JP4459167B2 - メントール含有平滑筋蠕動抑制剤 - Google Patents
メントール含有平滑筋蠕動抑制剤 Download PDFInfo
- Publication number
- JP4459167B2 JP4459167B2 JP2005511070A JP2005511070A JP4459167B2 JP 4459167 B2 JP4459167 B2 JP 4459167B2 JP 2005511070 A JP2005511070 A JP 2005511070A JP 2005511070 A JP2005511070 A JP 2005511070A JP 4459167 B2 JP4459167 B2 JP 4459167B2
- Authority
- JP
- Japan
- Prior art keywords
- menthol
- smooth muscle
- emulsion
- added
- weight
- 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.)
- Expired - Lifetime
Links
- 230000008855 peristalsis Effects 0.000 title claims description 41
- 239000003112 inhibitor Substances 0.000 title claims description 31
- 210000002460 smooth muscle Anatomy 0.000 title claims description 22
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 title description 2
- 229940041616 menthol Drugs 0.000 title description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 title 1
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims abstract description 49
- 239000000839 emulsion Substances 0.000 claims abstract description 32
- 238000002834 transmittance Methods 0.000 claims abstract description 25
- 239000002518 antifoaming agent Substances 0.000 claims abstract description 16
- 239000002245 particle Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims description 31
- 239000004094 surface-active agent Substances 0.000 claims description 18
- -1 polyoxyethylene Polymers 0.000 claims description 17
- 239000003921 oil Substances 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 12
- 239000000194 fatty acid Substances 0.000 claims description 12
- 229930195729 fatty acid Natural products 0.000 claims description 12
- 229930006000 Sucrose Natural products 0.000 claims description 11
- 239000005720 sucrose Substances 0.000 claims description 11
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 235000019438 castor oil Nutrition 0.000 claims description 5
- 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 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000004667 medium chain fatty acids Chemical group 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 50
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 12
- 238000001839 endoscopy Methods 0.000 abstract description 8
- 238000005187 foaming Methods 0.000 abstract description 8
- 239000006260 foam Substances 0.000 abstract description 6
- 230000008602 contraction Effects 0.000 abstract description 4
- 230000002572 peristaltic effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 4
- 230000002401 inhibitory effect Effects 0.000 abstract 2
- 230000016160 smooth muscle contraction Effects 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 31
- 239000004205 dimethyl polysiloxane Substances 0.000 description 23
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 23
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 23
- 239000000377 silicon dioxide Substances 0.000 description 22
- 235000012239 silicon dioxide Nutrition 0.000 description 22
- 239000007788 liquid Substances 0.000 description 18
- 230000002496 gastric effect Effects 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 14
- 239000003925 fat Substances 0.000 description 12
- 235000019197 fats Nutrition 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 9
- 229920000053 polysorbate 80 Polymers 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 8
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 8
- 235000019477 peppermint oil Nutrition 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 239000002562 thickening agent Substances 0.000 description 5
- 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 4
- 230000000694 effects Effects 0.000 description 4
- 238000004945 emulsification Methods 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- HOZOZZFCZRXYEK-GSWUYBTGSA-M butylscopolamine bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CCCC)=CC=CC=C1 HOZOZZFCZRXYEK-GSWUYBTGSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960002725 isoflurane Drugs 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 229950009846 scopolamine butylbromide Drugs 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 244000245214 Mentha canadensis Species 0.000 description 1
- 235000016278 Mentha canadensis Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960002028 atropine sulfate Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940088506 buscopan Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
- A61B1/273—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the upper alimentary canal, e.g. oesophagoscopes, gastroscopes
- A61B1/2736—Gastroscopes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
- A61B1/31—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the rectum, e.g. proctoscopes, sigmoidoscopes, colonoscopes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
従来、消化管内視鏡検査時の抗蠕動薬として抗コリン剤である臭化ブチルスコポラミン(商品名;ブスコパン注射液、日本ベーリンガーインゲルハイム株式会社製)やグルカゴンが用いられてきた。しかしながら臭化ブチルスコポラミンは緑内障、前立腺肥大、不整脈を有する患者には使用禁忌であり、グルカゴンは消化管蠕動抑制効果が非常に弱い等の問題があった。更に臭化ブチルスコポラミンは、静脈投与用又は筋肉内投与用であるため、検査直前又は検査中に行わなければならない。
また、これらの製剤の中には、投与により目の調節障害、眩暈などを起こす可能性が危惧されるものもあり、内視鏡検査時にこれらの製剤を投与された人は、検査終了後も暫くの間は自動車などの運転を避けねばならないなどの問題もあった。
Gastrointestinal Endoscopy,Vol.53,No.2,172〜177(2001)
すなわち本発明は、
(1)製剤全体に対し、L−メントールを0.01〜5.0重量%、界面活性剤を0.1〜10重量%、消泡剤を0.0001〜0.01重量%および油脂を0.1〜10重量%含有し、平均粒子径が100nm未満の乳剤からなるL−メントール含有平滑筋蠕動抑制剤、
(2)光透過率が50%以上である(1)記載の平滑筋蠕動抑制剤、
(3)光透過率が70%以上である(1)記載の平滑筋蠕動抑制剤、
(4)油脂が、中鎖脂肪酸トリグリセライド(MCT)である(1)〜(3)のいずれかに記載の平滑筋蠕動抑制剤、
(5)消泡剤が、シリコン系消泡剤より選ばれた少なくとも一種である請求項(1)〜(4)のいずれかに記載の平滑筋蠕動抑制剤、
(6)界面活性剤がポリオキシエチレン硬化ヒマシ油またはショ糖脂肪酸エステルから選ばれた少なくとも一種である(1)〜(5)のいずれかに記載の平滑筋蠕動抑制剤、
である。
また、本発明でL−メントールは、製剤全体に対して0.01〜5.0重量%使用し、好ましくは0.1〜3.0重量%、更に好ましくは0.3〜1.5重量%使用することができる。
また、本発明において、消泡剤の使用量は、製剤全体に対して通常0.0001〜0.01重量%、好ましくは、0.0005〜0.007重量%、更に好ましくは0.0007〜0.005である。
また、ポリオキシエチレン硬化ヒマシ油に加え、他の医薬品で使用することが可能な界面活性剤、例えば可食性の非イオン界面活性剤、イオン界面活性剤などがあげられ、これらのものを組み合わせて使用しても良い。
このようにして得られる本発明の平滑筋蠕動抑制剤である乳剤の消泡効果については直径33mm、内容30mLのガラス瓶に試料20mLを入れ、この瓶を振とう機(170回/分、ストローク40mm)で1分間振とうした後、泡が消失するまでの時間を測定することにより評価した。本発明の製剤は、泡消失までの時間が3分以内であることが好ましく、30秒以内であることがより好ましく、20秒以内であることが特に好ましい。
本発明の平滑筋蠕動抑制剤である乳剤の平均粒子径は100nm未満で、好ましくは70nm以下、更に好ましくは50nm以下、特に好ましくは30nm以下である。
なお、乳剤の平均粒子径の測定は、10mmセルに試料を2,3滴入れ、蒸留水を加えて試料溶液とし、この液を光散乱光度計(ELS8000、大塚電子株式会社)を用いて行った。
また、本発明の製剤は、光透過率が、50%以上であることが好ましく、特に70%以上であることが好ましい。
光透過率の測定は、10mmセルに試料溶液を入れ、U−2001形ダブルビーム分光光度計(株式会社日立製作所)にて測定波長900nmでおこなった。
i)まず、L−メントールを油脂に溶解させる。溶解は、室温下、又は加温下に行っても良い。次に、水に界面活性剤を加えてホモミキサーなどの攪拌機でよく分散させたものに、得られたL−メントールと油脂の均一な混合物を加え、ホモミキサーなどの攪拌機を用いて良く攪拌する。必要により、さらに超音波処理をしたり、高圧乳化機を用いるなどして製剤の粒子がなるべく均質かつ微細なものとなるようにする。その後、この調製された製剤を115℃、30分間オートクレーブ滅菌する。
ii)その他の方法としては、上記の方法にて製剤を調製し、オートクレーブによる加熱滅菌を行うことなく、60℃以上の温度で一週間程度保存する。
iii)また、その他の方法としては、水に界面活性剤を加え、ホモミキサーなどの攪拌機で分散させた後、メントールと油脂を加えてホモミキサーで約80℃、10分間程度攪拌する。
また、この油脂は、L−メントールの溶剤として使用することができ、L−メントールに対して0.5〜10重量倍、好ましくは、1〜5重量倍使用できる。なお、油脂は、乳剤全体に対しては通常0.1〜5重量%、好ましくは、0.5〜3重量%程度使用される。
また本発明の平滑筋蠕動抑制剤は、L−メントール、油脂および界面活性剤、消泡剤を含む水を攪拌すれば良いが、攪拌時加熱処理するか、攪拌混合した後加熱処理を行うことによって、より安定な製剤とすることができる。
また、加熱温度は、60℃以上であれば良く、好ましくは70℃〜130℃、特に好ましくは80℃〜121℃である。加熱滅菌を通常の脂肪乳剤などの加熱条件(110〜121℃)で行うことにより満足な結果が得られる。
さらに必要により、他の有効成分や、増粘剤、安定化剤、保存剤など適宜添加することができる。
増粘剤の添加量は、増粘剤の種類により異なるが、通常0.01〜5重量%の範囲で選択される。
安定化剤としては、例えばエデト酸ナトリウムなどが、保存剤としては、例えばソルビン酸、塩化ベンザルコニウム、パラベン等があげられ、それぞれの適量を添加することができる。
本発明の製剤は、長期保存後も安定で、たとえば25℃、1ヶ月保存後も乳剤の平均粒子径は100nm以上には増大せず、また光透過率も50%未満に低下することはない。
〔比較例1〕
〔試験例1〕
1分間振とう後、泡が消失するまでの時間を測定した。その結果を平均粒子径、光透過率とともに表1に示した。
〔試験例2〕
試験材料及び試験方法
一昼夜絶食したイヌ(約10Kg)に、麻酔前投薬として硫酸アトロピンを静脈内投与した後、チオペンタールナトリウムを静脈内投与し、麻酔導入した。気管内チューブを挿入・固定した。亜酸化窒素と酸素の混合ガスを吹送した。イソフルラン気化器よりイソフルランを送った。イソフルランの濃度は0.5%より徐々に上昇させ維持麻酔とした。
この麻酔下のイヌの腹部を正中線切開し、胃体部及び幽門部にストレインゲージフォーストランスデューサー(SGT)を、常法に従い固定した。
IMC(食間伝播性収縮運動)終了10分後に、エリスロマイシン6mg/匹を静脈内投与し、胃蠕動運動を誘発させた。その10分後に25℃、1ヶ月保存しておいた実施例7の組成物10mLを、胃カテーテルを通じて胃体部又は幽門部に投与し、蠕動をグラフに記録した。そして、組成物投与後10分毎の波形面積の変化率から蠕動抑制効果を見た。その結果を図1および2に示した。対象として、無処置の場合の波形変化率も求めた。
図1および図2から明らかなように、本発明の蠕動抑制剤はエリスロマイシン投与により誘発させた胃の胃体部および幽門部に噴霧し、無処置のものに比して有意に蠕動を抑制した。また、内視鏡検査時にも蠕動抑制剤の噴霧により泡立ちがなく、局所観察に全く支障がなかった。
Claims (6)
- 製剤全体に対し、L−メントールを0.01〜5.0重量%、界面活性剤を0.1〜10重量%、消泡剤を0.0001〜0.01重量%および油脂を0.1〜10重量%含有し、平均粒子径が100nm未満の乳剤からなるL−メントール含有平滑筋蠕動抑制剤。
- 光透過率が50%以上である請求項1記載の平滑筋蠕動抑制剤。
- 光透過率が70%以上である請求項1記載の平滑筋蠕動抑制剤。
- 油脂が中鎖脂肪酸トリグリセライド(MCT)である請求項1〜3のいずれかに記載の平滑筋蠕動抑制剤。
- 消泡剤が、シリコン系消泡剤より選ばれた少なくとも一種である請求項1〜4のいずれかに記載の平滑筋蠕動抑制剤。
- 界面活性剤がポリオキシエチレン硬化ヒマシ油またはショ糖脂肪酸エステルから選ばれた少なくとも一種である請求項1〜5のいずれかに記載の平滑筋蠕動抑制剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003186493 | 2003-06-30 | ||
JP2003186493 | 2003-06-30 | ||
PCT/JP2004/009096 WO2005000361A1 (ja) | 2003-06-30 | 2004-06-28 | メントール含有製剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2005000361A1 JPWO2005000361A1 (ja) | 2006-10-19 |
JP4459167B2 true JP4459167B2 (ja) | 2010-04-28 |
Family
ID=33549692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2005511070A Expired - Lifetime JP4459167B2 (ja) | 2003-06-30 | 2004-06-28 | メントール含有平滑筋蠕動抑制剤 |
Country Status (9)
Country | Link |
---|---|
US (2) | US20060121067A1 (ja) |
EP (2) | EP2311444B1 (ja) |
JP (1) | JP4459167B2 (ja) |
KR (1) | KR100985131B1 (ja) |
CN (2) | CN102038963B (ja) |
AT (1) | ATE538779T1 (ja) |
ES (2) | ES2379876T3 (ja) |
HK (2) | HK1098683A1 (ja) |
WO (1) | WO2005000361A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2019088274A1 (ja) * | 2017-11-01 | 2020-11-26 | 日本製薬株式会社 | 医薬組成物、医薬組成物の安定化方法、及び医薬組成物の保存安定性を評価する方法 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10441766B2 (en) * | 2007-08-08 | 2019-10-15 | Given Imaging Ltd. | Method for clearing a body lumen environment |
US20090275795A1 (en) * | 2008-05-02 | 2009-11-05 | Zassi Medical Evolutions, Inc. | Continent ostomy system with chemical neuromuscular control |
EP2950823B1 (en) * | 2013-02-01 | 2020-07-01 | Ddrops Company | Liquid menthol compositions |
CN108143717A (zh) * | 2018-02-12 | 2018-06-12 | 周基清 | 一种薄荷脑纳米乳剂及其制备方法 |
CN109011720B (zh) * | 2018-08-27 | 2020-10-02 | 南通市晗泰化工有限公司 | 一种污水处理用高效消泡剂及其制备方法和应用 |
CN110327471B (zh) * | 2019-01-24 | 2021-08-27 | 奥纳斯(北京)医药科技有限公司 | 一种内镜检查解痉消泡剂及其制备方法 |
CN110200906B (zh) * | 2019-07-25 | 2021-07-20 | 奥纳斯(北京)医药科技有限公司 | 一种l-薄荷醇水溶液及其制备方法 |
GB2617639A (en) * | 2020-01-31 | 2023-10-18 | Ghalili Babak | Stabilized menthol and other volatile compound compositions and methods |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3422189A (en) * | 1959-01-02 | 1969-01-14 | Moraine Products | Method and compositions for the treatment of gastro-intestinal disorders |
GB2006011B (en) * | 1977-08-04 | 1982-04-21 | Rhodes J | Carminative preparations containing essential oila their active components |
IT1243439B (it) * | 1990-10-10 | 1994-06-10 | Pulitzer Italiana | Derivato di mentolo ad azione spasmolitica |
JP3286350B2 (ja) * | 1992-08-07 | 2002-05-27 | 花王株式会社 | 透明水性組成物 |
CA2222407A1 (en) * | 1995-06-05 | 1996-12-12 | Ira D. Hill | Oral care ultramulsion based products |
JP3524717B2 (ja) * | 1997-06-13 | 2004-05-10 | 株式会社資生堂 | 油中水型乳化組成物及びこれを用いた乳化化粧料 |
US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
WO2003041632A2 (en) * | 2001-11-14 | 2003-05-22 | Texas Tech University | Eutectic-based self-nanoemulsified drug delivery system |
JP2003292450A (ja) * | 2002-02-01 | 2003-10-15 | Naoki Hiki | 胃蠕動抑制剤 |
JP4526120B2 (ja) * | 2002-05-22 | 2010-08-18 | 日本製薬株式会社 | L−メントール水中油型乳剤 |
WO2003097026A1 (fr) * | 2002-05-22 | 2003-11-27 | Nihon Pharmaceutical Co., Ltd. | Inhibiteur du peristaltisme de muscles lisses |
US6897195B2 (en) * | 2002-07-24 | 2005-05-24 | Nanjing Zhongshi Chemical Co. | Composition of menthol and menthyl lactate, its preparation method and its applications as a cooling agent |
-
2004
- 2004-06-28 AT AT04746565T patent/ATE538779T1/de active
- 2004-06-28 EP EP11151652A patent/EP2311444B1/en not_active Expired - Lifetime
- 2004-06-28 CN CN2010106116906A patent/CN102038963B/zh not_active Expired - Lifetime
- 2004-06-28 CN CN2004800185892A patent/CN1893982B/zh not_active Expired - Lifetime
- 2004-06-28 US US10/559,731 patent/US20060121067A1/en not_active Abandoned
- 2004-06-28 WO PCT/JP2004/009096 patent/WO2005000361A1/ja active Search and Examination
- 2004-06-28 EP EP04746565A patent/EP1640022B1/en not_active Expired - Lifetime
- 2004-06-28 JP JP2005511070A patent/JP4459167B2/ja not_active Expired - Lifetime
- 2004-06-28 KR KR1020057025392A patent/KR100985131B1/ko active IP Right Grant
- 2004-06-28 ES ES04746565T patent/ES2379876T3/es not_active Expired - Lifetime
- 2004-06-28 ES ES11151652T patent/ES2390162T3/es not_active Expired - Lifetime
-
2007
- 2007-05-15 HK HK07105126.9A patent/HK1098683A1/xx unknown
-
2009
- 2009-07-27 US US12/458,876 patent/US7993635B2/en not_active Expired - Lifetime
-
2011
- 2011-09-15 HK HK11109753.5A patent/HK1155640A1/xx unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2019088274A1 (ja) * | 2017-11-01 | 2020-11-26 | 日本製薬株式会社 | 医薬組成物、医薬組成物の安定化方法、及び医薬組成物の保存安定性を評価する方法 |
JP7300995B2 (ja) | 2017-11-01 | 2023-06-30 | 武田薬品工業株式会社 | 医薬組成物、医薬組成物の安定化方法、及び医薬組成物の保存安定性を評価する方法 |
Also Published As
Publication number | Publication date |
---|---|
ES2390162T3 (es) | 2012-11-07 |
ES2379876T3 (es) | 2012-05-04 |
KR20060032604A (ko) | 2006-04-17 |
HK1098683A1 (en) | 2007-07-27 |
HK1155640A1 (en) | 2012-05-25 |
JPWO2005000361A1 (ja) | 2006-10-19 |
KR100985131B1 (ko) | 2010-10-05 |
EP1640022B1 (en) | 2011-12-28 |
US7993635B2 (en) | 2011-08-09 |
CN1893982B (zh) | 2013-02-13 |
WO2005000361A1 (ja) | 2005-01-06 |
ATE538779T1 (de) | 2012-01-15 |
CN102038963A (zh) | 2011-05-04 |
US20090292028A1 (en) | 2009-11-26 |
EP2311444B1 (en) | 2012-06-27 |
EP1640022A1 (en) | 2006-03-29 |
EP2311444A1 (en) | 2011-04-20 |
CN1893982A (zh) | 2007-01-10 |
EP1640022A4 (en) | 2008-08-06 |
CN102038963B (zh) | 2013-09-11 |
US20060121067A1 (en) | 2006-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7993635B2 (en) | Menthol-containing formulation | |
US11304913B2 (en) | Analgesic compositions | |
JP5171262B2 (ja) | ソマトスタチン類似体製剤 | |
TW201138782A (en) | Low-oil pharmaceutical emulsion compositions comprising progestogen | |
JP5607083B2 (ja) | リルゾール水性懸濁液 | |
JP2002510279A (ja) | 徐放性水性エマルション | |
US8367738B2 (en) | Smooth muscle contraction inhibitors | |
JP4526120B2 (ja) | L−メントール水中油型乳剤 | |
JP7300995B2 (ja) | 医薬組成物、医薬組成物の安定化方法、及び医薬組成物の保存安定性を評価する方法 | |
JP4493003B2 (ja) | L−メントール含有低温安定性平滑筋蠕動抑制製剤 | |
EP2952207B1 (en) | Oil based pharmaceutical compositions for oral administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070405 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20091009 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20091019 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20091117 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091120 |
|
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: 20100205 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100209 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4459167 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140219 Year of fee payment: 4 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |