JP2018172316A - Nonaqueous composition containing adipose particle holding medicament, and method for producing the same - Google Patents
Nonaqueous composition containing adipose particle holding medicament, and method for producing the same Download PDFInfo
- Publication number
- JP2018172316A JP2018172316A JP2017070587A JP2017070587A JP2018172316A JP 2018172316 A JP2018172316 A JP 2018172316A JP 2017070587 A JP2017070587 A JP 2017070587A JP 2017070587 A JP2017070587 A JP 2017070587A JP 2018172316 A JP2018172316 A JP 2018172316A
- Authority
- JP
- Japan
- Prior art keywords
- drug
- fat
- emulsion
- water
- medicament
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 149
- 239000000203 mixture Substances 0.000 title claims abstract description 106
- 239000002245 particle Substances 0.000 title claims abstract description 88
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 239000003925 fat Substances 0.000 claims abstract description 133
- 239000000839 emulsion Substances 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 43
- 239000003921 oil Substances 0.000 claims abstract description 40
- 239000008346 aqueous phase Substances 0.000 claims abstract description 29
- 150000001413 amino acids Chemical class 0.000 claims abstract description 25
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims description 136
- 239000002960 lipid emulsion Substances 0.000 claims description 77
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 28
- 235000001014 amino acid Nutrition 0.000 claims description 24
- 239000004471 Glycine Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 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 claims description 8
- 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 claims description 8
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 7
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group 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 claims description 7
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 7
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 7
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 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 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 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 claims description 3
- 229930091371 Fructose Natural products 0.000 claims description 3
- 239000005715 Fructose Substances 0.000 claims description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 3
- 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 claims description 3
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 3
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 3
- 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 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004473 Threonine Substances 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 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 claims description 3
- 229940000635 beta-alanine Drugs 0.000 claims description 3
- 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 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 229960002591 hydroxyproline Drugs 0.000 claims description 3
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 3
- 229960000367 inositol Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 abstract description 11
- 239000000470 constituent Substances 0.000 abstract description 8
- 239000007924 injection Substances 0.000 abstract description 7
- 238000002347 injection Methods 0.000 abstract description 7
- 239000003889 eye drop Substances 0.000 abstract description 5
- 239000007923 nasal drop Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 235000019197 fats Nutrition 0.000 description 112
- 235000019198 oils Nutrition 0.000 description 33
- 239000000843 powder Substances 0.000 description 33
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 26
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 21
- 108010036949 Cyclosporine Proteins 0.000 description 21
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- 229960001265 ciclosporin Drugs 0.000 description 21
- 229930182912 cyclosporin Natural products 0.000 description 21
- 229940024606 amino acid Drugs 0.000 description 20
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 15
- -1 amproxicum Chemical compound 0.000 description 14
- 238000001914 filtration Methods 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- 235000002597 Solanum melongena Nutrition 0.000 description 11
- 238000004945 emulsification Methods 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- 150000004667 medium chain fatty acids Chemical class 0.000 description 11
- 239000012528 membrane Substances 0.000 description 11
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 6
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 6
- 229960003668 docetaxel Drugs 0.000 description 6
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 6
- 229960001967 tacrolimus Drugs 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 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 4
- 229940100662 nasal drops Drugs 0.000 description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 229950008882 polysorbate Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 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
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000002411 adverse Effects 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 229950000812 dexamethasone palmitate Drugs 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical class 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 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](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]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-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
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-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
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-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
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 235000008753 Papaver somniferum Nutrition 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- MSCCTZZBYHQMQJ-AZAGJHQNSA-N Tocopheryl nicotinate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C1=CC=CN=C1 MSCCTZZBYHQMQJ-AZAGJHQNSA-N 0.000 description 1
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- 229960001573 cabazitaxel Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- 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 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000014593 oils and fats Nutrition 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
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 229950009883 tocopheryl nicotinate Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、用時に注射用水や生理食塩水などの水系媒体と混合することで、薬物含有脂肪乳剤を調製することができる、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法に関する。 The present invention relates to a non-aqueous composition containing fat particles retaining a drug, and a method for producing the same, which can prepare a drug-containing fat emulsion by mixing with an aqueous medium such as water for injection and physiological saline at the time of use. .
薬物含有脂肪乳剤は、例えばステロイド（パルミチン酸デキサメサゾン）含有脂肪乳剤やプロスタグランジン（ＰＧＥ１）含有脂肪乳剤をはじめとするいくつかのものがすでに上市され、汎用されていることは当業者によく知られた事実である。しかしながら、それらの中には、安定性が劣るので冷所保存が必要であるといった制約を有しているものがある。 It is well known to those skilled in the art that several drug-containing fat emulsions have been put on the market and are widely used, including fat emulsions containing steroids (dexamethasone palmitate) and prostaglandin (PGE 1 ). It is a known fact. However, some of them have the restriction that they are inferior in stability and need to be stored in a cold place.
薬物含有脂肪乳剤の保存安定性を高める方法として、乳剤から水相を除去して乾燥状態に保つ方法が知られている。しかしながら、乳剤から水相を除去する方法として、これまでに提案されている、乳剤をマイナス数十℃で凍結乾燥する方法を採用した場合、時間もコストもかかる。従って、乳剤をより温和な条件下で乾燥することで乳剤から水相を除去し、薬物含有脂肪乳剤の保存安定性を高める方法が要望されていた。 As a method for enhancing the storage stability of a drug-containing fat emulsion, a method of removing the aqueous phase from the emulsion and keeping it dry is known. However, when a method of removing the aqueous phase from the emulsion by lyophilizing the emulsion at minus several tens of degrees Celsius, which has been proposed so far, it takes time and cost. Accordingly, there has been a demand for a method of removing the aqueous phase from the emulsion by drying the emulsion under milder conditions and enhancing the storage stability of the drug-containing fat emulsion.
そこで、本発明者は、注射剤や点眼剤や点鼻剤や吸入剤などとして用いることができる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができる、薬物を保持した脂肪粒子を含む非水系組成物を、温和な乾燥条件で製造する方法について、特許文献１において提案している。 Therefore, the present inventor retained a drug that can be prepared by mixing a drug-containing fat emulsion that can be used as an injection, eye drops, nasal drops, inhalants, etc. with an aqueous medium at the time of use. Patent Document 1 proposes a method for producing a non-aqueous composition containing fat particles under mild drying conditions.
特許文献１において本発明者が提案した薬物を保持した脂肪粒子を含む非水系組成物は、油脂の含量を最大で２ｍｇ／ｍＬにすることで製造された薬物含有脂肪乳剤から製造することができるものであり、薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができる。しかしながら、この非水系組成物は、油脂の含量が最大で２ｍｇ／ｍＬと少ない薬物含有脂肪乳剤から製造されたものであるため、脂肪粒子が担持することができる薬物の量に制限がある。従って、脂肪粒子がより多くの量の薬物を担持することができるようにより多くの量の油脂が用いられ、それでいて用時に水系媒体と混合することで、薬物含有脂肪乳剤を調製することができる非水系組成物が要望されている。 The non-aqueous composition containing fat particles retaining the drug proposed by the present inventor in Patent Document 1 can be produced from a drug-containing fat emulsion produced by making the fat content up to 2 mg / mL. The drug-containing fat emulsion can be prepared by mixing with an aqueous medium at the time of use. However, since this non-aqueous composition is manufactured from a drug-containing fat emulsion having a low fat content of 2 mg / mL at the maximum, the amount of drug that can be carried by fat particles is limited. Therefore, a larger amount of fat is used so that the fat particles can carry a larger amount of drug, yet it can be mixed with an aqueous medium at the time of use to prepare a drug-containing fat emulsion. There is a need for aqueous compositions.
そこで本発明は、特許文献１に記載の薬物を保持した脂肪粒子を含む非水系組成物よりも、脂肪粒子が多くの量の薬物を担持することができるように油脂の含量が多いにもかかわらず、注射剤や点眼剤や点鼻剤や吸入剤などとして用いることができる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができる、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法を提供することを目的とする。 Therefore, the present invention has a higher fat content so that the fat particles can carry a larger amount of the drug than the non-aqueous composition containing the fat particles holding the drug described in Patent Document 1. The drug-containing fat emulsion that can be used as injections, eye drops, nasal drops, inhalants, etc. can be prepared by mixing with an aqueous medium at the time of use. An object is to provide an aqueous composition and a method for producing the same.
本発明者は上記の点に鑑みて鋭意研究を行った結果、油脂の含量、油脂に対する薬物の重量比率、薬物と油脂の合計含量、乳化剤の含量を好適な数値範囲とすることにより製造された、２ｍｇ／ｍＬを超える量の油脂を用いているにもかかわらず濁度が小さい薬物含有脂肪乳剤に、水溶性担体として糖類やアミノ酸を加えて溶解した後、例えば６０℃といった温和な温度条件で乾燥処理すると、乳剤の水相が除去され、薬物を保持した脂肪粒子を含む非水系組成物に変換されること、この非水系組成物は、油脂の含量が多いにもかかわらず、水系媒体と混合することで、薬物含有脂肪乳剤への復元（再乳化）を安定に行うことができることを知見した。 As a result of intensive studies in view of the above points, the present inventor has been manufactured by setting the fat content, the weight ratio of the drug to the fat, the total content of the drug and fat, and the emulsifier content within a suitable numerical range. After adding sugars and amino acids as a water-soluble carrier to a drug-containing fat emulsion having a low turbidity despite the use of oils and fats in excess of 2 mg / mL, the mixture is dissolved under mild temperature conditions such as 60 ° C. The drying process removes the aqueous phase of the emulsion and converts it to a non-aqueous composition containing fat particles that retain the drug. It has been found that the mixing (re-emulsification) to the drug-containing fat emulsion can be performed stably by mixing.
以上の知見に基づいてなされた本発明の薬物を保持した脂肪粒子を含む非水系組成物は、請求項１記載の通り、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量が２〜１２０ｍｇ／ｍＬ（但し２ｍｇ／ｍＬを除く）、油脂に対する薬物の重量比率（薬物／油脂）が０．０００１〜５０（但し薬物と油脂の合計含量は最大で１２５ｍｇ／ｍＬ）、乳化剤の含量が３０〜２００ｍｇ／ｍＬ（但し３０ｍｇ／ｍＬを除く）であり、濁度が０．５以下である薬物含有脂肪乳剤に含まれる薬物を保持した脂肪粒子を、乳剤の水相が実質的に除去された状態で水溶性担体としての糖類および／またはアミノ酸に担持させてなることを特徴とする。
また、請求項２記載の非水系組成物は、請求項１記載の非水系組成物において、水溶性担体が糖類であることを特徴とする。
また、請求項３記載の非水系組成物は、請求項２記載の非水系組成物において、糖類がイノシトール、グルコース、ソルビトール、フルクトース、マンニトール、トレハロース、ラクトース、スクロース、マルトース、キシリトールから選択される少なくとも１種であることを特徴とする。
また、請求項４記載の非水系組成物は、請求項１記載の非水系組成物において、水溶性担体がアミノ酸であることを特徴とする。
また、請求項５記載の非水系組成物は、請求項４記載の非水系組成物において、アミノ酸がグリシン、アラニン、ノルバリン、セリン、スレオニン、システイン、メチオニン、プロリン、ヒドロキシプロリン、β−アラニン、γ−アミノ酪酸から選択される少なくとも１種であることを特徴とする。
また、請求項６記載の非水系組成物は、請求項１記載の非水系組成物において、脂肪粒子の平均粒子径が１〜２００ｎｍであることを特徴とする。
また、請求項７記載の非水系組成物は、請求項１記載の非水系組成物において、乳化剤の５０重量％以上がレシチンであることを特徴とする。
また、本発明の薬物を保持した脂肪粒子を含む非水系組成物の製造方法は、請求項８記載の通り、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量が２〜１２０ｍｇ／ｍＬ（但し２ｍｇ／ｍＬを除く）、油脂に対する薬物の重量比率（薬物／油脂）が０．０００１〜５０（但し薬物と油脂の合計含量は最大で１２５ｍｇ／ｍＬ）、乳化剤の含量が３０〜２００ｍｇ／ｍＬ（但し３０ｍｇ／ｍＬを除く）であり、濁度が０．５以下である薬物含有脂肪乳剤に、水溶性担体としての糖類および／またはアミノ酸を加えて溶解した後、乳剤の水相を除去することを特徴とする。
また、請求項９記載の製造方法は、請求項８記載の製造方法において、乳剤の水相の除去を１０〜８０℃の温度範囲での乾燥処理で行うことを特徴とする。
また、本発明の医薬品製剤は、請求項１０記載の通り、請求項１記載の薬物を保持した脂肪粒子を含む非水系組成物それ自体からなるかまたは他の成分と配合してなることを特徴とする。
The non-aqueous composition containing the fat particles retaining the drug of the present invention based on the above knowledge is, as described in claim 1, a drug-containing fat comprising at least a water-insoluble drug, an oil and fat, an emulsifier, and water as constituent components. The emulsion has an oil / fat content of 2 to 120 mg / mL (excluding 2 mg / mL) and a weight ratio of the drug to the oil / fat (drug / fat) of 0.0001 to 50 (provided that the total content of the drug and the oil / fat is maximum) 125 mg / mL), the emulsifier content is 30 to 200 mg / mL (excluding 30 mg / mL), and the fat particles retaining the drug contained in the drug-containing fat emulsion having a turbidity of 0.5 or less, The emulsion is characterized in that it is supported on a saccharide and / or amino acid as a water-soluble carrier in a state where the aqueous phase of the emulsion is substantially removed.
The non-aqueous composition according to claim 2 is characterized in that, in the non-aqueous composition according to claim 1, the water-soluble carrier is a saccharide.
The non-aqueous composition according to claim 3 is the non-aqueous composition according to claim 2, wherein the saccharide is at least selected from inositol, glucose, sorbitol, fructose, mannitol, trehalose, lactose, sucrose, maltose, and xylitol. It is one type.
The non-aqueous composition according to claim 4 is characterized in that, in the non-aqueous composition according to claim 1, the water-soluble carrier is an amino acid.
The non-aqueous composition according to claim 5 is the non-aqueous composition according to claim 4, wherein the amino acids are glycine, alanine, norvaline, serine, threonine, cysteine, methionine, proline, hydroxyproline, β-alanine, γ. -At least one selected from aminobutyric acid.
The non-aqueous composition according to claim 6 is the non-aqueous composition according to claim 1, wherein the average particle diameter of the fat particles is 1 to 200 nm.
The non-aqueous composition according to claim 7 is characterized in that, in the non-aqueous composition according to claim 1, 50% by weight or more of the emulsifier is lecithin.
The method for producing a non-aqueous composition containing fat particles retaining a drug according to the present invention is a drug-containing fat emulsion comprising a poorly water-soluble drug, an oil or fat, an emulsifier, and water as at least constituents as described in claim 8. The oil / fat content is 2 to 120 mg / mL (excluding 2 mg / mL), and the weight ratio of the drug to the oil (drug / fat) is 0.0001 to 50 (provided that the total content of the drug and the oil / fat is 125 mg / mL at maximum). mL), a sugar and / or amino acid as a water-soluble carrier is added to a drug-containing fat emulsion having an emulsifier content of 30 to 200 mg / mL (excluding 30 mg / mL) and a turbidity of 0.5 or less. After the dissolution, the aqueous phase of the emulsion is removed.
The manufacturing method according to claim 9 is characterized in that, in the manufacturing method according to claim 8, the aqueous phase of the emulsion is removed by a drying treatment in a temperature range of 10 to 80 ° C.
Further, the pharmaceutical preparation of the present invention is characterized in that, as described in claim 10, the non-aqueous composition containing the fat particles holding the drug according to claim 1 is itself or is blended with other components. And
本発明によれば、特許文献１に記載の薬物を保持した脂肪粒子を含む非水系組成物よりも、脂肪粒子が多くの量の薬物を担持することができるように油脂の含量が多いにもかかわらず、乳剤の安定性が特に求められる注射剤、薬物の溶解性と薬液の透明性が求められる点眼剤、薬物の吸収性向上のためにその担体の微粒子化が求められる点鼻剤、薬物が気管支や肺にたやすく到達して容易に吸収されるためにその担体の微粒子化が求められる吸入剤などとして用いることができる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができる、薬物を保持した脂肪粒子を含む非水系組成物を提供することができる。 According to the present invention, the fat and oil content is high so that the fat particles can carry a larger amount of the drug than the non-aqueous composition containing the fat particles holding the drug described in Patent Document 1. Regardless, injections that require particularly stable emulsions, eye drops that require drug solubility and solution transparency, and nasal drops and drugs that require a finer carrier to improve drug absorption Is prepared by mixing a drug-containing fat emulsion that can be used as an inhalant and the like that require fine particles of the carrier because it easily reaches the bronchi and lungs and is easily absorbed. A non-aqueous composition comprising drug-bearing fat particles can be provided.
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、水難溶性薬物、油脂、乳化剤、水を少なくとも構成成分とする薬物含有脂肪乳剤であって、油脂の含量が２〜１２０ｍｇ／ｍＬ（但し２ｍｇ／ｍＬを除く）、油脂に対する薬物の重量比率（薬物／油脂）が０．０００１〜５０（但し薬物と油脂の合計含量は最大で１２５ｍｇ／ｍＬ）、乳化剤の含量が３０〜２００ｍｇ／ｍＬ（但し３０ｍｇ／ｍＬを除く）であり、濁度が０．５以下である薬物含有脂肪乳剤に含まれる薬物を保持した脂肪粒子を、乳剤の水相が実質的に除去された状態で水溶性担体としての糖類および／またはアミノ酸に担持させてなることを特徴とするものである。 The non-aqueous composition containing fat particles retaining the drug of the present invention is a drug-containing fat emulsion containing at least water-insoluble drug, oil and fat, emulsifier, and water as constituents, and the fat and oil content is 2 to 120 mg / mL ( However, the weight ratio of the drug to the fat (drug / fat) is 0.0001 to 50 (however, the total content of the drug and the fat is 125 mg / mL at the maximum), and the content of the emulsifier is 30 to 200 mg / mL. (Excluding 30 mg / mL), and the fat particles retaining the drug contained in the drug-containing fat emulsion having a turbidity of 0.5 or less are water-soluble with the aqueous phase of the emulsion substantially removed. It is characterized by being supported on a saccharide and / or amino acid as a carrier.
本発明において、水難溶性薬物としては、日本薬局方・通則に規定の水への溶解性が「やや溶けにくい」（溶質１ｇまたは１ｍＬを溶かすために要する溶媒量が３０ｍＬ以上１００ｍＬ未満：溶質が薬物に相当し溶媒が水に相当）とされる以上に水難溶性のものが挙げられるが、より好適には「溶けにくい」（同、溶媒量が１００ｍＬ以上１０００ｍＬ未満）とされる以上に水難溶性のものが挙げられ、さらに好適には「極めて溶けにくい」（同、溶媒量が１０００ｍＬ以上１００００ｍＬ未満）とされる以上に水難溶性のものが挙げられ、最も好適には「ほとんど溶けない」（同、溶媒量が１００００ｍＬ以上）とされる以上に水難溶性のものが挙げられる。薬物は水難溶性であるとともに油難溶性であってもよい。薬物の種類は特段限定されるものではなく、シクロスポリンやタクロリムスなどの免疫抑制剤、エリスロマイシンやクラリスロマイシンなどの抗生物質、インドメタシンやアスピリンやイブプロフェンやケトプロフェンやジクロフェナックやアンピロキシカムやアセトアミノフェンなどの消炎鎮痛剤、パルミチン酸デキサメサゾンやフルオロメトロンやベタメサゾンやプロピオン酸ベクロメサゾンなどの合成副腎皮質ホルモン剤、ノルフロキサシンやレボフロキサシンなどの抗菌剤、ニコチン酸トコフェロールなどの循環器官用剤、エダラボンなどの脳保護薬、グリチンに例示されるグリチルリチン酸系化合物などの肝臓疾患用剤、プロスタグランジンＥ１、プロスタグランジンＥ２、プロスタグランジンＦ２α、プロスタグランジンＩ２の他、そのアルキルエステル（メチルエステル、エチルエステル、プロピルエステル、ブチルエステルなど）をはじめとする各種の誘導体を含むプロスタグランジン系化合物（プロスタン酸骨格を有する化合物）、酢酸トコフェロールなどのビタミンＥ剤、ヨード化ケシ油脂肪酸エチルエステルなどの造影剤、ビダラビン、アシクロビル、アデホピポキシルなどの抗ウィルス薬、マイトマイシン、イリノテカン、エトポシド、パクリタキセル、ドセタキセル、カバジタキセル、ウベニメクス、カルプラチン、シスプラチンなどの抗悪性腫瘍薬などを例示することができる。 In the present invention, the poorly water-soluble drug has the solubility in water as defined in the Japanese Pharmacopoeia / General Rules (somewhat difficult to dissolve) (the amount of solvent required to dissolve 1 g or 1 mL of solute is 30 mL or more and less than 100 mL: solute is drug) In which the solvent is equivalent to water), and more preferably, it is less soluble in water than that in which it is difficult to dissolve (the amount of the solvent is 100 mL or more and less than 1000 mL). More preferable are those that are hardly soluble in water, more preferably “very difficult to dissolve” (the amount of solvent is 1000 mL or more and less than 10,000 mL), and most preferably “almost insoluble” (the same, Examples of the water-solubility are more than the amount of the solvent is 10,000 mL or more. The drug may be sparingly soluble in water and poorly oil soluble. There are no particular limitations on the type of drug, immunosuppressants such as cyclosporine and tacrolimus, antibiotics such as erythromycin and clarithromycin, indomethacin, aspirin, ibuprofen, ketoprofen, diclofenac, amproxicum, and acetaminophen For analgesics, synthetic corticosteroids such as dexamethasone palmitate, fluorometholone, betamethasone and beclomesazone propionate, antibacterial agents such as norfloxacin and levofloxacin, cardiovascular agents such as tocopherol nicotinate, brain protective drugs such as edaravone, glycine for liver disease such as glycyrrhizic acid compounds exemplified, prostaglandin E 1, prostaglandin E 2, prostaglandin F 2.alpha, prostaglandin I Other, their alkyl esters (methyl ester, ethyl ester, propyl ester, butyl ester) prostaglandin compounds including various derivatives, including (a compound having a prostanoic acid skeleton), vitamin E such as tocopherol acetate Examples include contrast agents such as iodinated poppy oil fatty acid ethyl ester, antiviral drugs such as vidarabine, acyclovir, and adefopoxyl, mitomycin, irinotecan, etoposide, paclitaxel, docetaxel, cabazitaxel, ubenimex, calplatin, and cisplatin can do.
本発明において、油脂としては、大豆油、トウモロコシ油、ヤシ油、サフラワー油、エゴマ油、オリーブ油、ヒマシ油、綿実油などの植物油の他、ラノリンなどの動物油、卵黄油、魚油、流動パラフィンなどの鉱物油、中鎖脂肪酸トリグリセリド、化学合成トリグリセリド、ゲル化炭化水素など、油脂として用いることができる公知の油脂が挙げられる。 In the present invention, as fats and oils, vegetable oils such as soybean oil, corn oil, palm oil, safflower oil, sesame oil, olive oil, castor oil, cottonseed oil, animal oils such as lanolin, egg yolk oil, fish oil, liquid paraffin, etc. Well-known fats and oils that can be used as fats and oils, such as mineral oils, medium chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons, can be mentioned.
本発明において、乳化剤としては、レシチン（卵黄レシチン、大豆レシチン、水素添加卵黄レシチン、水素添加大豆レシチンなど）、ポリソルベート、ＰＥＧ−水添ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油などが挙げられる。中でも、レシチンを用いることが、乳化力が弱く、また、高濃度において粘度が高いことから取り扱いが必ずしも容易でないものの、安全性が高いことから好適である（レシチンを乳化剤として用いることができる他の物質と混合して用いてもよいがその場合の乳化剤におけるレシチンの割合は５０重量％以上であることが望ましい）。なお、水難溶性薬物がプロスタグランジン系化合物の場合、ホスファチジルエタノールアミンの含量が２重量％以下の乳化剤を用いることが望ましい（ホスファチジルエタノールアミンはプロスタグランジン系化合物の安定性に悪影響を与えるため）。例えばキューピー社製のＰＣ−９８Ｎは、ホスファチジルエタノールアミンの除去処理がなされた精製卵黄レシチン（ホスファチジルコリンの含量が９８重量％以上でホスファチジルエタノールアミンの含量が１重量％以下）として好適に用いることができる。 In the present invention, the emulsifier includes lecithin (egg yolk lecithin, soy lecithin, hydrogenated egg yolk lecithin, hydrogenated soy lecithin), polysorbate, PEG-hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc. Is mentioned. Among them, it is preferable to use lecithin because it has weak emulsifying power and is not always easy to handle because of its high viscosity at a high concentration, but it is preferable because of high safety (lecithin can be used as an emulsifier). The mixture may be used in combination with a substance, but the lecithin ratio in the emulsifier is preferably 50% by weight or more). When the poorly water-soluble drug is a prostaglandin compound, it is desirable to use an emulsifier with a phosphatidylethanolamine content of 2% by weight or less (since phosphatidylethanolamine adversely affects the stability of the prostaglandin compound). . For example, PC-98N manufactured by Kewpie Corporation can be suitably used as purified egg yolk lecithin from which phosphatidylethanolamine has been removed (the content of phosphatidylcholine is 98% by weight or more and the content of phosphatidylethanolamine is 1% by weight or less). .
本発明の薬物を保持した脂肪粒子を含む非水系組成物を製造するために用いる薬物含有脂肪乳剤について、油脂の含量を２〜１２０ｍｇ／ｍＬ（２ｍｇ／ｍＬを除く）と規定するのは、２ｍｇ／ｍＬ以下であると脂肪乳剤が担持できる薬物の量が少なくなってしまう一方、１２０ｍｇ／ｍＬよりも多いと油脂の量が多すぎることで乳化が困難になるからである。油脂の含量は３〜１１０ｍｇ／ｍＬが望ましく、５〜１０５ｍｇ／ｍＬがより望ましく、１０〜１００ｍｇ／ｍＬがさらに望ましい。油脂に対する薬物の重量比率（薬物／油脂）を０．０００１〜５０（但し薬物と油脂の合計含量は最大で１２５ｍｇ／ｍＬ）と規定するのは、０．０００１よりも小さいと薬物に対して油脂が過多となり、患者に対して無用な油脂を投与することになってしまう一方、５０よりも大きいと油脂に対して薬物が過多となり、薬物の安定性が損なわれ、薬物が凝集や析出しやすくなるからである。油脂に対する薬物の重量比率は０．００１〜２０が望ましく、０．０１〜１０がより望ましい。薬物と油脂の合計含量を最大で１２５ｍｇ／ｍＬと規定するのは、１２５ｍｇ／ｍＬよりも多いと透明性を有する脂肪乳剤を得るための乳化が困難になるからである。薬物と油脂の合計含量は３〜１２０ｍｇ／ｍＬが望ましい。乳化剤の含量を３０〜２００ｍｇ／ｍＬ（但し３０ｍｇ／ｍＬを除く）と規定するのは、３０ｍｇ／ｍＬ以下であると乳化剤の量に対する油脂の量が多すぎることで乳化が困難になる一方、２００ｍｇ／ｍＬよりも多いと乳剤の粘度が高くなることで乳化が困難になるからである（とりわけレシチンを用いた場合に顕著である）。乳化剤の含量は４０〜１８０ｍｇ／ｍＬが望ましく、５０〜１６０ｍｇ／ｍＬがより望ましい。油脂に対する乳化剤の重量比率（乳化剤／油脂）を１〜３００とすることで、含まれる脂肪粒子が小さい、濁度が０．５以下の乳剤が得やすくなる。なお、薬物の含量は例えば０．０１〜５０ｍｇ／ｍＬであってよい。２ｍｇ／ｍＬを超える量の油脂を用いることで、脂溶性がある薬物は油脂に溶解することにより、脂溶性がない薬物は水と油脂の界面において乳化剤と共存することにより、より多くの量が脂肪乳剤に担持される。以上で説明した薬物含有脂肪乳剤の組成は、油脂の含量が多いにもかかわらず、水系媒体と混合することで、薬物含有脂肪乳剤への復元を安定に行うことができる、薬物を保持した脂肪粒子を含む非水系組成物を製造するために重要な要素となる（とりわけ乳化剤の含量は重要である）。 For the drug-containing fat emulsion used for producing a non-aqueous composition containing fat particles retaining the drug of the present invention, the oil content is defined as 2 to 120 mg / mL (excluding 2 mg / mL). When the amount is less than / mL, the amount of drug that can be carried by the fat emulsion decreases, whereas when the amount exceeds 120 mg / mL, the amount of fats and oils is too large to make emulsification difficult. The content of fat / oil is desirably 3 to 110 mg / mL, more desirably 5 to 105 mg / mL, and further desirably 10 to 100 mg / mL. The weight ratio of drug to fat (drug / fat) is defined as 0.0001 to 50 (provided that the total content of drug and fat is 125 mg / mL at the maximum). However, if it is larger than 50, the drug is excessive with respect to the fat and oil, the stability of the drug is impaired, and the drug is likely to aggregate and precipitate. Because it becomes. The weight ratio of the drug to the fat is preferably 0.001 to 20, and more preferably 0.01 to 10. The reason why the total content of the drug and the fat / oil is defined as 125 mg / mL at the maximum is that emulsification for obtaining a fat emulsion having transparency becomes difficult if the total content is more than 125 mg / mL. The total content of drug and fat is preferably 3 to 120 mg / mL. The content of the emulsifier is defined as 30 to 200 mg / mL (excluding 30 mg / mL). When the amount is not more than 30 mg / mL, emulsification becomes difficult due to the excessive amount of oil and fat with respect to the amount of emulsifier, while 200 mg This is because when the amount is more than / mL, the viscosity of the emulsion becomes high and emulsification becomes difficult (particularly when lecithin is used). The emulsifier content is desirably 40 to 180 mg / mL, and more desirably 50 to 160 mg / mL. By setting the weight ratio of the emulsifier to the fat / oil (emulsifier / oil / fat) to 1 to 300, an emulsion having small fat particles and a turbidity of 0.5 or less can be easily obtained. The drug content may be, for example, 0.01 to 50 mg / mL. By using fats and oils in an amount exceeding 2 mg / mL, fat-soluble drugs are dissolved in fats and oils, and non-fat-soluble drugs coexist with emulsifiers at the interface between water and fats. Supported on fat emulsion. The composition of the drug-containing fat emulsion described above is a fat containing a drug that can be stably restored to a drug-containing fat emulsion by mixing with an aqueous medium, despite the high fat content. It is an important factor for producing a non-aqueous composition containing particles (especially the emulsifier content is important).
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、以下の方法で製造することができる。まず、油脂の含量、油脂に対する薬物の重量比率、薬物と油脂の合計含量、乳化剤の含量を上記の数値範囲に設定し、自体公知の手順、例えば、薬物、油脂、乳化剤をいったん均一に混合して溶解させて油相とし、これに水を加えた後、あるいは水を加えながら、超音波乳化機を用いて乳化したり、また、強力に撹拌して粗乳化液を調製し（例えば回転数が１００００〜１５０００ｒｐｍで５〜３０分間の攪拌による）、次いで粗乳化液をマントンゴーリンホモジナイザーなどの高圧乳化機を用いて乳化したりすることにより薬物含有脂肪乳剤を製造する。乳化機の運転条件や乳化時間を調節すれば、脂肪粒子の粒子径分布を狭くすることができる。また、脂肪粒子の粒子径分布を狭くするために、乳化は複数回行ってもよい（例えば３〜５０回）。特筆すべきは、油脂の含量、油脂に対する薬物の重量比率、薬物と油脂の合計含量、乳化剤の含量を上記の数値範囲に設定することで、超音波乳化機を用いて乳化することによって、また、高圧乳化機を用いて例えば１５００バール以下、望ましくは３５０〜１０００バールの圧力で乳化することによって、脂肪粒子の平均粒子径が２００ｎｍ以下、好適には１８０ｎｍ以下、より好適には１２０ｎｍ以下であり（下限は例えば１ｎｍ）、濁度が０．５以下、好適には０．４以下、より好適には０．３以下の薬物含有脂肪乳剤が得やすくなる点にある。 The non-aqueous composition containing fat particles retaining the drug of the present invention can be produced by the following method. First, the fat content, the weight ratio of the drug to the fat, the total content of the drug and fat, and the emulsifier content are set within the above numerical ranges, and the procedure known per se, for example, the drug, fat and emulsifier are once mixed uniformly. The oil phase is dissolved to form an oil phase, and after adding water or while adding water, the mixture is emulsified using an ultrasonic emulsifier, or stirred strongly to prepare a crude emulsion (for example, the number of rotations). Is then stirred at 10000-15000 rpm for 5-30 minutes), and then the crude emulsion is emulsified using a high-pressure emulsifier such as Manton Gorin homogenizer to produce a drug-containing fat emulsion. By adjusting the operating conditions and emulsification time of the emulsifier, the particle size distribution of the fat particles can be narrowed. Moreover, in order to narrow the particle size distribution of the fat particles, emulsification may be performed a plurality of times (for example, 3 to 50 times). It should be noted that by setting the content of the oil and fat, the weight ratio of the drug to the oil and fat, the total content of the drug and the oil and the content of the emulsifier in the above numerical range, emulsification using an ultrasonic emulsifier, The average particle size of the fat particles is 200 nm or less, preferably 180 nm or less, more preferably 120 nm or less, by emulsification using a high-pressure emulsifier, for example, at a pressure of 1500 bar or less, preferably 350 to 1000 bar. (The lower limit is, for example, 1 nm), and it is easy to obtain a drug-containing fat emulsion having a turbidity of 0.5 or less, preferably 0.4 or less, and more preferably 0.3 or less.
次に、以上のようにして製造された薬物含有脂肪乳剤に、水溶性担体として糖類やアミノ酸を加えて溶解した後、乳剤の水相を除去する。水溶性担体として用いることができる糖類としては、イノシトール、グルコース、ソルビトール、フルクトース、マンニトールなどの単糖類、トレハロース、ラクトース、スクロース、マルトースなどの二糖類の他、キシリトールなどが挙げられる。アミノ酸としては、グリシン、アラニン、ノルバリン、セリン、スレオニン、システイン、メチオニン、プロリン、ヒドロキシプロリン、β−アラニン、γ−アミノ酪酸などの中性アミノ酸の他、リジン、アルギニン、オルニチン、シトルリンなどの塩基性アミノ酸などが挙げられる。糖類やアミノ酸の溶解量は２０〜１０００ｍｇ／ｍＬが望ましく、５０〜７００ｍｇ／ｍＬがより望ましい。但し、用いる糖類やアミノ酸の飽和溶解量が上記の上限値未満の場合には飽和溶解量を上限とする。糖類やアミノ酸の溶解量が少なすぎると、薬物を保持した脂肪粒子に対して糖類やアミノ酸が過少となり、薬物を保持した脂肪粒子を含む非水系組成物が安定に得られず（本発明の非水系組成物は油脂の含量が多いことで多数の脂肪粒子を含むので、糖類やアミノ酸の溶解量が少なすぎると、乳剤の水相を除去した後に個々の脂肪粒子が糖類やアミノ酸中に分散されることができず、脂肪粒子の合一（凝集）が起こりやい）、結果として、水系媒体と混合した際、薬物含有脂肪乳剤への復元を安定に行うことができない恐れがある。一方、糖類やアミノ酸の溶解量が多すぎると、患者に対して糖類やアミノ酸を無用に投与することになってしまう。薬物含有脂肪乳剤に糖類やアミノ酸を加えて溶解した後の乳剤の水相の除去は、どのような方法で行ってもよいが、１０〜８０℃の温度範囲での乾燥処理で行うことが、乳剤に含まれる薬物の劣化を引き起こすことなく、薬物を保持した脂肪粒子を含む非水系組成物を効率よく低コストで得ることができる点において望ましい。乾燥処理は減圧乾燥、噴霧乾燥、流動乾燥、通風乾燥などを好適に採用することができるが、温度条件は３０〜７０℃がより望ましく、４０〜６０℃がさらに望ましい。このようにして製造される本発明の薬物を保持した脂肪粒子を含む非水系組成物が優れた保存安定性を有するためには、その水分率は１０％以下が望ましい。 Next, saccharides and amino acids are added and dissolved in the drug-containing fat emulsion produced as described above as a water-soluble carrier, and then the aqueous phase of the emulsion is removed. Examples of the saccharide that can be used as the water-soluble carrier include monosaccharides such as inositol, glucose, sorbitol, fructose, and mannitol, disaccharides such as trehalose, lactose, sucrose, and maltose, and xylitol. Amino acids include basic amino acids such as lysine, arginine, ornithine and citrulline, as well as neutral amino acids such as glycine, alanine, norvaline, serine, threonine, cysteine, methionine, proline, hydroxyproline, β-alanine, and γ-aminobutyric acid. Examples include amino acids. The amount of saccharide or amino acid dissolved is preferably 20 to 1000 mg / mL, more preferably 50 to 700 mg / mL. However, when the saturated dissolution amount of the saccharide or amino acid to be used is less than the above upper limit value, the saturated dissolution amount is made the upper limit. If the amount of saccharides and amino acids dissolved is too small, the amount of saccharides and amino acids is too small relative to the fat particles holding the drug, and a non-aqueous composition containing the fat particles holding the drug cannot be obtained stably (non-invention of the present invention). Since the aqueous composition contains a large number of fat particles due to the high fat content, if the amount of saccharides and amino acids dissolved is too small, the individual fat particles are dispersed in the saccharides and amino acids after the aqueous phase of the emulsion is removed. As a result, when mixed with an aqueous medium, it may not be possible to stably restore the drug-containing fat emulsion. On the other hand, if the amount of saccharide or amino acid dissolved is too large, the saccharide or amino acid is unnecessarily administered to the patient. The removal of the aqueous phase of the emulsion after the saccharides and amino acids are added to the drug-containing fat emulsion and dissolution may be performed by any method, but may be performed by a drying treatment in a temperature range of 10 to 80 ° C. This is desirable in that a non-aqueous composition containing fat particles retaining a drug can be obtained efficiently and at low cost without causing deterioration of the drug contained in the emulsion. As the drying treatment, vacuum drying, spray drying, fluidized drying, ventilation drying and the like can be suitably employed, but the temperature condition is more preferably 30 to 70 ° C, and further preferably 40 to 60 ° C. In order for the non-aqueous composition containing fat particles retaining the drug of the present invention thus produced to have excellent storage stability, the water content is desirably 10% or less.
なお、本発明の薬物を保持した脂肪粒子を含む非水系組成物を製造するために用いる薬物含有脂肪乳剤の構成成分としてプロピレングリコール、グリセリン、マクロゴール、乳酸、ポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、コンドロイチン硫酸またはその塩（ナトリウム塩など）、ヒアルロン酸またはその塩（ナトリウム塩など）、グリチルリチン酸またはその塩（ナトリウム塩やアンモニウム塩など）などをさらに用いることで、薬物の溶解性の向上、乳剤や薬物の安定性の向上、乳剤の等張化などを図ってもよい。これらの含量は０．０２〜３００ｍｇ／ｍＬが望ましく、０．２〜１００ｍｇ／ｍＬがより望ましい。０．０２ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、３００ｍｇ／ｍＬよりも多いと粘度が高くなることで乳化が困難になったり、乳剤が酸性化されて不安定になったりしやすくなる。 In addition, propylene glycol, glycerin, macrogol, lactic acid, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, chondroitin are used as components of the drug-containing fat emulsion used for producing the non-aqueous composition containing fat particles retaining the drug of the present invention. By further using sulfuric acid or its salt (such as sodium salt), hyaluronic acid or its salt (such as sodium salt), glycyrrhizic acid or its salt (such as sodium salt or ammonium salt), it is possible to improve drug solubility, Improvement of drug stability, isotonicity of the emulsion, and the like may be achieved. These contents are preferably 0.02 to 300 mg / mL, and more preferably 0.2 to 100 mg / mL. When the amount is less than 0.02 mg / mL, the effect is difficult to be exhibited. On the other hand, when the amount is more than 300 mg / mL, the viscosity becomes high and emulsification becomes difficult, and the emulsion tends to be acidified and unstable. Become.
また、薬物含有脂肪乳剤の構成成分としてオレイン酸、ステアリン酸、リノール酸、リノレン酸、パルミチン酸、パルミトレイン酸、ミリスチン酸などの高級脂肪酸をさらに用いることで、乳剤の安定化を図ってもよい。高級脂肪酸の含量は０．００１〜１０ｍｇ／ｍＬが望ましく、０．０１〜５ｍｇ／ｍＬがより望ましい。０．００１ｍｇ／ｍＬよりも少ないと効果が発揮されにくくなる一方、１０ｍｇ／ｍＬよりも多いと薬物に対して劣化を招く危険性が生じる。なお、水難溶性薬物がプロスタグランジン系化合物の場合、これらの高級脂肪酸は用いないことが望ましい（プロスタグランジン系化合物の安定性に悪影響を与えるため）。 Further, the emulsion may be stabilized by further using higher fatty acids such as oleic acid, stearic acid, linoleic acid, linolenic acid, palmitic acid, palmitoleic acid, and myristic acid as constituents of the drug-containing fat emulsion. The content of higher fatty acids is preferably 0.001 to 10 mg / mL, and more preferably 0.01 to 5 mg / mL. When the amount is less than 0.001 mg / mL, the effect is hardly exhibited, while when the amount is more than 10 mg / mL, there is a risk of causing deterioration of the drug. When the poorly water-soluble drug is a prostaglandin compound, it is desirable not to use these higher fatty acids (in order to adversely affect the stability of the prostaglandin compound).
また、薬物含有脂肪乳剤の構成成分として糖類をさらに用いることで、乳剤中に時として発生しうる析出浮遊物の発生を効果的に抑制することができる。好適な糖類としては、上述の水溶性担体として用いることができる糖類の他、デキストリン、シクロデキストリン、デキストランなどが挙げられる。糖類の含量は１０〜６００ｍｇ／ｍＬが望ましい。 Further, by further using saccharides as a constituent of the drug-containing fat emulsion, it is possible to effectively suppress the occurrence of precipitation suspended matter that sometimes occurs in the emulsion. Suitable saccharides include dextrin, cyclodextrin, dextran and the like in addition to the saccharides that can be used as the above-mentioned water-soluble carrier. The sugar content is preferably 10 to 600 mg / mL.
また、薬物含有脂肪乳剤の構成成分として自体公知のｐＨ調整剤（クエン酸など）や浸透圧調整剤をさらに用い、ｐＨを調整したり（例えば４〜８）、浸透圧を調整したりしてもよい。なお、必要に応じて防腐剤や抗酸化剤などを構成成分としてもよいことは言うまでもない。また、薬物含有脂肪乳剤は、水溶性薬物を構成成分とすることを妨げるものではない。 Further, a pH adjusting agent (citric acid or the like) or an osmotic pressure adjusting agent known per se can be further used as a component of the drug-containing fat emulsion to adjust the pH (for example, 4 to 8) or to adjust the osmotic pressure. Also good. Needless to say, preservatives and antioxidants may be used as constituents as necessary. The drug-containing fat emulsion does not prevent the water-soluble drug from being a constituent component.
本発明の薬物を保持した脂肪粒子を含む非水系組成物は、その製造過程における薬物含有脂肪乳剤の水相を除去する前の段階や製造後に高圧蒸気滅菌を行うことができる。高圧蒸気滅菌は、一般的な条件（例えば１２０〜１２２℃×１０〜１５分間）で行えばよい。また、その製造過程における乳剤の水相を除去する前の段階であれば、例えば脂肪粒子の平均粒子径を２００ｎｍ以下に設定することで、ろ過滅菌を行うことができる。このようにして製造される本発明の薬物を保持した脂肪粒子を含む非水系組成物は、保存安定性に優れるので常温保存ができる（但し薬物が非常に不安定なものである場合はこの限りでない）。本発明の薬物を保持した脂肪粒子を含む非水系組成物は、注射用水や生理食塩水などの水系媒体と混合することで、薬物含有脂肪乳剤への復元を安定に行うことができる。本発明の薬物を保持した脂肪粒子を含む非水系組成物に混合する水系媒体の量を、必要に応じて調整することで、透明性を有する薬物含有脂肪乳剤を調製することができるが、こうして調製される薬物含有脂肪乳剤が透明性を有することは、変質や異物混入の有無、配合変化の目視での確認を容易にする他、投与される患者に対して安心感を与える。このように本発明の薬物を保持した脂肪粒子を含む非水系組成物は、それ自体を用時溶解型の医薬品製剤として用いることができる他、各種の医薬品添加物（製剤助剤など）と配合して経口剤や外用剤などの様々な形態の医薬品製剤とすることもできる。ここで特筆すべきは、従来から知られている大量の油脂（例えば１０ｍｇ／ｍＬ以上）を用いて調製された乳白状の薬物含有脂肪乳剤は、例えば６０℃といった温和な温度条件での乾燥処理で乳剤の水相を除去すると、薬物を保持した脂肪粒子を含む非水系組成物が得られないことで、その復元をもはや行うことができないということである（この事実はこれまでに提案されている薬物含有脂肪乳剤の乾燥方法が凍結乾燥に限定されていることを裏付けるものである）。 The non-aqueous composition containing fat particles retaining the drug of the present invention can be autoclaved before or after the aqueous phase of the drug-containing fat emulsion in the production process is removed. High-pressure steam sterilization may be performed under general conditions (for example, 120 to 122 ° C. for 10 to 15 minutes). Moreover, if it is a stage before removing the aqueous phase of the emulsion in the production process, filtration sterilization can be performed, for example, by setting the average particle diameter of fat particles to 200 nm or less. The non-aqueous composition containing the fat particles retaining the drug of the present invention produced in this way is excellent in storage stability and can be stored at room temperature (provided that this is not necessary if the drug is very unstable). Not) The non-aqueous composition containing fat particles retaining the drug of the present invention can be stably restored to a drug-containing fat emulsion by mixing with an aqueous medium such as water for injection or physiological saline. A drug-containing fat emulsion having transparency can be prepared by adjusting the amount of the aqueous medium mixed with the non-aqueous composition containing the fat particles holding the drug of the present invention as necessary. The transparency of the prepared drug-containing fat emulsion facilitates visual confirmation of the presence or absence of alteration, foreign matter contamination, and change in formulation, and also gives the patient a sense of security. As described above, the non-aqueous composition containing the fat particles holding the drug of the present invention can be used as a pharmaceutical preparation which is dissolved at the time of use, and is combined with various pharmaceutical additives (formulation aids, etc.). Thus, various forms of pharmaceutical preparations such as oral preparations and external preparations can be prepared. What should be noted here is that the milky white drug-containing fat emulsion prepared using a large amount of conventionally known fats and oils (for example, 10 mg / mL or more) is subjected to a drying treatment under a mild temperature condition such as 60 ° C. The removal of the emulsion's aqueous phase in step 2 does not result in a non-aqueous composition containing fat particles that retain the drug, which can no longer be restored (this fact has been previously proposed). This confirms that the method for drying drug-containing fat emulsions is limited to lyophilization).
以下、本発明を実施例によって詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is limited to the following description and is not interpreted.
実施例１：シクロスポリンを保持した脂肪粒子を含む非水系組成物（その１）
３０ｍＬビーカーにシクロスポリン４０ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ：日清オイリオ社製、以下同じ）５００ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ：キユーピー社製、以下同じ）１．９ｇ、プロピレングリコール２００ｍｇを採り、ホットスターラーで加温し、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた黄色の薄濁したシクロスポリン含有脂肪乳剤２０ｍＬに、水溶性担体としてトレハロース５ｇを加えて均一溶解した。得られたトレハロース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするシクロスポリンを保持した脂肪粒子を含む非水系組成物（黄色粉末、水分率：１０％以下）を得た。この黄色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、黄色の濁ったシクロスポリン含有脂肪乳剤を復元することができた（表１，２参照）。
Example 1: Non-aqueous composition containing fat particles retaining cyclosporine (Part 1)
In a 30 mL beaker, take 40 mg of cyclosporine, 500 mg of medium chain fatty acid triglyceride (ODO: manufactured by Nisshin Oillio Co., Ltd., the same shall apply hereinafter), 1.9 g of purified egg yolk lecithin (PL-100M: manufactured by QP Corporation, the same applies hereinafter), and 200 mg of propylene glycol. The mixture was heated with a stirrer and emulsified with an ultrasonic emulsifier until the emulsion became uniform while adding pure water so that the total amount became 20 mL (about 30 minutes). To 20 mL of the resulting yellow turbid cyclosporine-containing fat emulsion, 5 g of trehalose as a water-soluble carrier was added and uniformly dissolved. The obtained trehalose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). After removing the aqueous phase of the emulsion and returning the inside of the flask to normal pressure using sterile air, a non-aqueous composition containing fat particles retaining the desired cyclosporine (yellow powder, moisture content: 10 % Or less). When 300 mg of this yellow powder was put in a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a yellow cloudy cyclosporine-containing fat emulsion could be restored (see Tables 1 and 2).
実施例２：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その１）
３０ｍＬビーカーにプロスタグランジンＥ１６００μｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）２００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ：キユーピー社製、以下同じ）２ｇ、プロピレングリコール２００ｍｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた無色の微濁したプロスタグランジンＥ１含有脂肪乳剤２０ｍＬに、水溶性担体としてマルトース１２ｇを加えて均一溶解した。得られたマルトース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、無色の薄濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表１，２参照）。
Example 2: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 1)
In a 30 mL beaker, prostaglandin E 1 600 μg, medium-chain fatty acid triglyceride (ODO) 200 mg, purified egg yolk lecithin (PC-98N: manufactured by QP Corporation, the same shall apply hereinafter) 2 g and propylene glycol 200 mg are taken and heated with a hot stirrer, nitrogen In an air stream, emulsification was performed with an ultrasonic emulsifier while adding pure water so that the total amount was 20 mL (about 30 minutes). To the resulting colorless fine Nigoshi prostaglandin E 1 containing fat emulsion 20 mL, it was uniformly dissolved maltose 12g added as a water-soluble carrier. The obtained maltose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, so that the non-aqueous composition containing the fat particles holding the desired prostaglandin E 1 (white powder, Moisture content: 10% or less) was obtained. When 300 mg of this white powder was taken into a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid prostaglandin E 1- containing fat emulsion could be recovered (Table 1, 2).
実施例３：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その２）
３０ｍＬビーカーにプロスタグランジンＥ１６００μｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）４００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ）３ｇ、プロピレングリコール２００ｍｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた無色の微濁したプロスタグランジンＥ１含有脂肪乳剤２０ｍＬに、水溶性担体としてトレハロース５ｇを加えて均一溶解した。得られたトレハロース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、無色の濁ったプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表１，２参照）。
Example 3: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 2)
Take a prostaglandin E 1 600 μg, medium chain fatty acid triglyceride (ODO) 400 mg, purified egg yolk lecithin (PC-98N) 3 g, and propylene glycol 200 mg in a 30 mL beaker and warm with a hot stirrer to a total volume of 20 mL under a nitrogen stream. While adding pure water, the mixture was emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 30 minutes). To the resulting colorless fine Nigoshi prostaglandin E 1 containing fat emulsion 20 mL, were uniformly dissolved trehalose 5g added as a water-soluble carrier. The obtained trehalose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, so that the non-aqueous composition containing the fat particles holding the desired prostaglandin E 1 (white powder, Moisture content: 10% or less) was obtained. When 300 mg of this white powder was taken into a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid prostaglandin E 1- containing fat emulsion could be recovered (Tables 1 and 2). reference).
実施例４：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その３）
３０ｍＬビーカーにプロスタグランジンＥ１６００μｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）２００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ）２ｇ、プロピレングリコール２ｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた無色の微濁したプロスタグランジンＥ１含有脂肪乳剤２０ｍＬに、水溶性担体としてマルトース１０ｇを加えて均一溶解した。得られたマルトース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、無色の薄濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表１，２参照）。
Example 4: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 3)
Take a prostaglandin E 1 600 μg, medium chain fatty acid triglyceride (ODO) 200 mg, purified egg yolk lecithin (PC-98N) 2 g, and propylene glycol 2 g in a 30 mL beaker and warm with a hot stirrer to a total volume of 20 mL under a nitrogen stream. While adding pure water, the mixture was emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 30 minutes). 10 g of maltose as a water-soluble carrier was added and uniformly dissolved in 20 mL of the obtained colorless and turbid prostaglandin E 1- containing fat emulsion. The obtained maltose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, so that the non-aqueous composition containing the fat particles holding the desired prostaglandin E 1 (white powder, Moisture content: 10% or less) was obtained. When 300 mg of this white powder was taken into a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid prostaglandin E 1- containing fat emulsion could be recovered (Table 1, 2).
実施例５：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その４）
３０ｍＬビーカーにプロスタグランジンＥ１６００μｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）３００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ）３ｇ、プロピレングリコール１．２ｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた無色の微濁したプロスタグランジンＥ１含有脂肪乳剤２０ｍＬに、水溶性担体としてマルトース１０ｇを加えて均一溶解した。得られたマルトース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、無色の薄濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表１，２参照）。
Example 5: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (Part 4)
In a 30 mL beaker, 600 μg of prostaglandin E 1 , 300 mg of medium chain fatty acid triglyceride (ODO), 3 g of purified egg yolk lecithin (PC-98N) and 1.2 g of propylene glycol are heated and heated with a hot stirrer. While adding pure water to 20 mL, the mixture was emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 30 minutes). 10 g of maltose as a water-soluble carrier was added and uniformly dissolved in 20 mL of the obtained colorless and turbid prostaglandin E 1- containing fat emulsion. The obtained maltose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, so that the non-aqueous composition containing the fat particles holding the desired prostaglandin E 1 (white powder, Moisture content: 10% or less) was obtained. When 300 mg of this white powder was taken into a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid prostaglandin E 1- containing fat emulsion could be recovered (Table 1, 2).
実施例６：プロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（その５）
３０ｍＬビーカーにプロスタグランジンＥ１６００μｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）３００ｍｇ、精製卵黄レシチン（ＰＣ−９８Ｎ）２．４ｇ、グリセリン２００ｍｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約３０分間）。得られた無色の微濁したプロスタグランジンＥ１含有脂肪乳剤２０ｍＬに、水溶性担体としてトレハロース１０ｇを加えて均一溶解した。得られたトレハロース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末３００ｍｇを試験管に採り、純水３ｍＬを加えて１分間、手で振とうしたところ、無色の薄濁したプロスタグランジンＥ１含有脂肪乳剤を復元することができた（表１，２参照）。
Example 6: Non-aqueous composition containing fat particles retaining prostaglandin E 1 (part 5)
In a 30 mL beaker, prostaglandin E 1 600 μg, medium chain fatty acid triglyceride (ODO) 300 mg, purified egg yolk lecithin (PC-98N) 2.4 g, and glycerin 200 mg are heated with a hot stirrer, and the total volume is 20 mL under a nitrogen stream. While adding pure water, the mixture was emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 30 minutes). 10 g of trehalose as a water-soluble carrier was added and uniformly dissolved in 20 mL of the resulting colorless and cloudy prostaglandin E 1- containing fat emulsion. The obtained trehalose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, so that the non-aqueous composition containing the fat particles holding the desired prostaglandin E 1 (white powder, Moisture content: 10% or less) was obtained. When 300 mg of this white powder was taken into a test tube and 3 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid prostaglandin E 1- containing fat emulsion could be recovered (Table 1, 2).
実施例７：ドセタキセルを保持した脂肪粒子を含む非水系組成物
３０ｍＬビーカーにドセタキセル８０ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）１００ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ）８００ｍｇを採り、ホットスターラーで加温し、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約１５分間）。得られた黄色の薄濁したドセタキセル含有脂肪乳剤２０ｍＬに、水溶性担体としてトレハロース４ｇを加えて均一溶解した。得られたトレハロース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするドセタキセルを保持した脂肪粒子を含む非水系組成物（黄色粉末、水分率：１０％以下）を得た。この白色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、黄色の濁ったドセタキセル含有脂肪乳剤を復元することができた（表１，２参照）。
Example 7: Non-aqueous composition containing fat particles retaining docetaxel Take 80 mg of docetaxel, 100 mg of medium chain fatty acid triglyceride (ODO), 800 mg of purified egg yolk lecithin (PL-100M) in a 30 mL beaker and warm with a hot stirrer. While adding pure water so that the total amount becomes 20 mL, the mixture was emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 15 minutes). To 20 mL of the resulting yellow turbid docetaxel-containing fat emulsion, 4 g of trehalose was added as a water-soluble carrier and uniformly dissolved. The obtained trehalose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). After removing the aqueous phase of the emulsion and returning the inside of the flask to normal pressure using sterile air, a non-aqueous composition containing fat particles retaining the desired docetaxel (yellow powder, moisture content: 10 % Or less). When 150 mg of this white powder was put into a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, a yellow cloudy docetaxel-containing fat emulsion could be restored (see Tables 1 and 2). .
実施例８：タクロリムスを保持した脂肪粒子を含む非水系組成物
３０ｍＬビーカーにタクロリムス４０ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）１ｇ、精製卵黄レシチン（ＰＣ−９８Ｎ）４ｇ、グリセリン２００ｍｇを採り、ホットスターラーで加温し、窒素気流下、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約１５分間）。得られた無色の微濁したタクロリムス含有脂肪乳剤２０ｍＬに、水溶性担体としてマルトース１０ｇを加えて均一溶解した。得られたマルトース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするタクロリムスを保持した脂肪粒子を含む非水系組成物（白色粉末、水分率：１０％以下）を得た。この白色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、無色の薄濁したタクロリムス含有脂肪乳剤を復元することができた（表１，２参照）。
Example 8: Non-aqueous composition containing fat particles retaining tacrolimus Take 40 mg of tacrolimus, 1 g of medium chain fatty acid triglyceride (ODO), 4 g of purified egg yolk lecithin (PC-98N), 200 mg of glycerin and add with a hot stirrer. The mixture was warmed and emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 15 minutes) while adding pure water to a total volume of 20 mL under a nitrogen stream. To 20 mL of the obtained colorless and cloudy tacrolimus-containing fat emulsion, 10 g of maltose as a water-soluble carrier was added and uniformly dissolved. The obtained maltose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). After removing the aqueous phase of the emulsion and returning the inside of the flask to normal pressure using sterile air, a non-aqueous composition containing fat particles retaining the target tacrolimus (white powder, moisture content: 10 % Or less). When 150 mg of this white powder was put into a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, a colorless, turbid tacrolimus-containing fat emulsion could be restored (see Tables 1 and 2). ).
実施例９：シクロスポリンを保持した脂肪粒子を含む非水系組成物（その２）
３０ｍＬビーカーにシクロスポリン４０ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）５００ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ）１ｇ、プロピレングリコール４６０ｍｇを採り、ホットスターラーで加温し、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約１５分間）。得られた黄色の微濁したシクロスポリン含有脂肪乳剤２０ｍＬに、水溶性担体としてマルトース１０ｇを加えて均一溶解した。得られたマルトース溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするシクロスポリンを保持した脂肪粒子を含む非水系組成物（薄黄色粉末、水分率：１０％以下）を得た。この薄黄色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、黄色の薄濁したシクロスポリン含有脂肪乳剤を復元することができた（表１，２参照）。
Example 9: Non-aqueous composition containing fat particles retaining cyclosporine (part 2)
Take 40 mg of cyclosporine, 500 mg of medium-chain fatty acid triglyceride (ODO), 1 g of purified egg yolk lecithin (PL-100M), and 460 mg of propylene glycol in a 30 mL beaker, heat with a hot stirrer, and add pure water so that the total amount becomes 20 mL. While being emulsified with an ultrasonic emulsifier until the emulsion became uniform (about 15 minutes). 10 g of maltose as a water-soluble carrier was added and uniformly dissolved in 20 mL of the resulting yellow turbid cyclosporine-containing fat emulsion. The obtained maltose-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). After removing the aqueous phase of the emulsion and returning the inside of the flask to normal pressure using sterile air, a non-aqueous composition containing light particles retaining the desired cyclosporine (light yellow powder, moisture content: 10% or less). When 150 mg of this pale yellow powder was put in a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, a yellow, turbid cyclosporine-containing fat emulsion could be restored (Tables 1 and 2). reference).
実施例１０：グリチンを保持した脂肪粒子を含む非水系組成物（その１）
３０ｍＬビーカーにグリチン１００ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）５０ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ）２００ｍｇ、ポリソルベート（ポリソルベート８０）８００ｍｇを採り、ホットスターラーで加温し、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約２０分間）。得られた黄色の微濁したグリチン含有脂肪乳剤２０ｍＬに、水溶性担体としてマンニトール４ｇを加えて均一溶解した。得られたマンニトール溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするグリチンを保持した脂肪粒子を含む非水系組成物（黄色粉末、水分率：１０％以下）を得た。この白色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、黄色の薄濁したグリチン含有脂肪乳剤を復元することができた（表１，２参照）。
Example 10: Non-aqueous composition containing fat particles retaining glycine (Part 1)
In a 30 mL beaker, take 100 mg of glycine, 50 mg of medium-chain fatty acid triglyceride (ODO), 200 mg of purified egg yolk lecithin (PL-100M), and 800 mg of polysorbate (polysorbate 80), heat with a hot stirrer, and add pure water so that the total amount becomes 20 mL Was added until the emulsion became uniform (about 20 minutes). To 20 mL of the resulting yellow turbid glycine-containing fat emulsion, 4 g of mannitol as a water-soluble carrier was added and uniformly dissolved. The obtained mannitol-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask and heated under a water bath at 60 ° C. under reduced pressure (evaporation). After removing the aqueous phase of the emulsion and returning the inside of the flask to normal pressure using sterile air, a non-aqueous composition containing fat particles retaining the target glycine (yellow powder, moisture content: 10 % Or less). When 150 mg of this white powder was taken into a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, a yellow turbid glycine-containing fat emulsion could be recovered (see Tables 1 and 2). ).
実施例１１：グリチンを保持した脂肪粒子を含む非水系組成物（その２）
３０ｍＬビーカーにグリチン１００ｍｇ、中鎖脂肪酸トリグリセリド（ＯＤＯ）１００ｍｇ、精製卵黄レシチン（ＰＬ−１００Ｍ）７００ｍｇ、ポリソルベート（ポリソルベート８０）３００ｍｇを採り、ホットスターラーで加温し、全量が２０ｍＬになるように純水を添加しながら超音波乳化機で乳剤が均一になるまで乳化した（約２０分間）。得られた黄色の薄濁したグリチン含有脂肪乳剤２０ｍＬに、水溶性担体としてγ−アミノ酪酸４ｇを加えて均一溶解した。得られたγ−アミノ酪酸溶解脂肪乳剤を、無菌ブース内で、０．２２μｍφのＣＡ膜でろ過滅菌した後、１００ｍＬナスフラスコに入れて、６０℃のウォーターバスで加温下、減圧乾燥（エバポレーション）を行って乳剤の水相を除去してから、無菌空気を用いてフラスコ内を常圧に戻すことで、目的とするグリチンを保持した脂肪粒子を含む非水系組成物（黄色粉末、水分率：１０％以下）を得た。この白色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、黄色の薄濁したグリチン含有脂肪乳剤を復元することができた（表１，２参照）。
Example 11: Non-aqueous composition containing fat particles retaining glycine (part 2)
In a 30 mL beaker, take 100 mg of glycine, 100 mg of medium-chain fatty acid triglyceride (ODO), 700 mg of purified egg yolk lecithin (PL-100M), 300 mg of polysorbate (polysorbate 80), heat with a hot stirrer, and add pure water to a total volume of 20 mL Was added until the emulsion became uniform (about 20 minutes). To 20 mL of the resulting yellow cloudy glycine-containing fat emulsion, 4 g of γ-aminobutyric acid was added as a water-soluble carrier and uniformly dissolved. The obtained γ-aminobutyric acid-dissolved fat emulsion was sterilized by filtration through a 0.22 μmφ CA membrane in a sterile booth, then placed in a 100 mL eggplant flask, and dried under reduced pressure while heating in a 60 ° C. water bath (evaporation). The aqueous phase of the emulsion is removed, and then the inside of the flask is returned to normal pressure using sterile air, whereby a non-aqueous composition containing fat particles retaining the target glycine (yellow powder, moisture) Rate: 10% or less). When 150 mg of this white powder was taken into a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, a yellow turbid glycine-containing fat emulsion could be recovered (see Tables 1 and 2). ).
比較例１：シクロスポリンを含む非水系組成物
精製卵黄レシチン（ＰＬ−１００Ｍ）３００ｍｇを用いること以外は実施例１と同様の操作を行うと、黄色の濁ったシクロスポリン含有脂肪乳剤から、薄黄色粉末であるシクロスポリンを含む非水系組成物が得られた。この薄黄色粉末１５０ｍｇを試験管に採り、純水１．５ｍＬを加えて１分間、手で振とうしたところ、相分離が起こり、シクロスポリン含有脂肪乳剤を復元することができなかった。
Comparative Example 1: Non-aqueous composition containing cyclosporine When the same operation as in Example 1 was performed except that 300 mg of purified egg yolk lecithin (PL-100M) was used, a yellow turbid cyclosporin-containing fat emulsion was obtained as a pale yellow powder. A non-aqueous composition containing some cyclosporine was obtained. When 150 mg of this pale yellow powder was put in a test tube and 1.5 mL of pure water was added and shaken by hand for 1 minute, phase separation occurred and the cyclosporine-containing fat emulsion could not be restored.
なお、濁度の測定は、紫外分光光度計（ＵＶ１８００：島津製作所社製）を用い、サンプルをセル幅が１ｃｍの測定セルに入れて波長λ＝６２０ｎｍで行った（ブランクは水）。サンプルが透けて見え、凝集や沈殿などの変質や異物混入の有無、配合変化を目視で容易に確認できる透明〜半透明領域はＡｂｓ（吸光度）＝０．５以下であるので、この濁度を合否の境界とした。平均粒子径の測定は、光子相関法を用いた粒子径測定装置（ナノサイザーＺＳ：マルバーン社製）を用いて行った。水分率の測定は、加熱乾燥式水分計（ＭＸ−５０：Ａ＆Ｄ社製）またはカールフィッシャー水分計（京都電子社製）を用いて行った。 The turbidity was measured using an ultraviolet spectrophotometer (UV1800: manufactured by Shimadzu Corporation), and the sample was placed in a measurement cell having a cell width of 1 cm at a wavelength λ = 620 nm (blank is water). The sample can be seen through, and the transparent to translucent region where Abs (absorbance) = 0.5 or less can be easily confirmed by visual inspection of alteration such as agglomeration and precipitation, presence or absence of foreign matter, and change in composition. It was set as a pass / fail boundary. The average particle size was measured using a particle size measuring apparatus (Nanosizer ZS: manufactured by Malvern) using a photon correlation method. The moisture content was measured using a heat drying moisture meter (MX-50: manufactured by A & D) or a Karl Fischer moisture meter (manufactured by Kyoto Electronics Co., Ltd.).
製剤例１：シクロスポリン含有含嗽剤用粉末
実施例１で得たシクロスポリンを保持した脂肪粒子を含む非水系組成物（黄色粉末）１４．５ｇ、白糖３．５ｇ、カルメロースナトリウム２．０ｇを小型混合機で攪拌混合することにより、シクロスポリン含有含嗽剤用粉末を得た。
Formulation Example 1: Powder for gargle containing cyclosporine 14.5 g of non-aqueous composition (yellow powder) containing fat particles retaining cyclosporin obtained in Example 1, 3.5 g of sucrose, 2.0 g of carmellose sodium By stirring and mixing with a machine, a cyclosporine-containing powder for gargle was obtained.
製剤例２：プロスタグランジンＥ１含有注射剤用液体
実施例２で得たプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末）それ自体を、プロスタグランジンＥ１含有注射剤用液体とした。
Formulation Example 2: prostaglandin E 1 nonaqueous composition containing fat particles prostaglandin E 1 obtained in injection containing liquid Example 2 was maintained (white powder) per se, containing prostaglandin E 1 A liquid for injection was prepared.
製剤例３：プロスタグランジンＥ１含有軟膏
実施例３で得たプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末）１１．９ｇに、６０℃で加温溶解したマクロゴール軟膏８８．１ｇを攪拌しながら徐々に加え、均一になるまで混合し、冷却固化することにより、プロスタグランジンＥ１含有軟膏を得た。
Formulation Example 3: Prostaglandin E 1- containing ointment Macro dissolved in 11.9 g of non-aqueous composition (white powder) containing fat particles retaining prostaglandin E 1 obtained in Example 3 at 60 ° C. slowly added with stirring a goal ointment 88.1 g, and mixed until uniform, by cooling and solidified to obtain a prostaglandin E 1 containing ointment.
製剤例４：プロスタグランジンＥ１含有ゲル
実施例４で得たプロスタグランジンＥ１を保持した脂肪粒子を含む非水系組成物（白色粉末）１１．９ｇを注射用水２５ｍＬに混合した後、４．５％カルメロースナトリウム溶液７５ｍＬを加えて十分に練合することにより、プロスタグランジンＥ１含有ゲルを得た。
Formulation Example 4: prostaglandin E 1 nonaqueous composition containing fat particles holding the prostaglandin E 1 obtained in containing gel Example 4 was mixed with (white powder) 11.9 g water for injection 25 mL, 4 by thoroughly kneaded by adding .5% carmellose sodium solution 75 mL, to obtain a prostaglandin E 1 containing gel.
製剤例５：シクロスポリン含有経口シロップ剤用粉末
実施例９で得たシクロスポリンを保持した脂肪粒子を含む非水系組成物（薄黄色粉末）３７．６８ｇ、白糖２．２７ｇ、パラオキシ安息香酸メチル３３ｍｇ、パラオキシ安息香酸プロピル１７ｍｇを小型混合機で攪拌混合することにより、シクロスポリン含有経口シロップ剤用粉末を得た。
Formulation Example 5: Powder for cyclosporine-containing oral syrup 37.68 g of non-aqueous composition containing light particles retaining cyclosporin obtained in Example 9 (light yellow powder), 2.27 g of sucrose, 33 mg of methyl parahydroxybenzoate, paraoxy Cyclosporine-containing powder for oral syrup was obtained by stirring and mixing 17 mg of propyl benzoate with a small mixer.
本発明は、特許文献１に記載の薬物を保持した脂肪粒子を含む非水系組成物よりも、脂肪粒子が多くの量の薬物を担持することができるように油脂の含量が多いにもかかわらず、注射剤や点眼剤や点鼻剤や吸入剤などとして用いることができる薬物含有脂肪乳剤を、用時に水系媒体と混合することで調製することができる、薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法を提供することができる点において産業上の利用可能性を有する。 The present invention has a higher fat content so that the fat particles can carry a larger amount of the drug than the non-aqueous composition containing the fat particles holding the drug described in Patent Document 1. Drug-containing fat emulsions that can be used as injections, eye drops, nasal drops, inhalants, etc., can be prepared by mixing with aqueous media at the time of use, non-aqueous systems containing drug-containing fat particles The present invention has industrial applicability in that a composition and a method for producing the composition can be provided.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017070587A JP6957813B2 (en) | 2017-03-31 | 2017-03-31 | Non-aqueous composition containing fat particles holding a drug and a method for producing the same. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017070587A JP6957813B2 (en) | 2017-03-31 | 2017-03-31 | Non-aqueous composition containing fat particles holding a drug and a method for producing the same. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2018172316A true JP2018172316A (en) | 2018-11-08 |
| JP6957813B2 JP6957813B2 (en) | 2021-11-02 |
Family
ID=64108266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017070587A Active JP6957813B2 (en) | 2017-03-31 | 2017-03-31 | Non-aqueous composition containing fat particles holding a drug and a method for producing the same. |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6957813B2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09136836A (en) * | 1995-09-13 | 1997-05-27 | Nippon Shinyaku Co Ltd | Pge1-containing lyophilizing preparation |
| JP2013018737A (en) * | 2011-07-11 | 2013-01-31 | Fujifilm Corp | Freeze-dried preparation and method for producing the same |
| JP2014012737A (en) * | 2013-10-21 | 2014-01-23 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
-
2017
- 2017-03-31 JP JP2017070587A patent/JP6957813B2/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09136836A (en) * | 1995-09-13 | 1997-05-27 | Nippon Shinyaku Co Ltd | Pge1-containing lyophilizing preparation |
| JP2013018737A (en) * | 2011-07-11 | 2013-01-31 | Fujifilm Corp | Freeze-dried preparation and method for producing the same |
| JP2014012737A (en) * | 2013-10-21 | 2014-01-23 | Techno Guard Kk | Nonaqueous composition containing adipose particle holding medicament, and method for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6957813B2 (en) | 2021-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2968011T3 (en) | New cannabinoid formulations | |
| JP5340954B2 (en) | Drug-containing fat emulsion and method for producing the same | |
| US8211948B2 (en) | Lyophilized nanoemulsion | |
| JP5497336B2 (en) | Non-aqueous composition containing drug-containing fat particles and method for producing the same | |
| US20050186230A1 (en) | Elemene compositions containing liquid oil | |
| TW201521719A (en) | A composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same | |
| JPH06157294A (en) | Fine-granular fat preparation | |
| CA2576060A1 (en) | Macrolides containing oil-in-water emulsions | |
| JP7456599B2 (en) | Drug-containing fat emulsion and its manufacturing method | |
| US9950003B2 (en) | Pectin based nanoparticles | |
| US11173127B2 (en) | Potato protein nanoparticles | |
| KR100211772B1 (en) | Lyophilized emulsion containing an active substance | |
| JP5620561B2 (en) | Non-aqueous composition containing drug-containing fat particles and method for producing the same | |
| JP7149611B2 (en) | NON-AQUEOUS COMPOSITION HOLDING DRUG AND METHOD FOR MANUFACTURING SAME | |
| WO2015121378A1 (en) | Liquid phospholipid-containing compositions for the preparation of pharmaceuticals | |
| Wasim et al. | Unlocking the Potential of Oleanolic Acid: Integrating Pharmacological Insights and Advancements in Delivery Systems | |
| JP6815497B2 (en) | A composition having self-emulsifying property, a method for producing the same, a nanoemulsion, and a method for producing the same. | |
| JP6957813B2 (en) | Non-aqueous composition containing fat particles holding a drug and a method for producing the same. | |
| JP7097593B2 (en) | A non-aqueous composition containing fat particles holding a drug and a method for producing the same. | |
| JP2016034918A (en) | Composition for delivery of poorly water-soluble antioxidant substance | |
| RU2605616C1 (en) | Liposomal agent based on ubiquinol and preparation method thereof | |
| CA2911837A1 (en) | Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery | |
| JPH09136836A (en) | Pge1-containing lyophilizing preparation | |
| RU2448731C2 (en) | Phospholipid composition | |
| JP2013018737A (en) | Freeze-dried preparation and method for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200330 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20210129 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210302 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210426 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210602 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210824 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210913 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6957813 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |