JPH11302197A - Hyaluronic acid-stabilizing composition - Google Patents
Hyaluronic acid-stabilizing compositionInfo
- Publication number
- JPH11302197A JPH11302197A JP12271598A JP12271598A JPH11302197A JP H11302197 A JPH11302197 A JP H11302197A JP 12271598 A JP12271598 A JP 12271598A JP 12271598 A JP12271598 A JP 12271598A JP H11302197 A JPH11302197 A JP H11302197A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- composition
- hyaluronic acid
- pharmaceutically acceptable
- acceptable 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 118
- 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 claims abstract description 82
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 80
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 80
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000126 substance Substances 0.000 claims abstract description 33
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 28
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 17
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000004471 Glycine Substances 0.000 claims abstract description 13
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 13
- 239000004220 glutamic acid Substances 0.000 claims abstract description 13
- 239000004310 lactic acid Substances 0.000 claims abstract description 13
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 13
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 12
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 12
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001630 malic acid Substances 0.000 claims abstract description 12
- 235000011090 malic acid Nutrition 0.000 claims abstract description 12
- 239000011975 tartaric acid Substances 0.000 claims abstract description 12
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 12
- 235000011054 acetic acid Nutrition 0.000 claims abstract description 11
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 11
- 238000003860 storage Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 14
- 239000003112 inhibitor Substances 0.000 claims description 10
- 239000002158 endotoxin Substances 0.000 claims description 8
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 5
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 5
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 5
- 230000007774 longterm Effects 0.000 abstract description 11
- 238000004321 preservation Methods 0.000 abstract description 7
- 239000000654 additive Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 24
- 230000000996 additive effect Effects 0.000 description 15
- 229960002989 glutamic acid Drugs 0.000 description 11
- 229960002449 glycine Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- -1 specifically Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 230000003204 osmotic effect Effects 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 2
- 241000561734 Celosia cristata Species 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000001520 comb Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000003946 cyclohexylamines Chemical class 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 229920005646 polycarboxylate Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 235000019265 sodium DL-malate Nutrition 0.000 description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
- 235000011088 sodium lactate Nutrition 0.000 description 2
- 229940005581 sodium lactate Drugs 0.000 description 2
- 239000001394 sodium malate Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229940074404 sodium succinate Drugs 0.000 description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 2
- 239000001433 sodium tartrate Substances 0.000 description 2
- 229960002167 sodium tartrate Drugs 0.000 description 2
- 235000011004 sodium tartrates Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241001529572 Chaceon affinis Species 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 229920000045 Dermatan sulfate Polymers 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920000288 Keratan sulfate Polymers 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
- 241000239218 Limulus Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution 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
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 description 1
- 229940051593 dermatan sulfate Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、ヒアルロン酸を含
有する組成物に関し、より詳細には、組成物の溶液を長
期保存してもｐＨ変化及び分子量低下が極めて少ないヒ
アルロン酸含有組成物に関する。また本発明は、ヒアル
ロン酸含有溶液のｐＨ変化抑制剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition containing hyaluronic acid, and more particularly, to a hyaluronic acid-containing composition which undergoes very little change in pH and molecular weight even when a solution of the composition is stored for a long period of time. The present invention also relates to a pH change inhibitor for the hyaluronic acid-containing solution.
【０００２】[0002]
【従来の技術】本発明に最も近い先行技術について説明
する。2. Description of the Related Art The prior art closest to the present invention will be described.
【０００３】特開平８−１０４６４２号公報には、ヒア
ルロン酸溶液にクエン酸および／またはクエン酸塩が添
加されてなるヒアルロン酸ナトリウム注射液用安定化組
成物が記載されている。[0003] JP-A-8-104462 discloses a stabilized composition for injection of sodium hyaluronate obtained by adding citric acid and / or citrate to a hyaluronic acid solution.
【０００４】特開平９−２２７３８５号公報には、(A)
ヒアルロン酸および／またはヒアルロン酸塩、および
(B)ポリカルボン酸およびその塩、ポリオール、糖質並
びにアミノ酸およびその塩よりなる群から選ばれる少な
くとも１種の粘度安定化剤を含有してなり、且つ３７℃
における粘度が２,０００センチポアズ未満である水溶
液からなることを特徴とする眼手術補助剤が記載されて
いる。ポリカルボン酸およびその塩として具体的には、
クエン酸ナトリウムおよびカルボキシビニルポリマーが
記載されている。Japanese Patent Application Laid-Open No. 9-227385 discloses (A)
Hyaluronic acid and / or hyaluronate, and
(B) at least one viscosity stabilizer selected from the group consisting of polycarboxylic acids and salts thereof, polyols, saccharides, and amino acids and salts thereof, and
An ophthalmic surgery adjuvant characterized by comprising an aqueous solution having a viscosity of less than 2,000 centipoise at. Specifically, as the polycarboxylic acid and a salt thereof,
Sodium citrate and carboxyvinyl polymers have been described.
【０００５】特開平１０−７２３７６号公報には、(A)
ヒアルロン酸およびヒアルロン酸塩よりなる群から選ば
れる少なくとも一種の第１の化合物、並びに(B)粘度安
定化剤として、ポリオール、ポリカルボン酸、ポリカル
ボン酸塩および糖質よりなる群から選ばれる少なくとも
一種の第２の化合物を含有してなり、粘度が２〜２００
０mm2／Ｓであることを特徴とする点眼水溶液が記載さ
れている。ポリカルボン酸およびその塩として具体的に
は、クエン酸ナトリウムおよびカルボキシビニルポリマ
ーが記載されている。ポリカルボン酸として具体的に
は、クエン酸およびカルボキシビニルポリマーが記載さ
れている。またポリカルボン酸塩として具体的には、ク
エン酸塩およびエデト酸二ナトリウムが記載されてい
る。[0005] JP-A-10-72376 discloses (A)
At least one first compound selected from the group consisting of hyaluronic acid and hyaluronic acid salt, and (B) as a viscosity stabilizer, at least one selected from the group consisting of polyols, polycarboxylic acids, polycarboxylates and carbohydrates It contains a second compound and has a viscosity of 2 to 200.
An aqueous ophthalmic solution characterized by 0 mm 2 / S is described. Sodium citrate and carboxyvinyl polymers are specifically described as polycarboxylic acids and salts thereof. Specifically, citric acid and carboxyvinyl polymers are described as polycarboxylic acids. In addition, citrate and disodium edetate are specifically described as polycarboxylates.
【０００６】上記先行技術は、いずれもヒアルロン酸の
安定化（低分子化の抑制）を主目的としているが、ｐＨ
変化を抑制するという技術思想については記載もないし
示唆もない。[0006] The above prior arts are mainly aimed at stabilizing hyaluronic acid (suppressing the reduction of molecular weight).
There is no description or suggestion about the technical concept of suppressing change.
【０００７】また酒石酸、コハク酸、酢酸、グルタミン
酸、グリシン、リンゴ酸及び乳酸からなる物質群から選
ばれる１又は２以上の物質またはその薬学的に許容され
る塩をヒアルロン酸に共存させた組成物や、これらの物
質をヒアルロン酸含有組成物のｐＨ変化抑制剤として用
いることについて記載も示唆もない。Also, a composition comprising one or more substances selected from the substance group consisting of tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid and lactic acid, or a pharmaceutically acceptable salt thereof, in the presence of hyaluronic acid. There is no description or suggestion that these substances are used as a pH change inhibitor in a hyaluronic acid-containing composition.
【０００８】[0008]
【発明が解決しようとする課題】特に医薬品としてヒア
ルロン酸製剤を提供するためには、ヒアルロン酸製剤の
長期保存による種々の変化を極力抑え、ヒアルロン酸製
剤製造時の物性を極力維持せしめることが望まれる。In particular, in order to provide a hyaluronic acid preparation as a drug, it is desirable to minimize various changes due to long-term storage of the hyaluronic acid preparation and to maintain the physical properties during production of the hyaluronic acid preparation as much as possible. It is.
【０００９】第１に、ヒアルロン酸は長期保存によって
低分子化するため、その低分子化が抑制された安定なヒ
アルロン酸製剤を提供することが望まれてきており、こ
れについては前記したような先行技術が存在する。加え
て、長期保存によるｐＨの変化が極めて少ないヒアルロ
ン酸製剤が提供できれば、長期保存後であってもヒアル
ロン酸製剤製造時の物性にさらに近い状態でヒアルロン
酸製剤が提供できる。First, since hyaluronic acid is reduced in molecular weight by long-term storage, it has been desired to provide a stable hyaluronic acid preparation in which the reduction in molecular weight is suppressed, as described above. Prior art exists. In addition, if a hyaluronic acid preparation having a very small change in pH due to long-term storage can be provided, the hyaluronic acid preparation can be provided in a state closer to the physical properties at the time of manufacturing the hyaluronic acid preparation even after long-term storage.
【００１０】特に低濃度のヒアルロン酸溶液製剤を提供
し保存する場合においては、低分子化等の物性変化が非
常に起こりやすいため、ヒアルロン酸溶液製剤製造時の
物性に極力近い状態のまま保持せしめることが特に必要
とされる。In particular, when providing and storing a low-concentration hyaluronic acid solution preparation, changes in physical properties such as a reduction in molecular weight are very likely to occur. It is especially needed.
【００１１】本発明の目的は、長期保存してもヒアルロ
ン酸が安定に保持、すなわち低分子化が極力抑制され、
かつｐＨ変化が極めて少ないヒアルロン酸含有組成物を
提供することである。An object of the present invention is to maintain hyaluronic acid stably even when stored for a long period of time, that is, to minimize the reduction of molecular weight,
Another object of the present invention is to provide a hyaluronic acid-containing composition having a very small change in pH.
【００１２】[0012]
【課題を解決するための手段】本発明者らは、ヒアルロ
ン酸含有組成物に共存せしめる物質について鋭意検討を
行った。ヒアルロン酸にクエン酸を共存させた公知の組
成物では、長期保存によるヒアルロン酸の低分子化は抑
制されるものの、ｐＨは比較的大きく変化することが示
された。Means for Solving the Problems The present inventors have intensively studied substances which can coexist in a hyaluronic acid-containing composition. In the known composition in which citric acid was coexisted with hyaluronic acid, it was shown that the lowering of the molecular weight of hyaluronic acid due to long-term storage was suppressed, but the pH changed relatively largely.
【００１３】さらに検討を行った結果、ヒアルロン酸に
添加剤、具体的には酒石酸、コハク酸、酢酸、グルタミ
ン酸、グリシン、リンゴ酸又は乳酸を共存させると、長
期保存によるヒアルロン酸の低分子化が抑制されるだけ
でなく、ｐＨの変化も顕著に抑制されることを見いだ
し、本発明を完成するに至った。As a result of further study, it was found that when an additive, specifically, tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid or lactic acid coexists with hyaluronic acid, the molecular weight of hyaluronic acid is reduced by long-term storage. The inventors have found that not only the suppression but also the change in pH is remarkably suppressed, and the present invention has been completed.
【００１４】すなわち本発明は、下記のヒアルロン酸含
有組成物（以下、単に「本発明組成物」という）であ
る。That is, the present invention relates to the following hyaluronic acid-containing composition (hereinafter, simply referred to as “the composition of the present invention”).
【００１５】(A)ヒアルロン酸またはその薬学的に許容
される塩と、下記物質群から選ばれる１又は２以上の物
質またはその薬学的に許容される塩とを含有するヒアル
ロン酸含有組成物。 (物質群)酒石酸、コハク酸、酢酸、グルタミン酸、グリ
シン、リンゴ酸、乳酸(A) A hyaluronic acid-containing composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, and one or more substances selected from the following substance group or a pharmaceutically acceptable salt thereof. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
【００１６】(B)下記の性質を有する溶液組成物である
上記(A)記載のヒアルロン酸含有組成物。 (性質) (1)組成物のｐＨが６〜８である。 (2)組成物を遮光かつ６０℃の条件下で２週間保存した
ときに、下記の性質を有する。 (a)保存開始時のｐＨを基準としたとき、保存後のｐＨ
の変化が±０．１以下である。 (b)保存開始時のヒアルロン酸またはその薬学的に許容
される塩の重量平均分子量を１００％とした時、保存後
の当該重量平均分子量の相対値が７０％以上である。(B) The hyaluronic acid-containing composition according to the above (A), which is a solution composition having the following properties. (Properties) (1) The pH of the composition is from 6 to 8. (2) The composition has the following properties when stored under light-shielded conditions at 60 ° C. for 2 weeks. (a) Based on the pH at the start of storage, the pH after storage
Is ± 0.1 or less. (b) Assuming that the weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof at the start of storage is 100%, the relative value of the weight average molecular weight after storage is 70% or more.
【００１７】(C)組成物中のヒアルロン酸またはその薬
学的に許容される塩の重量平均分子量が５０万〜４００
万である、上記(A)又は(B)記載の組成物。(C) Hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition has a weight average molecular weight of 500,000 to 400
The composition according to the above (A) or (B), wherein
【００１８】(D)組成物中のヒアルロン酸またはその薬
学的に許容される塩の濃度が０．０５〜２．５％(W/V)
である、上記(A)〜(C)のいずれか１つに記載の組成物。(D) the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition is 0.05 to 2.5% (W / V)
The composition according to any one of the above (A) to (C), wherein
【００１９】(E)組成物中のヒアルロン酸またはその薬
学的に許容される塩の濃度が０．０５〜０．４％(W/V)
である、上記(D)記載の組成物。(E) The concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition is 0.05 to 0.4% (W / V).
The composition according to the above (D), wherein
【００２０】(F)組成物中の下記物質群から選ばれる１
又は２以上の物質またはその薬学的に許容される塩の濃
度が０．０１〜１０％である、上記(A)〜(E)のいずれか
１つに記載の組成物。 (物質群)酒石酸、コハク酸、酢酸、グルタミン酸、グリ
シン、リンゴ酸、乳酸(F) 1 selected from the following substance group in the composition:
Or the composition according to any one of the above (A) to (E), wherein the concentration of two or more substances or a pharmaceutically acceptable salt thereof is 0.01 to 10%. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
【００２１】(G)組成物中のエンドトキシン濃度が、
０．１ＥＵ／ｍＬ以下である、上記(A)〜(F)のいずれか
１つに記載の組成物。(G) The endotoxin concentration in the composition is
The composition according to any one of the above (A) to (F), wherein the composition is 0.1 EU / mL or less.
【００２２】(H)ヒアルロン酸またはその薬学的に許容
される塩が、ヒアルロン酸ナトリウムである、上記(A)
〜(G)のいずれか１つに記載の組成物。(H) The above (A), wherein the hyaluronic acid or a pharmaceutically acceptable salt thereof is sodium hyaluronate.
-The composition according to any one of (G).
【００２３】また本発明は、下記のヒアルロン酸含有溶
液のｐＨ変化抑制剤（以下、単に「本発明抑制剤」とい
う）である。The present invention also relates to the following pH change inhibitor (hereinafter, simply referred to as "the inhibitor of the present invention") of a hyaluronic acid-containing solution.
【００２４】(I)下記物質群から選ばれる１又は２以上
の物質またはその薬学的に許容される塩からなる、ヒア
ルロン酸含有溶液のｐＨ変化抑制剤。 (物質群)酒石酸、コハク酸、酢酸、グルタミン酸、グリ
シン、リンゴ酸、乳酸(I) A pH change inhibitor for a hyaluronic acid-containing solution, comprising one or more substances selected from the following substance groups or a pharmaceutically acceptable salt thereof. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
【００２５】[0025]
【発明の実施の形態】以下、本発明組成物についてさら
に詳細に説明する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the composition of the present invention will be described in more detail.
【００２６】＜１＞ヒアルロン酸またはその薬学的に許
容される塩 本発明組成物で用いるヒアルロン酸またはその薬学的に
許容される塩の由来は特に限定されず、鶏冠、臍帯、ヒ
アルロン酸を産生する微生物等から分離、精製されたヒ
アルロン酸を用いることができる。特に、高純度に精製
され、医薬として混入が許されない物質を実質的に含ま
ないものが好ましい。<1> Hyaluronic acid or a pharmaceutically acceptable salt thereof Hyaluronic acid or a pharmaceutically acceptable salt thereof used in the composition of the present invention is not particularly limited, and can produce cockscomb, umbilical cord, and hyaluronic acid. Hyaluronic acid that has been separated and purified from microorganisms and the like can be used. In particular, those which are highly purified and substantially do not contain a substance which is not allowed to be mixed as a medicine are preferable.
【００２７】ヒアルロン酸の薬学的に許容される塩とし
ては、例えば、アルカリ金属塩（ナトリウム塩、リチウ
ム塩、カリウム塩等）、アルカリ土類金属塩、アンモニ
ウム塩等の無機塩基との塩、又はジエタノールアミン
塩、シクロヘキシルアミン塩、アミノ酸塩等の有機塩基
との塩のうち、薬学的に許容される塩を用いることがで
きる。なかでもヒアルロン酸ナトリウムであることが好
ましい。The pharmaceutically acceptable salts of hyaluronic acid include, for example, salts with inorganic bases such as alkali metal salts (sodium salt, lithium salt, potassium salt and the like), alkaline earth metal salts and ammonium salts, or Among salts with organic bases such as diethanolamine salt, cyclohexylamine salt and amino acid salt, pharmaceutically acceptable salts can be used. Of these, sodium hyaluronate is preferred.
【００２８】ヒアルロン酸またはその薬学的に許容され
る塩の重量平均分子量は、特に限定されないが、５０万
〜４００万程度が好ましく、６０万〜２５０万程度がよ
り好ましく、６０万〜１２０万程度がさらに好ましい。The weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof is not particularly limited, but is preferably about 500,000 to 4,000,000, more preferably about 600,000 to 2.5,000,000, and more preferably about 600,000 to 1.2,000,000. Is more preferred.
【００２９】本発明組成物中のヒアルロン酸またはその
薬学的に許容される塩の濃度も特に限定されないが、溶
液組成物として提供する場合は０．０５〜２．５％(W/
V)であることが好ましい。また本発明組成物は特に低濃
度のヒアルロン酸含有溶液組成物において非常に有用で
あることから、本発明組成物中を溶液組成物として提供
する場合のヒアルロン酸またはその薬学的に許容される
塩の濃度は０．０５〜０．８％(W/V)であるものがより
好ましく、０．０５〜０．４％(W/V)であるものが特に
好ましい。The concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition of the present invention is not particularly limited, but when provided as a solution composition, it is 0.05 to 2.5% (W /
V). In addition, the composition of the present invention is very useful especially in a low-concentration hyaluronic acid-containing solution composition. Therefore, when the composition of the present invention is provided as a solution composition, hyaluronic acid or a pharmaceutically acceptable salt thereof is used. Is more preferably 0.05 to 0.8% (W / V), particularly preferably 0.05 to 0.4% (W / V).
【００３０】なおヒアルロン酸またはその薬学的に許容
される塩の誘導体も、本発明において用いることができ
る。Derivatives of hyaluronic acid or a pharmaceutically acceptable salt thereof can also be used in the present invention.
【００３１】＜２＞添加剤 本発明組成物で用いる添加剤は、酒石酸、コハク酸、酢
酸、グルタミン酸、グリシン、リンゴ酸及び乳酸からな
る群から選ばれる１又は２以上の物質若しくはその薬学
的に許容される塩であり、本発明組成物中のヒアルロン
酸またはその薬学的に許容される塩を安定化（低分子化
を抑制）し、本発明組成物のｐＨ変化を抑制する作用を
有する。この作用は、公知の添加剤であるクエン酸ナト
リウムに比して顕著である。なお後述の実施例に記載さ
れている低分子化抑制およびｐＨ変化抑制の結果からみ
ると、これらの添加剤の中でも乳酸、グルタミン酸、酒
石酸、リンゴ酸またはコハク酸が好ましく、特に乳酸ま
たはグルタミン酸が好ましい。<2> Additives The additives used in the composition of the present invention are one or more substances selected from the group consisting of tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid and lactic acid, or pharmaceutically acceptable substances thereof. It is an acceptable salt and has the effect of stabilizing hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition of the present invention (suppressing the lowering of the molecular weight) and suppressing a change in the pH of the composition of the present invention. This effect is remarkable as compared with the known additive sodium citrate. In view of the results of the suppression of low molecular weight and suppression of pH change described in Examples described later, lactic acid, glutamic acid, tartaric acid, malic acid or succinic acid is preferable among these additives, and lactic acid or glutamic acid is particularly preferable. .
【００３２】上記添加剤の薬学的に許容される塩として
は、例えば、アルカリ金属塩（ナトリウム塩、リチウム
塩、カリウム塩等）、アルカリ土類金属塩、アンモニウ
ム塩等の無機塩基との塩、又はジエタノールアミン塩、
シクロヘキシルアミン塩、アミノ酸塩等の有機塩基との
塩のうち、薬学的に許容される塩を用いることができ
る。Examples of the pharmaceutically acceptable salts of the above-mentioned additives include salts with inorganic bases such as alkali metal salts (sodium salt, lithium salt, potassium salt, etc.), alkaline earth metal salts, ammonium salts and the like. Or diethanolamine salt,
Among salts with organic bases such as cyclohexylamine salt and amino acid salt, pharmaceutically acceptable salts can be used.
【００３３】上記添加剤は、生理学上許容され、医薬と
して使用できる程度の純度であり、かつ医薬として混入
が許されない物質を実質的に含まないものが好ましい。It is preferable that the above-mentioned additive is physiologically acceptable, has such a purity that it can be used as a medicament, and does not substantially contain a substance which is not allowed to be mixed as a medicament.
【００３４】上記添加剤は、活性炭処理等によりエンド
トキシン濃度を低減させておくことが好ましい。It is preferable that the endotoxin concentration of the above additives is reduced by activated carbon treatment or the like.
【００３５】本発明組成物中の上記添加剤の濃度も特に
限定されないが、溶液組成物として提供する場合は０．
０１〜１０％(W/V)であることが好ましく、０．０１〜
１％(W/V)であることがより好ましく、０．１〜１％(W/
V)であることが極めて好ましい。The concentration of the above-mentioned additives in the composition of the present invention is not particularly limited.
It is preferably from 0.01 to 10% (W / V), and from 0.01 to
1% (W / V) is more preferable, and 0.1 to 1% (W / V).
V) is very particularly preferred.
【００３６】本発明組成物で用いる上記添加剤は、その
まま本発明抑制剤の有効成分として用いることができ、
これにより本発明抑制剤が提供される。The above additives used in the composition of the present invention can be used as they are as active ingredients of the inhibitor of the present invention.
This provides the inhibitor of the present invention.
【００３７】本発明組成物は、上述のヒアルロン酸また
はその薬学的に許容される塩と、添加剤とを混合するこ
とによって製造することができる。なお、本発明組成物
を溶液組成物として提供する場合には、上述のヒアルロ
ン酸またはその薬学的に許容される塩および添加剤を、
生理学的に許容され、かつ上述のヒアルロン酸またはそ
の薬学的に許容される塩および添加剤を溶解可能な溶媒
に溶解することによって製造することができる。上述の
ヒアルロン酸またはその薬学的に許容される塩および添
加剤を溶解可能な溶媒としては、例えば水(蒸留水)や生
理食塩液等が挙げられるが、これらに限定されるもので
はない。The composition of the present invention can be produced by mixing the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof with an additive. When the composition of the present invention is provided as a solution composition, the above-described hyaluronic acid or a pharmaceutically acceptable salt and additive thereof,
It can be produced by dissolving the above-mentioned physiologically acceptable hyaluronic acid or a pharmaceutically acceptable salt thereof and an additive in a soluble solvent. Examples of the solvent in which the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof and an additive can be dissolved include, for example, water (distilled water) and a physiological saline solution, but are not limited thereto.
【００３８】なお本発明組成物を溶液組成物として製造
する際には、本発明組成物のｐＨが６〜８となるよう
に、必要に応じて適宜ｐＨを調整する必要がある。もち
ろん、上述のヒアルロン酸またはその薬学的に許容され
る塩および添加剤を溶媒に溶解させた時のｐＨが既に６
〜８の範囲にあるならば、敢えてｐＨを調整する必要は
ない。しかしこの場合でも、ｐＨ６〜８の範囲における
所望の特定ｐＨに調整するために、必要に応じて適宜ｐ
Ｈを調整することもできる。When the composition of the present invention is produced as a solution composition, it is necessary to appropriately adjust the pH as needed so that the pH of the composition of the present invention is 6 to 8. Of course, when the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof and an additive are dissolved in a solvent, the pH is already 6
If it is in the range of ８8, there is no need to adjust the pH. However, even in this case, p is appropriately adjusted as necessary in order to adjust to a desired specific pH in the range of pH 6 to 8.
H can also be adjusted.
【００３９】ｐＨの調整方法は特に限定されないが、例
えば後述の緩衝剤を適宜添加してｐＨを調整する方法が
挙げられる。The method of adjusting the pH is not particularly limited, and examples thereof include a method of adjusting the pH by appropriately adding a buffer described below.
【００４０】本発明組成物を溶液組成物として製造する
際には、本発明組成物の生理食塩液に対する浸透圧比が
１．０〜１．２となるように、必要に応じて適宜浸透圧
比を調整することが好ましい。もちろん、上述のヒアル
ロン酸またはその薬学的に許容される塩および添加剤を
溶媒に溶解させた時の生理食塩液に対する浸透圧比が既
に１．０〜１．２の範囲にあるならば、敢えて浸透圧比
を調整する必要はない。しかしこの場合でも、前記浸透
圧比の範囲における所望の特定浸透圧比に調整するため
に、必要に応じて適宜浸透圧比を調整することもでき
る。When the composition of the present invention is prepared as a solution composition, the osmotic pressure ratio is appropriately adjusted as necessary so that the osmotic pressure ratio of the composition of the present invention to physiological saline is 1.0 to 1.2. Adjustment is preferred. Of course, if the osmotic pressure ratio to the physiological saline when the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof and an additive are dissolved in a solvent is already in the range of 1.0 to 1.2, the osmosis is intentionally performed. There is no need to adjust the pressure ratio. However, even in this case, the osmotic pressure ratio can be appropriately adjusted as needed in order to adjust to a desired specific osmotic pressure ratio in the range of the osmotic pressure ratio.
【００４１】浸透圧比の調整方法は特に限定されない
が、例えば後述の緩衝剤、塩化ナトリウム等の塩類、糖
類等を適宜添加する方法等が挙げられる。The method of adjusting the osmotic pressure ratio is not particularly limited, and examples thereof include a method of appropriately adding a buffer, a salt such as sodium chloride, a saccharide and the like described below.
【００４２】このようにして得られた溶液組成物として
の本発明組成物は、さらに活性炭に接触させることによ
って、エンドトキシン濃度を０．１ＥＵ／ｍＬ以下とす
ることが好ましい。The composition of the present invention thus obtained as a solution composition is preferably brought into contact with activated carbon to reduce the endotoxin concentration to 0.1 EU / mL or less.
【００４３】＜３＞本発明組成物の性質 本発明組成物は、上述したヒアルロン酸またはその薬学
的に許容される塩と、上述した添加剤とを含有している
組成物であり、溶液組成物とした場合に下記の性質を有
していることを特徴とする。 (1)組成物のｐＨが６〜８である。 (2)組成物を遮光かつ６０℃の条件下で２週間保存した
ときに、下記の性質を有する。 (a)保存開始時のｐＨを基準としたとき、保存後のｐＨ
の変化が±０．１以下である。 (b)保存開始時のヒアルロン酸またはその薬学的に許容
される塩の重量平均分子量を１００％とした時、保存後
の当該重量平均分子量の相対値が７０％以上である。<3> Properties of the composition of the present invention The composition of the present invention is a composition containing the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof and the above-mentioned additive, and a solution composition It is characterized by having the following properties when manufactured. (1) The pH of the composition is 6-8. (2) The composition has the following properties when stored under light-shielded conditions at 60 ° C. for 2 weeks. (a) Based on the pH at the start of storage, the pH after storage
Is ± 0.1 or less. (b) Assuming that the weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof at the start of storage is 100%, the relative value of the weight average molecular weight after storage is 70% or more.
【００４４】溶液組成物としての本発明組成物のｐＨ
は、ｐＨメーターを用いる等、当業者に周知慣用の技術
を用いて測定することができる。PH of the composition of the present invention as a solution composition
Can be measured using a commonly used technique known to those skilled in the art, such as using a pH meter.
【００４５】また、本発明組成物中のヒアルロン酸また
はその薬学的に許容される塩の重量平均分子量は、極限
粘度からLaurent式等を用いて求める方法や、光散乱法
等、当業者に周知慣用の技術を用いて測定することがで
きる。The weight-average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition of the present invention is well known to those skilled in the art, for example, by a method obtained from the intrinsic viscosity using Laurent's equation or the like, or a light scattering method. It can be measured using conventional techniques.
【００４６】なお、溶液組成物としての本発明組成物中
のエンドトキシン濃度は、０．１ＥＵ／ｍＬ以下である
ことが好ましい。本発明組成物中のエンドトキシン濃度
は、当業者に周知慣用のエンドトキシンの測定法を用い
て測定することができるが、カブトガニ・アメボサイト
・ライセート成分を用いるリムルス試験法が好ましい。
なおＥＵ（エンドトキシン単位）は、日本工業規格 生
化学試薬通則（ＪＩＳＫ ８００８）に従って測定・算
出できる。The concentration of endotoxin in the composition of the present invention as a solution composition is preferably 0.1 EU / mL or less. The endotoxin concentration in the composition of the present invention can be measured by a commonly used method for measuring endotoxin well-known to those skilled in the art, but a Limulus test using a horseshoe crab, amebosite and lysate component is preferred.
EU (endotoxin unit) can be measured and calculated in accordance with Japanese Industrial Standards for Biochemical Reagents (JISK 8008).
【００４７】また溶液組成物としての本発明組成物の生
理食塩液に対する浸透圧比は１．０〜１．２であること
が好ましい。The osmotic pressure ratio of the composition of the present invention as a solution composition to physiological saline is preferably 1.0 to 1.2.
【００４８】なお本発明組成物には、生理学的に許容さ
れ、本発明組成物中のヒアルロン酸またはその薬学的に
許容される塩の低分子化を引き起こさず、本発明組成物
の長期保存によるｐＨ変化を惹起せず、かつ上述した本
発明組成物の性質を維持する限りにおいて、さらに他の
物質を適宜添加してもよい。このような物質としては、
医薬担体や薬理活性成分等を挙げることができる。The composition of the present invention is physiologically acceptable, does not cause a reduction in molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition of the present invention, and is obtained by long-term storage of the composition of the present invention. Other substances may be appropriately added as long as they do not cause a pH change and maintain the above-mentioned properties of the composition of the present invention. Such substances include:
Pharmaceutical carriers and pharmacologically active ingredients can be mentioned.
【００４９】医薬担体としては、慣用の賦形剤、結合
剤、滑沢剤、着色剤、崩壊剤、緩衝剤、等張化剤、保存
剤、無痛化剤、界面活性剤、乳化剤、溶解補助剤、懸濁
化剤、分散剤、基剤、粘着剤等、通常医薬に用いられる
ものが例示される。これら医薬担体の中でも、本発明組
成物の長期保存によるｐＨ変化をより一層抑制するため
に、緩衝剤を添加することが好ましい。緩衝剤は、ｐＨ
６〜８の範囲で緩衝作用を発揮するものが好ましく、例
えば、塩酸、水酸化ナトリウム、炭酸ナトリウム、炭酸
水素ナトリウム、リン酸二水素カリウム、リン酸水素二
カリウム、リン酸二水素ナトリウム、リン酸水素二ナト
リウム、アミノ酢酸、安息香酸ナトリウム、エタノール
アミン、アルギニン、エチレンジアミンまたはこれらの
混合物が例示されるが、これらに限定されるものではな
い。Pharmaceutical carriers include conventional excipients, binders, lubricants, coloring agents, disintegrants, buffers, isotonic agents, preservatives, soothing agents, surfactants, emulsifiers, dissolution aids. Examples which are usually used in medicine, such as agents, suspending agents, dispersants, bases, and adhesives, are exemplified. Among these pharmaceutical carriers, it is preferable to add a buffer in order to further suppress the pH change due to long-term storage of the composition of the present invention. The buffer is pH
Those exhibiting a buffering action in the range of 6 to 8 are preferable. For example, hydrochloric acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Examples include, but are not limited to, disodium hydrogen, aminoacetic acid, sodium benzoate, ethanolamine, arginine, ethylenediamine or mixtures thereof.
【００５０】薬理活性成分としては、コンドロイチン硫
酸、デルマタン硫酸、ヘパラン硫酸、ヘパリン、ケラタ
ン硫酸等のグリコサミノグリカン等が挙げられる。Examples of the pharmacologically active ingredient include glycosaminoglycans such as chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, and keratan sulfate.
【００５１】本発明組成物は、そのまま医薬品として投
与するための最終剤形として用いることができ、あるい
は他の最終剤形医薬品の原料として使用することもでき
る。The composition of the present invention can be used as a final dosage form to be administered as a pharmaceutical as it is, or can be used as a raw material for other final dosage forms.
【００５２】本発明組成物をそのまま医薬品として投与
する場合の最終剤形は、投与方法、投与部位等に応じて
当業者が適宜設定することができるが、例えば注射剤、
点眼剤、外用剤等が例示される。この場合、本発明組成
物をアンプル、バイアル、注射用シリンジ、点眼用容
器、外用剤用容器等の適当な容器に充填・密封し、その
まま流通させあるいは保存して投与に供することができ
る。When the composition of the present invention is directly administered as a pharmaceutical, the final dosage form can be appropriately determined by those skilled in the art according to the administration method, administration site and the like.
Examples include eye drops and external preparations. In this case, the composition of the present invention can be filled and sealed in a suitable container such as an ampoule, a vial, a syringe for injection, a container for eye drops, a container for external preparations, and distributed or stored as it is for administration.
【００５３】[0053]
【実施例】次に、実施例により本発明をさらに具体的に
説明するが、この実施例は本発明の一例を示すものであ
り、これに限定されるものではない。EXAMPLES Next, the present invention will be described in more detail with reference to Examples, which are illustrative of the present invention and are not intended to limit the present invention.
【００５４】まず、本実施例において共通して用いた方
法等について説明する。First, a method and the like commonly used in this embodiment will be described.
【００５５】下記処方により、ヒアルロン酸含有組成物
（溶液組成物）を製造した。 ヒアルロン酸ナトリウム （鶏冠由来、重量平均分子量８２万〜９５万） ０．０８％ 塩化ナトリウム ０．９％ リン酸二水素ナトリウム ０．１ｍＭ リン酸水素二ナトリウム １．５ｍＭ 添加剤 ０．６％A hyaluronic acid-containing composition (solution composition) was prepared according to the following formulation. Sodium hyaluronate (from cockscomb, weight average molecular weight 820,000 to 950,000) 0.08% Sodium chloride 0.9% Sodium dihydrogen phosphate 0.1 mM Disodium hydrogen phosphate 1.5 mM Additive 0.6%
【００５６】このヒアルロン酸含有組成物を遮光かつ６
０℃の条件下で２週間保存して、保存開始時、１週間目
及び２週間目のそれぞれの時点における重量平均分子量
及びｐＨを測定した。なお重量平均分子量は、第十三改
正日本薬局方一般試験法第３６項粘度試験法に従って極
限粘度を測定し、Laurentらの式により算出した。また
保存開始時の重量平均分子量を１００％とした時の相対
値を算出した。This hyaluronic acid-containing composition is protected from light and
After preservation for 2 weeks at 0 ° C., the weight average molecular weight and pH were measured at the beginning of the preservation, the first week and the second week respectively. The weight-average molecular weight was calculated by Laurent et al. By measuring the intrinsic viscosity according to the thirteenth revised Japanese Pharmacopoeia General Test Method, Section 36, Viscosity Test Method. Further, a relative value was calculated assuming that the weight average molecular weight at the start of storage was 100%.
【００５７】またｐＨは、ガラス電極によるｐＨ計によ
って測定し、保存開始時のｐＨとの差を算出した。The pH was measured by a pH meter using a glass electrode, and the difference from the pH at the start of storage was calculated.
【００５８】（実施例１）添加剤として、未添加(添加
剤を加えない)、クエン酸ナトリウム(公知)、酒石酸ナ
トリウム、コハク酸ナトリウム、酢酸ナトリウム、リン
ゴ酸ナトリウムおよびエデト酸ナトリウム(エチレンジ
アミン四酢酸；EDTA)をそれぞれ用いて、前述の処方で
ヒアルロン酸含有組成物を製造し、前述の条件で保存し
て、前述の方法で重量平均分子量及びｐＨを測定・算出
した。Example 1 As additives, no additives (no additives), sodium citrate (known), sodium tartrate, sodium succinate, sodium acetate, sodium malate and sodium edetate (ethylenediaminetetraacetic acid) EDTA), a hyaluronic acid-containing composition was produced according to the above-mentioned formulation, stored under the above-mentioned conditions, and the weight-average molecular weight and pH were measured and calculated by the above-mentioned methods.
【００５９】重量平均分子量の結果を表１に、ｐＨの結
果を表２に示す。なお表の中で、開始時、１Ｗおよび２
Ｗは、それぞれ保存開始時、１週間目および２週間目を
意味する。またＮＤは測定・算出していないことを意味
する。Table 1 shows the results of the weight average molecular weight, and Table 2 shows the results of the pH. In the table, at the start, 1W and 2W
W means the first week and the second week at the start of storage, respectively. ND means that no measurement or calculation was performed.
【００６０】[0060]
【表１】 [Table 1]
【００６１】[0061]
【表２】 [Table 2]
【００６２】（実施例２）添加剤として、未添加(添加
剤を加えない)、クエン酸ナトリウム(公知)、Ｌ−グル
タミン酸、グリシンおよび乳酸ナトリウムをそれぞれ用
いて、前述の処方でヒアルロン酸含有組成物を製造し、
前述の条件で保存して、前述の方法で重量平均分子量及
びｐＨを測定・算出した。Example 2 A hyaluronic acid-containing composition was prepared by the above-mentioned formulation, using, as additives, unadded (no additives), sodium citrate (known), L-glutamic acid, glycine and sodium lactate, respectively. Manufacture things,
After storage under the above conditions, the weight average molecular weight and the pH were measured and calculated by the above method.
【００６３】重量平均分子量の結果を表３に、ｐＨの結
果を表４に示す。Table 3 shows the results of the weight average molecular weight, and Table 4 shows the results of the pH.
【００６４】[0064]
【表３】 [Table 3]
【００６５】[0065]
【表４】 [Table 4]
【００６６】以上の結果から、添加剤を添加しない(未
添加)場合は、ｐＨの変化は少ないが分子量の低下が大
きいことが明らかとなった。また添加剤として公知のク
エン酸ナトリウムを用いた場合は分子量の低下は少ない
がｐＨの変化が大きいことが明らかとなった。また添加
剤としてポリカルボン酸の一種であるエデト酸ナトリウ
ムを用いた場合は、ｐＨの変化は少ないが分子量の低下
が大きいことが明らかとなった。From the above results, it was clarified that when no additive was added (no addition), the change in pH was small but the molecular weight was significantly reduced. In addition, it was revealed that when a known sodium citrate was used as an additive, the decrease in molecular weight was small, but the change in pH was large. When sodium edetate, which is a kind of polycarboxylic acid, was used as an additive, it was found that the change in pH was small, but the molecular weight was significantly reduced.
【００６７】それに対し、添加剤として酒石酸ナトリウ
ム、コハク酸ナトリウム、酢酸ナトリウム、Ｌ−グルタ
ミン酸、グリシン、リンゴ酸ナトリウムまたは乳酸ナト
リウムをそれぞれ用いた場合は、分子量の低下も少な
く、またｐＨの変化も少ないことが明らかとなった。On the other hand, when sodium tartrate, sodium succinate, sodium acetate, L-glutamic acid, glycine, sodium malate or sodium lactate are used as additives, the molecular weight decreases little and the pH changes little. It became clear.
【００６８】このように、ポリカルボン酸(塩)の中で
も、特定のポリカルボン酸(塩)のみがヒアルロン酸の低
分子化抑制とｐＨ変化抑制の両方の効果を兼ね備えてい
ることが本発明者らにより初めて明らかにされた。Thus, among the polycarboxylic acids (salts), only the specific polycarboxylic acids (salts) have both the effect of suppressing the reduction of molecular weight of hyaluronic acid and the effect of suppressing the pH change. Were first revealed by them.
【００６９】[0069]
【発明の効果】本発明組成物は、ヒアルロン酸またはそ
の薬学的に許容される塩と、添加剤として下記物質群か
ら選ばれる１又は２以上の物質またはその薬学的に許容
される塩とを含有している。 (物質群)酒石酸、コハク酸、酢酸、グルタミン酸、グリ
シン、リンゴ酸、乳酸The composition of the present invention comprises hyaluronic acid or a pharmaceutically acceptable salt thereof, and one or more substances selected from the following substance group or a pharmaceutically acceptable salt thereof as an additive. Contains. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
【００７０】このような組成物構成を選択することによ
り、特に溶液組成物形態において長期保存によるヒアル
ロン酸の低分子化及びｐＨ変化を公知の組成物に比して
顕著に抑制でき、これにより、長期保存後であっても組
成物製造時の物性に極めて近い組成物を提供することが
できる。また本発明組成物の構成を選択することによ
り、本発明組成物を溶液組成物として製造する際、ヒア
ルロン酸を溶媒と混合して溶解させる時のヒアルロン酸
の低分子化を抑制することができる。したがって本発明
組成物は、特に低分子化等の物性変化が起こりやすい低
濃度のヒアルロン酸溶液において極めて有用である。By selecting such a composition, particularly in the form of a solution composition, the reduction of the molecular weight of hyaluronic acid and the change in pH due to long-term storage can be significantly suppressed as compared with known compositions. Even after long-term storage, it is possible to provide a composition having extremely close physical properties at the time of production of the composition. In addition, by selecting the constitution of the composition of the present invention, when producing the composition of the present invention as a solution composition, it is possible to suppress the reduction in molecular weight of hyaluronic acid when dissolving by mixing hyaluronic acid with a solvent. . Therefore, the composition of the present invention is extremely useful especially in a low-concentration hyaluronic acid solution in which a change in physical properties such as low molecular weight is likely to occur.
【００７１】このような本発明組成物を用いることによ
り、長期保存が可能、取扱いが容易、安全かつ有効な医
薬品を提供することができる。By using such a composition of the present invention, it is possible to provide a drug which can be stored for a long period of time, is easy to handle, is safe and effective.
【００７２】また、本発明抑制剤は上記添加剤からなる
ヒアルロン酸含有溶液のｐＨ変化抑制剤であり、ヒアル
ロン酸含有溶液のｐＨ変化のみならず低分子化も顕著に
抑制することができる。Further, the inhibitor of the present invention is a pH change inhibitor for a hyaluronic acid-containing solution comprising the above-mentioned additives, and can remarkably suppress not only a pH change of a hyaluronic acid-containing solution but also a reduction in molecular weight.
Claims (9)
れる塩と、下記物質群から選ばれる１又は２以上の物質
またはその薬学的に許容される塩とを含有するヒアルロ
ン酸含有組成物。 (物質群)酒石酸、コハク酸、酢酸、グルタミン酸、グリ
シン、リンゴ酸、乳酸1. A hyaluronic acid-containing composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, and one or more substances selected from the following substance group or a pharmaceutically acceptable salt thereof. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
求項１記載のヒアルロン酸含有組成物。 (性質) (1)組成物のｐＨが６〜８である。 (2)組成物を遮光かつ６０℃の条件下で２週間保存した
ときに、下記の性質を有する。 (a)保存開始時のｐＨを基準としたとき、保存後のｐＨ
の変化が±０．１以下である。 (b)保存開始時のヒアルロン酸またはその薬学的に許容
される塩の重量平均分子量を１００％とした時、保存後
の当該重量平均分子量の相対値が７０％以上である。2. The hyaluronic acid-containing composition according to claim 1, which is a solution composition having the following properties. (Properties) (1) The pH of the composition is from 6 to 8. (2) The composition has the following properties when stored under light-shielded conditions at 60 ° C. for 2 weeks. (a) Based on the pH at the start of storage, the pH after storage
Is ± 0.1 or less. (b) Assuming that the weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof at the start of storage is 100%, the relative value of the weight average molecular weight after storage is 70% or more.
的に許容される塩の重量平均分子量が５０万〜４００万
である、請求項１又は２記載の組成物。3. The composition according to claim 1, wherein the weight-average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition is from 500,000 to 4,000,000.
的に許容される塩の濃度が０．０５〜２．５％(W/V)で
ある、請求項１〜３のいずれか１項記載の組成物。4. The composition according to claim 1, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition is 0.05 to 2.5% (W / V). Composition.
的に許容される塩の濃度が０．０５〜０．４％(W/V)で
ある、請求項４記載の組成物。5. The composition according to claim 4, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the composition is 0.05 to 0.4% (W / V).
は２以上の物質またはその薬学的に許容される塩の濃度
が０．０１〜１０％である、請求項１〜５のいずれか１
項記載の組成物。 (物質群) 酒石酸、コハク酸、酢酸、グルタミン酸、グリシン、リ
ンゴ酸、乳酸6. The composition according to claim 1, wherein the concentration of one or more substances selected from the following substance group or a pharmaceutically acceptable salt thereof in the composition is 0.01 to 10%. 1
The composition according to Item. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
１ＥＵ／ｍＬ以下である、請求項１〜６のいずれか１項
記載の組成物。7. The composition according to claim 1, wherein the concentration of endotoxin in the composition is 0.5.
The composition according to any one of claims 1 to 6, which is 1 EU / mL or less.
れる塩が、ヒアルロン酸ナトリウムである、請求項１〜
７のいずれか１項記載の組成物。8. The method according to claim 1, wherein the hyaluronic acid or a pharmaceutically acceptable salt thereof is sodium hyaluronate.
The composition according to any one of claims 7 to 10.
物質またはその薬学的に許容される塩からなる、ヒアル
ロン酸含有溶液のｐＨ変化抑制剤。 (物質群) 酒石酸、コハク酸、酢酸、グルタミン酸、グリシン、リ
ンゴ酸、乳酸9. A pH change inhibitor for a hyaluronic acid-containing solution, comprising one or more substances selected from the following substance groups or a pharmaceutically acceptable salt thereof. (Substance group) Tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12271598A JPH11302197A (en) | 1998-04-17 | 1998-04-17 | Hyaluronic acid-stabilizing composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12271598A JPH11302197A (en) | 1998-04-17 | 1998-04-17 | Hyaluronic acid-stabilizing composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11302197A true JPH11302197A (en) | 1999-11-02 |
Family
ID=14842811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12271598A Pending JPH11302197A (en) | 1998-04-17 | 1998-04-17 | Hyaluronic acid-stabilizing composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11302197A (en) |
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1998
- 1998-04-17 JP JP12271598A patent/JPH11302197A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011152428A (en) * | 2001-11-05 | 2011-08-11 | Seikagaku Kogyo Co Ltd | High epithelial distension retaining composition |
| US7807657B2 (en) | 2002-08-16 | 2010-10-05 | Denki Kagaku Kogyo Kabushiki Kaisha | Separate type medical material |
| JP2005154305A (en) * | 2003-11-21 | 2005-06-16 | Showa Yakuhin Kako Kk | Method for producing hyaluronic acid-containing composition |
| US8927491B2 (en) | 2010-12-28 | 2015-01-06 | Depuy Mitek, Llc | Methods for forming compositions for treating joints comprising bone morphogenetic protein and hyaluronic acid |
| US11090328B2 (en) | 2010-12-28 | 2021-08-17 | Medos International Sarl | Compositions and methods for treating joints |
| US9561260B2 (en) | 2010-12-28 | 2017-02-07 | Depuy Mitek, Llc | Compositions for treating joints comprising bone morphogenetic protein and hyaluronic acid |
| WO2012118192A1 (en) * | 2011-03-02 | 2012-09-07 | 電気化学工業株式会社 | Aqueous solution containing hyaluronic acid or salt thereof |
| JPWO2012118192A1 (en) * | 2011-03-02 | 2014-07-07 | 電気化学工業株式会社 | An aqueous solution containing hyaluronic acid or a salt thereof |
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| WO2017131130A1 (en) | 2016-01-29 | 2017-08-03 | 生化学工業株式会社 | Stabilized aqueous composition comprising chondroitin sulfate and hyaluronic acid |
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