JP4879332B2 - 神経障害性疼痛抑制薬 - Google Patents
神経障害性疼痛抑制薬 Download PDFInfo
- Publication number
- JP4879332B2 JP4879332B2 JP2010034766A JP2010034766A JP4879332B2 JP 4879332 B2 JP4879332 B2 JP 4879332B2 JP 2010034766 A JP2010034766 A JP 2010034766A JP 2010034766 A JP2010034766 A JP 2010034766A JP 4879332 B2 JP4879332 B2 JP 4879332B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- neuropathic pain
- ascorbic acid
- ascorbyl phosphate
- salt
- 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.)
- Active
Links
- 208000004296 neuralgia Diseases 0.000 title claims description 42
- 208000021722 neuropathic pain Diseases 0.000 title claims description 42
- 239000003112 inhibitor Substances 0.000 title description 10
- -1 L-ascorbic acid-2-phosphate ester Chemical class 0.000 claims description 93
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 8
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims 1
- 229930064664 L-arginine Natural products 0.000 claims 1
- 235000014852 L-arginine Nutrition 0.000 claims 1
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 claims 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 claims 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000003860 topical agent Substances 0.000 claims 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 48
- 239000002674 ointment Substances 0.000 description 32
- 239000011575 calcium Substances 0.000 description 28
- 229960005070 ascorbic acid Drugs 0.000 description 24
- 208000002193 Pain Diseases 0.000 description 22
- 239000011668 ascorbic acid Substances 0.000 description 20
- 235000010323 ascorbic acid Nutrition 0.000 description 20
- 230000036407 pain Effects 0.000 description 20
- 241000700159 Rattus Species 0.000 description 17
- 229930012538 Paclitaxel Natural products 0.000 description 16
- 229960001592 paclitaxel Drugs 0.000 description 16
- 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 16
- 150000000996 L-ascorbic acids Chemical class 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 15
- 230000003040 nociceptive effect Effects 0.000 description 12
- 210000003141 lower extremity Anatomy 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 5
- 208000035154 Hyperesthesia Diseases 0.000 description 5
- 208000000114 Pain Threshold Diseases 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 239000000203 mixture Chemical group 0.000 description 5
- 230000037040 pain threshold Effects 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000002211 L-ascorbic acid Substances 0.000 description 4
- 235000000069 L-ascorbic acid Nutrition 0.000 description 4
- 238000010162 Tukey test Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 229940071097 ascorbyl phosphate Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 229940108949 paclitaxel injection Drugs 0.000 description 2
- 230000008058 pain sensation Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DBSABEYSGXPBTA-RXSVEWSESA-N (2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;phosphoric acid Chemical compound OP(O)(O)=O.OC[C@H](O)[C@H]1OC(=O)C(O)=C1O DBSABEYSGXPBTA-RXSVEWSESA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 101150028074 2 gene Proteins 0.000 description 1
- POXUQBFHDHCZAD-UHFFFAOYSA-N 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxy-2h-furan-5-one Chemical compound O1C(C)(C)OCC1C1C(O)=C(O)C(=O)O1 POXUQBFHDHCZAD-UHFFFAOYSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 240000008574 Capsicum frutescens Species 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000004404 Intractable Pain Diseases 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
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 239000001390 capsicum minimum Substances 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002009 diols Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- HYHGLHONPBPZGJ-YCWPWOODSA-L disodium;[(2r)-2-[(1s)-1,2-dihydroxyethyl]-3-hydroxy-5-oxo-2h-furan-4-yl] phosphate Chemical compound [Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP(O)([O-])=O)=C1[O-] HYHGLHONPBPZGJ-YCWPWOODSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229940090016 tegretol Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
しかし、アスコルビン酸は、熱や酸化に対して非常に不安定であり、不活性化されたり分解されたりしやすいため、必ずしも十分な生理作用が得られない場合がある。
また、リン酸エステル部が分岐したアルキル基を有するL−アスコルビン酸−2−リン酸エステルまたはその塩からなるアスコルビン酸誘導体(後述する化1参照)は、美白化粧品として生体浸透性が好ましいことが知られている(特許文献3)。
また、上記数値から換算すれば、この発明に係るアスコルビン酸誘導体の有効投与(塗布)量は、成人(約60kg)に対し有効濃度として0.1〜20重量%程度を含有する外用剤とし、これを症状に応じて適宜な回数だけ塗布して用いることができ、例えば1日に1〜10回、通常5〜6回(数回)程度の投与回数は好ましい。
なお、この発明に係る神経障害性疼痛抑制薬は、皮膚外用に向けたものであり、特にクリーム製剤または液状の形をとることが好ましい。
有効成分として用いる薬剤として、両親媒性アスコルビン酸(2−[2−(1,3,3−トリメチル−n−ブチル)−5,7,7−トリメチル−n−オクチル]−L−アスコルビルホスフェート)(HBCサイエンス社製:disodium isostearyl 2−0−1−ascorbyl phosphate)(以下、DI−VCPと略称する。)、硫化水素ナトリウム(キシダ化学社製:NaHS)またはアスコルビン酸(Sigma Ltd. St Louis, MO, USA)を使用して以下の製剤を行なった。
5%(w/w)セタノール(キシダ化学社製)含有ソルベース(明治薬品社製)1g当り、0.8または2.4mM DI−VCP水溶液100μLを加えて軟膏とした。同様に2.4mMアスコルビン酸水溶液を用いた軟膏剤も作製した。
機械的侵害受容閾値の測定は、Randall-Selitto法により行った。圧刺激鎮痛効果測定装置(MK-300, 室町機械, 東京)を使用し、ラットの右後肢に30g/sで機械的圧刺激を与え、もがき反応もしくは鳴き声を指標として機械的侵害受容閾値を測定した。また、後肢の損傷を防ぐため、加える圧刺激は500gを限度とした。得られた結果は薬物投与前またはパクリタキセル投与開始前の機械的侵害受容閾値を100%とし、以下の数式により算出した値で示した。
機械的侵害受容閾値AIC(% baseline)={得られた閾値/(NaHS投与前またはパクリタキセル投与開始前の閾値)}×100
パクリタキセル(以下、PTXと略記する。)誘起神経障害性疼痛モデルの作製はPolomanoら(PolomanoらPain 2001;94:293-304)の方法に従って行った。パクリタキセル投与前にベースライン閾値を測定後、パクリタキセル注射液(ブリストル・マイヤーズ社製)6mg/mLを生理食塩水で3倍希釈し、2mg/kgの用量で投与初日を0日目とし、続いて2、4および6日目の、計4回ラットに腹腔内投与した(合計8mg/kg)。各投与前および10、14日目にも痛覚閾値を測定して経過観察を行い、14日目以降に痛覚閾値の低下を確認した後、以降の実験に使用した。コントロール群にはパクリタキセル注射液の溶媒 (Cremophor EL (polyethoxylated castor oil)/ethanol; 50/50%)を3倍希釈して同様のスケジュールで投与した。
NaHS誘起神経障害性疼痛実験では、DI−VCP軟膏またはアスコルビン酸軟膏を60nmol/pawの用量で塗布し、その90分後にNaHSを1nmol/paw (10μM溶液,100 μL/paw)の用量でラットの足底皮下へ投与した。
[実施例1および比較例1について]
図1、2は、NaHS足底皮下投与により誘起される痛覚過敏に対するアスコルビン酸軟膏およびDI−VCP軟膏塗布の効果を示している。NaHS1nmol/pawおよび生理食塩水は投与容量100μL/pawで足底皮下投与した。disodium isostearyl 2-O-l-ascorbyl phosphate(DI−VCP)含有軟膏またはアスコルビン酸含有軟膏は、60nmol/pawの用量でNaHS投与90分前にラット右後肢表面に塗布した(塗布量250mg/paw)。図中の各折れ線は6−8例の平均値±標準誤差を示し、*および**は生理食塩水含有軟膏塗布後に生理食塩水足底内投与群に対する有意差を示す(P<0.05,P<0.01,Tukey法)。##は生理食塩水含有軟膏塗布後にNaHS投与群に対する有意差を示す(P<0.01,Tukey法)。
図3、4は、パクリタキセル誘起神経障害性疼痛に対するアスコルビン酸軟膏塗布の影響を示している。パクリタキセルは、投与初日を0日目として、その後2、4および6日目に2mg/kgの用量で腹腔内投与した。パクリタキセル投与14日後以降のラットに対し、アスコルビン酸含有軟膏を60nmol/pawの用量でラット右後肢表面に塗布した(塗布量250mg/paw)。図中の各折れ線は5−7例の平均値±標準誤差を示し、*および**はコントロールにおける生理食塩水含有軟膏塗布群に対する有意差を示す(P<0.05, P<0.01,Tukey法)。
アスコルビン酸軟膏を60nmol/pawの用量になるように、パクリタキセル処置ラットの片側後肢に塗布したところ、処置側(図3)、反対側(図4)ともに痛覚閾値に影響は認められなかった。
図5、6は、パクリタキセル誘起神経障害性疼痛に対するDI−VCP軟膏塗布の効果を示している。パクリタキセルは、投与初日を0日目として、その後2、4および6日目に2mg/kgの用量で腹腔内投与した。パクリタキセル投与14日後以降のラットに対し、アスコルビン酸含有軟膏を60nmol/pawの用量でラット右後肢表面に塗布した(塗布量250mg/paw)。図中の各折れ線は5−7例の平均値±標準誤差を示し、*および**はコントロールにおける生理食塩水含有軟膏塗布群に対する有意差を示し、#および##はパクリタキセル投与群の生理食塩水塗布群に対する有意差を示す(P<0.05,P<0.01,Tukey法)。
[処方例1](外用軟膏)
2−[2−(1,3,3−トリメチル−n−ブチル)−5,7,7−トリメチル−n−オクチル]−L−アスコルビルホスフェート(DI−VCP) 2.0
ワセリン 25.0
ステアルルアルコール 20.0
プロピレングリコール 12.0
ポリオキシエチレン硬化ヒマシ油 4.0
モノステアリン酸グリセリン 1.0
パラオキシ安息香酸メチル 0.1
パラオキシ安息香酸プロピル 適量
精製水 残余
2−ビス(2オクチルドデシル)−L−アスコルビルホスフェート 5.0
グリセリン 15.0
エタノール 5.0
カルボキシビニルポリマー 1.5
水酸化ナトリウム 0.2
防腐剤 適量
製水 残余
2−(2−ヘキシルデシル)−L−アスコルビルホスフェート 5.0
グリセリン 10.0
プロピレングリコール 5.0
防腐剤 適量
精製水 残余
Claims (5)
- 化1の式中のR1またはR2が、2位で分岐した炭素数4〜30のアルキル基である請求項1に記載の神経障害性疼痛抑制性の皮膚外用剤。
- 分枝したアルキル基が、2−ヘプチルウンデシル基、2−オクチルデシル基、2−オクチルドデシル基、2−ヘキシルデシル基、2−ヘキシルドデシル基、2−イソヘプチルイソウンデシル基、16−メチルヘプタデシル基または2−(1,3,3−トリメチル−n−ブチル)−5,7,7−トリメチル−n−オクチル基である請求項1に記載の神経障害性疼痛抑制性の皮膚外用剤。
- 塩が、L−アスコルビン酸−2−リン酸エステルのナトリウム塩、カリウム塩、マグネシウム塩もしくはカルシウム塩からなる無機塩である請求項1〜3のいずれかに記載の神経障害性疼痛抑制性の皮膚外用剤。
- 塩が、L−アルギニン、L−リジン、グアニンもしくは塩基性有機アミン類からなる有機塩である請求項1〜3のいずれかに記載の神経障害性疼痛抑制性の皮膚外用剤。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010034766A JP4879332B2 (ja) | 2010-02-19 | 2010-02-19 | 神経障害性疼痛抑制薬 |
PCT/JP2011/052366 WO2011102243A1 (ja) | 2010-02-19 | 2011-02-04 | 神経障害性疼痛抑制薬 |
EP11744531.2A EP2537519B1 (en) | 2010-02-19 | 2011-02-04 | Neuropathic pain alleviating agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010034766A JP4879332B2 (ja) | 2010-02-19 | 2010-02-19 | 神経障害性疼痛抑制薬 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2011168549A JP2011168549A (ja) | 2011-09-01 |
JP4879332B2 true JP4879332B2 (ja) | 2012-02-22 |
Family
ID=44482832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010034766A Active JP4879332B2 (ja) | 2010-02-19 | 2010-02-19 | 神経障害性疼痛抑制薬 |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2537519B1 (ja) |
JP (1) | JP4879332B2 (ja) |
WO (1) | WO2011102243A1 (ja) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5218191B1 (ja) | 1967-10-31 | 1977-05-20 | ||
JP2926412B2 (ja) | 1989-05-19 | 1999-07-28 | 株式会社林原生物化学研究所 | α―グリコシル―L―アスコルビン酸とその製造方法並びに用途 |
JP3827195B2 (ja) * | 1998-08-10 | 2006-09-27 | 株式会社日本ハイポックス | 消炎鎮痛剤 |
JP4190539B2 (ja) * | 2004-03-25 | 2008-12-03 | 東洋ビューティ株式会社 | アスコルビン酸誘導体および美白化粧料 |
-
2010
- 2010-02-19 JP JP2010034766A patent/JP4879332B2/ja active Active
-
2011
- 2011-02-04 EP EP11744531.2A patent/EP2537519B1/en active Active
- 2011-02-04 WO PCT/JP2011/052366 patent/WO2011102243A1/ja active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2011102243A1 (ja) | 2011-08-25 |
EP2537519A4 (en) | 2013-08-07 |
EP2537519A1 (en) | 2012-12-26 |
JP2011168549A (ja) | 2011-09-01 |
EP2537519B1 (en) | 2017-04-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11357792B2 (en) | Method of administration and treatment | |
CO6241170A2 (es) | Administracion de oligonucleotidos antisentido complementarios a la apolipoproteina b humana | |
US20020187943A1 (en) | Bioavailable composition of natural and synthetic hca | |
CN1309552A (zh) | 含有海水的药物、保健和/或化妆组合物及其应用 | |
KR20200042440A (ko) | 고형종양, 과다색소침착 및 통풍의 전이를 억제하기 위한 완충제의 비경구 비전신적 투여 | |
ES2585253T3 (es) | Composiciones para prevenir la pérdida de cabello o para estimular el crecimiento del cabello | |
JP2024010082A (ja) | オートファジーおよびリポファジーを調節するためのβ-ヒドロキシ-β-メチルブチレート(HMB)の組成物および使用方法 | |
JP4411414B2 (ja) | 糖尿病性神経障害の治療に対する組成物及びその方法 | |
JP2020506959A (ja) | エダラボンの経口又は胃内投与を含む処置 | |
JP2016027036A (ja) | 外用組成物、化粧料、経皮吸収促進用組成物、外用組成物における有効成分の経皮吸収性を高める方法、経皮投与型医薬及び点眼用組成物 | |
JP6775419B2 (ja) | 末梢神経障害の予防又は改善用組成物 | |
ES2950096T3 (es) | Método para aliviar los síntomas del síndrome premenstrual | |
CN110520107A (zh) | 用于局部肠递送的五氮杂大环状环配合物 | |
US11406609B2 (en) | Compositions and methods of use of β-hydroxy-β-methylbutyrate (HMB) for modulating autophagy and lipophagy | |
JP4879332B2 (ja) | 神経障害性疼痛抑制薬 | |
KR20130097121A (ko) | 암 전이를 치료하기 위한 방법 및 조성물 | |
RU2240131C1 (ru) | Средство "артровит" для профилактики и лечения артритов и артрозов | |
CN109640974A (zh) | 多咖啡酰基奎尼酸的酰胺衍生物、其制备方法和用途 | |
EP3863596A1 (en) | Compositions and methods for treating and preventing leber's hereditary optic neuropathy | |
TR201004720T1 (tr) | Majör depresif bozukluğun tedavisi için o-desmetil venlafaksin | |
EP3265089B1 (en) | New use of the isoquinoline derivative salsolinol for diabetic wound healing | |
JP6294773B2 (ja) | 口腔粘膜疾患の予防または治療用経口製剤 | |
JP5023323B2 (ja) | アクアポリン5の発現亢進剤 | |
RU2715679C1 (ru) | Способ снижения прооксидантного действия антиконвульсантов в эксперименте | |
KR20120102214A (ko) | 한방복합 생약 소염 진통 외용제 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20110329 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110520 |
|
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: 20111115 |
|
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: 20111129 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4879332 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: 20141209 Year of fee payment: 3 |
|
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 |
|
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 |