Ltd. | Pharmaceutical composition comprising cefuroxime |
JP6200893B2 (ja) * | 2011-10-31 | 2017-09-20 | ノバルティス アーゲー | パゾパニブ製剤 |
CN108338936A (zh) * | 2017-01-23 | 2018-07-31 | 刘全忠 | 敏感皮肤防护露的制备及使用 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1323161A (en) * | 1970-02-16 | 1973-07-11 | Wyeth John & Brother Ltd | Penicillin composition |
CA1094545A (en) * | 1976-02-16 | 1981-01-27 | Michael Gregson | Cephalosporin antibiotics |
GB1571683A (en) * | 1976-02-16 | 1980-07-16 | Glaxo Operations Ltd | Ester derivatives of cefuroxime |
YU44680B (en) * | 1982-07-30 | 1990-12-31 | Glaxo Lab Ltd | Process for obtaining very pure amorphous form of cephuroxim axetile |
GB8320520D0 (en) * | 1983-07-29 | 1983-09-01 | Glaxo Group Ltd | Chemical process |
GB8524001D0 (en) * | 1985-09-30 | 1985-11-06 | Glaxo Group Ltd | Pharmaceutical composition |
NL193682C (nl) * | 1987-05-14 | 2000-07-04 | Glaxo Group Ltd | Beklede cefuroximaxetilsamenstelling. |
US4992276A (en) * | 1988-12-14 | 1991-02-12 | Warner-Lambert Company | Antiseptic compositions containing hexahydro-5-pyrimidinamine compounds and thymol and methods for preparing same |
DE69332801T2 (de) * | 1992-11-30 | 2004-01-29 | Kv Pharm Co | Geschmacksmaskierte pharmazeutische substanzen |
IT1277426B1 (it) * | 1995-08-03 | 1997-11-10 | Acs Dobfar Spa | Forma cristallina biodisponibile del cefuroxima axetil |
NZ299077A (en) * | 1996-07-26 | 1998-06-26 | Apotex Inc | Preparation of amorphous cefuroxime axetil (a cephalosporin derivative) by dissolving crystalline cefuroxim axetil in a highly polar solvent, typically dmso and/or dmf |
US6190591B1 (en) * | 1996-10-28 | 2001-02-20 | General Mills, Inc. | Embedding and encapsulation of controlled release particles |
CA2209868C (en) * | 1997-08-15 | 2001-08-14 | Bernard Charles Sherman | Pharmaceutical compositions comprising cefuroxime axetil |
GB9726781D0 (en) * | 1997-12-19 | 1998-02-18 | Glaxo Group Ltd | Pharmaceutical composition |
AT413647B (de) * | 1998-11-26 | 2006-04-15 | Sandoz Ag | Verwendung eines copolymerisats aus 1-vinyl-2-pyrrolidon und vinylacetat zur herstellung von cefuroximaxetil-hältigen tabletten |
-
2002
- 2002-11-20 HR HR20020924A patent/HRP20020924A2/hr not_active Application Discontinuation
- 2002-11-20 HR HR20020923A patent/HRP20020923A2/hr not_active Application Discontinuation
- 2002-11-20 ES ES200202670A patent/ES2201932B2/es not_active Expired - Fee Related
- 2002-11-20 CZ CZ200213690U patent/CZ12993U1/cs not_active IP Right Cessation
- 2002-11-21 FR FR0214587A patent/FR2832635B1/fr not_active Expired - Fee Related
- 2002-11-21 GB GB0227215A patent/GB2383536B/en not_active Expired - Fee Related
- 2002-11-21 GR GR20020100506A patent/GR1004522B/el unknown
- 2002-11-21 BE BE2002/0667A patent/BE1014078A6/fr not_active IP Right Cessation
- 2002-11-21 DE DE60236952T patent/DE60236952D1/de not_active Expired - Lifetime
- 2002-11-21 SI SI200230920T patent/SI1446126T1/sl unknown
- 2002-11-21 CH CH01954/02A patent/CH693982A5/de not_active IP Right Cessation
- 2002-11-21 RU RU2002131380/15A patent/RU2241460C2/ru active
- 2002-11-21 DE DE20218068U patent/DE20218068U1/de not_active Expired - Lifetime
- 2002-11-21 JP JP2002337570A patent/JP3497503B2/ja not_active Expired - Fee Related
- 2002-11-21 TR TR2002/02559A patent/TR200202559A2/xx unknown
- 2002-11-21 MX MXPA02011561A patent/MXPA02011561A/es active IP Right Grant
- 2002-11-21 ES ES02777359T patent/ES2347536T3/es not_active Expired - Lifetime
- 2002-11-21 IT IT002470A patent/ITMI20022470A1/it unknown
- 2002-11-21 KR KR1020047007847A patent/KR100979328B1/ko active IP Right Grant
- 2002-11-21 EP EP02777359A patent/EP1446126B1/en not_active Expired - Lifetime
- 2002-11-21 CN CNB021522375A patent/CN1297274C/zh not_active Expired - Lifetime
- 2002-11-21 AU AU2002302147A patent/AU2002302147B2/en not_active Ceased
- 2002-11-21 IL IL16197202A patent/IL161972A0/xx unknown
- 2002-11-21 AU AU2002338950A patent/AU2002338950A1/en not_active Abandoned
- 2002-11-21 US US10/301,452 patent/US20030161888A1/en not_active Abandoned
- 2002-11-21 AT AT02777359T patent/ATE473006T1/de active
- 2002-11-21 NZ NZ533092A patent/NZ533092A/en not_active IP Right Cessation
- 2002-11-21 PT PT02777359T patent/PT1446126E/pt unknown
- 2002-11-21 DK DK02777359.7T patent/DK1446126T3/da active
- 2002-11-21 DE DE10254412A patent/DE10254412A1/de not_active Withdrawn
- 2002-11-21 ZA ZA200209473A patent/ZA200209473B/xx unknown
- 2002-11-21 BE BE2002/0668A patent/BE1015217A5/fr not_active IP Right Cessation
- 2002-11-21 CA CA002408198A patent/CA2408198C/en not_active Expired - Lifetime
- 2002-11-21 WO PCT/EP2002/013150 patent/WO2003043638A1/en not_active Application Discontinuation
- 2002-11-21 HU HU0204026A patent/HUP0204026A3/hu unknown
- 2002-11-21 BR BR0204767-5A patent/BR0204767A/pt not_active IP Right Cessation
- 2002-11-21 PL PL357259A patent/PL205325B1/pl unknown
-
2004
- 2004-05-13 IL IL161972A patent/IL161972A/en active IP Right Grant
- 2004-05-18 CO CO04045861A patent/CO5580783A2/es not_active Application Discontinuation
- 2004-06-22 NO NO20042620A patent/NO335273B1/no not_active IP Right Cessation
-
2010
- 2010-09-13 CY CY20101100828T patent/CY1110778T1/el unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100402035C (zh) * | 2005-07-07 | 2008-07-16 | 石药集团中奇制药技术(石家庄)有限公司 | 一种微囊化头孢呋辛酯的药物组合物 |
CN102440960A (zh) * | 2011-09-01 | 2012-05-09 | 山东鲁抗医药股份有限公司 | 一种头孢呋辛酯干混悬剂药物组合物及其制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1421206A (zh) | 药物组合物 | |
CN1030964C (zh) | 用于制备具有减少了苦味的阿扎利得组合物的方法 | |
CN101137350B (zh) | 包含利福昔明的胃稳定药物制剂 | |
CN1174740C (zh) | 掩味的药用液体制剂 | |
CN1178659C (zh) | 控释活性化合物的药物制剂 | |
CN1366878A (zh) | 含有活性成分的质地遮蔽颗粒 | |
CN1744881A (zh) | 苦味减轻了的药物组合物 | |
JP2023506225A (ja) | 液体タシメルテオン製剤及びそれを使用する方法 | |
CN1903183A (zh) | 替比夫定分散片及其制备方法 | |
CN1823800A (zh) | 掩盖苦味的含螺旋霉素的口服组合物 | |
CN1771936A (zh) | 一种稳定的青蒿素及青蒿素衍生物药物组合物 | |
CN107625734B (zh) | 一种无水吞服掩味制剂及其制备方法 | |
CN1989964A (zh) | 洛哌丁胺口服药物组合物 | |
WO2004014337A2 (en) | A process for the preparation of dispersible tablet of cephalexin | |
CN101002790B (zh) | 一种克拉霉素缓释片及其制备方法 | |
CN1903869A (zh) | 替比夫定的衍生物盐及其制备方法和药物应用 | |
CN1939263A (zh) | 含有头孢克洛的口含制剂及其制备方法 | |
CN1839820A (zh) | 含西酞普兰和环糊精的抗抑郁口服药用组合物 | |
CN1798562A (zh) | 用于口服给药的包含伊曲康唑的组合物 | |
WO1999018965A1 (en) | Oral compositions containing a cephalosporin antibiotic | |
CN1634114A (zh) | 克林霉素磷酸酯口腔崩解片 | |
CN1943553A (zh) | 含有头孢曲松的口含制剂及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20070131 |