CN116270446B - A lipoic acid injection composition for mesoderm and a preparation method thereof - Google Patents
A lipoic acid injection composition for mesoderm and a preparation method thereof Download PDFInfo
- Publication number
- CN116270446B CN116270446B CN202310120129.5A CN202310120129A CN116270446B CN 116270446 B CN116270446 B CN 116270446B CN 202310120129 A CN202310120129 A CN 202310120129A CN 116270446 B CN116270446 B CN 116270446B
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- CN
- China
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- weight
- parts
- cyclodextrin
- composition
- lipoic acid
- 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.)
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Links
- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 98
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 98
- 239000000203 mixture Substances 0.000 title claims abstract description 87
- 238000002347 injection Methods 0.000 title claims abstract description 77
- 239000007924 injection Substances 0.000 title claims abstract description 77
- 210000003716 mesoderm Anatomy 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 title claims abstract 14
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 53
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 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 30
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 29
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 29
- 239000003381 stabilizer Substances 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 230000003204 osmotic effect Effects 0.000 claims abstract description 16
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 claims description 35
- 108010087806 Carnosine Proteins 0.000 claims description 35
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims description 35
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims description 35
- 229940044199 carnosine Drugs 0.000 claims description 35
- 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 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 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 claims description 13
- 229940014041 hyaluronate Drugs 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- 230000001954 sterilising effect Effects 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000001116 FEMA 4028 Substances 0.000 claims description 7
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 7
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 7
- 229960004853 betadex Drugs 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 206010013786 Dry skin Diseases 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- VJVOFLWZDWLHNR-MRCUWXFGSA-N icosan-9-yl (z)-docos-13-enoate Chemical compound CCCCCCCCCCCC(CCCCCCCC)OC(=O)CCCCCCCCCCC\C=C/CCCCCCCC VJVOFLWZDWLHNR-MRCUWXFGSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 4
- 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 4
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 3
- 230000003064 anti-oxidating effect Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 229960000281 trometamol Drugs 0.000 claims description 3
- 208000012641 Pigmentation disease Diseases 0.000 claims 1
- 230000007794 irritation Effects 0.000 abstract description 14
- 239000000843 powder Substances 0.000 abstract description 7
- 238000005538 encapsulation Methods 0.000 abstract 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 90
- 238000007254 oxidation reaction Methods 0.000 description 15
- 230000003647 oxidation Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 230000006872 improvement Effects 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000002000 scavenging effect Effects 0.000 description 4
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000037149 energy metabolism Effects 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 description 2
- IZFHEQBZOYJLPK-SSDOTTSWSA-N (R)-dihydrolipoic acid Chemical compound OC(=O)CCCC[C@@H](S)CCS IZFHEQBZOYJLPK-SSDOTTSWSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229930183167 cerebroside Natural products 0.000 description 2
- RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 238000005562 fading Methods 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000013441 quality evaluation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Chemical group O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
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- 230000001133 acceleration Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical group O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
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- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
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- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
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- 239000012535 impurity Substances 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
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- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
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- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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Abstract
本申请公开了一种应用于中胚层的硫辛酸注射液组合物及其制备方法，其中硫辛酸注射液组合物包括硫辛酸、环糊精、稳定剂、调节剂、pH调节剂、渗透压调节剂。选用环糊精溶解硫辛酸粉末，提高了硫辛酸的溶解度，并利用其包裹性提高了注射液的后期稳定性，同时，添加透明质酸及其盐减少了因环糊精带来的对中胚层的刺激性，使用者的舒适感受得到明显提升。The present application discloses a lipoic acid injection composition for mesoderm and a preparation method thereof, wherein the lipoic acid injection composition comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator, and an osmotic pressure regulator. Cyclodextrin is selected to dissolve lipoic acid powder, thereby increasing the solubility of lipoic acid, and utilizing its encapsulation property to increase the late stability of the injection. At the same time, the addition of hyaluronic acid and its salt reduces the irritation to the mesoderm caused by cyclodextrin, and the user's comfort is significantly improved.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to a lipoic acid injection composition applied to mesoderm and a preparation method of the composition.
Background
Lipoic acid, the first natural product isolated from pig liver, is currently available by chemical synthesis. Lipoic acid is a cofactor for pyruvate dehydrogenase and is present in many cases in the liver, kidney and heart. The previous knowledge of the oxidation resistance of alpha-lipoic acid and its reduced dihydrolipoic acid has been kept in its energy metabolism, and a great deal of research work now shows that the oxidation resistance of alpha-lipoic acid and its reduced dihydrolipoic acid and its preventive and therapeutic effects in various diseases. Because the oxidation-reduction potential of the a-lipoic acid is very low, the molecule is small, and the alpha-lipoic acid is a natural metabolic substance, so that a plurality of medical scientists are widely conducted on the research on the oxidation resistance and the medical application of the a-lipoic acid, and the alpha-lipoic acid becomes a hot research subject. Lipoic acid is almost insoluble in water, the solubility in water is only 1g/L (20 ℃), the related substances of the lipoic acid are obviously out of standard after long-term placement of the injection, the color of the liquid medicine is light, the pH value is reduced, and the stability is poor.
Aiming at the problems, a plurality of technical schemes are improved at home and abroad. The method comprises the steps of preparing the lipoic acid into powder injection, wherein the lipoic acid has poor water solubility, the problem of difficult or difficult re-dissolution occurs, the sterility assurance level is lower than the terminal sterilization level, preparing the lipoic acid into injection by the researcher, adding excipients such as meglumine, ethylenediamine and the like as cosolvent, wherein the obtained injection has poor long-term stability, related substances are continuously increased, and adding antioxidant sodium bisulphite into the injection by the researcher, wherein the pH value of the injection prepared by the prescription is continuously increased in the long-term storage process, and the stability cannot be guaranteed.
At present, medicines for improving skin color by mesoderm are mostly combined use of hyaluronic acid and derivatives thereof, tranexamic acid or glutathione and other raw materials, and combined use of injection of the raw materials or combined use mode of freeze-dried powder and injection. At the application end in the market, complex use of doctors is caused, and the risk of pollution is also caused. Even though some products are prepared by mixing the respective raw material injection solutions, the powder lipoic acid is not directly used for mesodermal products.
For example, chinese patent document CN201910704274.1 discloses a pharmaceutical composition for mesoderm therapy for reducing skin pigment and treating pain and a preparation method thereof, which refers to adding lipoic acid injection, non-lipoic acid powder, and the problem of stability of injection prepared from lipoic acid powder which cannot be solved, and meanwhile, the production cost of preparing the composition by directly using lipoic acid injection is high. Chinese patent document CN101961312a discloses a lipoic acid composition containing lipoic acid, a solubilizer, an antioxidant, etc., but does not indicate whether it can be applied to mesoderm and its safety.
The lipoic acid injection on the market at present is used for treating the paresthesia caused by diabetic peripheral neuropathy, can be used for intravenous injection or intramuscular injection, but is not injected in mesoderm (subcutaneous), the subcutaneous injection is to inject liquid medicine into the tissue between skin and muscle, and the intramuscular injection is mostly used for injecting medicines with strong irritation or medicines with larger dosage. The lipoic acid is more irritant, and is less researched and applied in the mesoderm injection field. How to dissolve lipoic acid well, reduce the stimulus of lipoic acid, make it suitable for mesoderm (subcutaneous) injection, and ensure the stability of injection at the same time is a problem that the person skilled in the art needs to solve.
Disclosure of Invention
The lipoic acid has poor solubility, a large amount of alkali liquor is added for dissolution in the common solution in the market, but the alkali is extremely easy to degrade the effective drug content, so that the cyclodextrin is added into the lipoic acid injection to avoid excessive addition of alkali, effectively avoid the degradation of the effective matters and the excessive alkali to bring more clinical irritation to patients, and simultaneously compound hyaluronic acid or salt thereof to further reduce irritation.
The application provides a lipoic acid injection composition applied to mesoderm and a preparation method thereof, which solves the problems of dissolution and stability of the lipoic acid injection on one hand, solves the problems of poor permeability and slow effect of the traditional smearing type product on the other hand, rapidly solves the problems of dark yellow and rough skin, simultaneously solves the problems of irritation and safety in mesoderm injection,
Specifically, the application adopts the following technical scheme:
1. A lipoic acid injection composition applied to mesoderm comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator and an osmotic pressure regulator.
2. The composition according to item 1, wherein the lipoic acid is 0.1 to 10 parts by weight, preferably 0.5 to 5.0 parts by weight, relative to 100 parts by weight of the composition.
3. The composition according to item 1 or 2, wherein the cyclodextrin is 0.05 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.
4. The composition according to any one of claims 1 to 3, wherein the stabilizer is 0.02 to 5 parts by weight, preferably 0.1 to 1.5 parts by weight, relative to 100 parts by weight of the composition.
5. The composition according to any one of claims 1 to 4, wherein the regulator is 0.05 to 5 parts by weight, preferably 0.2 to 2.0 parts by weight, relative to 100 parts by weight of the composition.
6. The composition according to any one of claims 1-5, wherein the cyclodextrin is an α -cyclodextrin, a β -cyclodextrin or a γ -cyclodextrin, preferably the cyclodextrin is a β -cyclodextrin, further preferably hydroxypropyl- β -cyclodextrin.
7. The composition according to any one of claims 1 to 6, wherein the regulator is hyaluronic acid or a salt thereof, preferably the hyaluronic acid or a salt thereof is selected from one or more of sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, calcium hyaluronate.
8. The composition of any one of claims 1-7, wherein the hyaluronic acid or salt thereof has a molecular weight of 2500-3500KDa, preferably a molecular weight of 3000KDa.
9. The composition according to any one of the claims 1 to 8, wherein the mass ratio of the lipoic acid, the cyclodextrin and the regulator is 1 (0.05 to 0.5): 0.01 to 0.4, preferably 1 (0.1 to 0.3): 0.02 to 0.2.
10. The composition according to any one of claims 1 to 9, wherein the mass ratio of the lipoic acid, the cyclodextrin and the stabilizer is 1 (0.1 to 0.5): 0.2 to 2.
11. The composition according to any one of claims 1 to 10, wherein the stabilizer comprises carnosine and EDTA-2Na, preferably the mass ratio of carnosine and EDTA-2Na is 1 (0.5 to 2).
12. The composition according to item 11, wherein the mass ratio of lipoic acid, carnosine and EDTA-2Na is (1-20): 1 (0.1-5), preferably (2-10): 1 (0.5-1).
13. The composition of any of claims 1-12, wherein the pH adjuster is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide, or triethanolamine.
14. The composition according to any one of claims 1 to 13, wherein the pH adjuster is 0.001 to 1.0 parts by weight relative to 100 parts by weight of the composition.
15. A method for preparing injection composition for mesoderm, comprising,
Dissolving cyclodextrin in injectable water, adding lipoic acid, stirring until the solution is clear and transparent, regulating pH value of the solution with pH regulator, and regulating osmotic pressure with osmotic pressure regulator;
and adding a regulator after sterile filtration, uniformly stirring, and sterilizing to obtain the injection composition.
16. The method according to item 15, wherein the preparation method is carried out at 40-50 ℃.
17. The method according to item 15 or 16, wherein the pH value of the solution is adjusted to 8.5 to 9.5 with a pH adjustor.
18. The method according to any one of claims 15 to 17, wherein the pH range of the injection composition obtained after sterilization is 7.0 to 7.3 and the osmotic pressure is 230 to 330mosmol/kg.
19. Use of the injectable composition of any one of items 1 to 14 or the injectable composition prepared by the method of any one of items 15 to 18 for the antioxidation of skin, the reduction of skin pigments, the alleviation of skin roughness or the alleviation of skin treatment pain.
20. Use of hyaluronic acid or a salt thereof for alleviating irritation of cyclodextrin.
21. Use of carnosine and EDTA-2Na for stabilizing lipoic acid.
22. Use of carnosine and EDTA-2Na to prevent oxidation of lipoic acid.
23. Use of carnosine and EDTA-2Na to prevent the discoloration of lipoic acid.
Effects of the invention
1. According to the lipoic acid injection disclosed by the application, the cyclodextrin is selected to dissolve lipoic acid powder, so that the solubility of lipoic acid is improved, the coating property of lipoic acid is utilized to improve the later-stage stability of the injection, and meanwhile, the addition of hyaluronic acid and salt thereof reduces the irritation of mesoderm caused by cyclodextrin, so that the comfort feeling of a user is obviously improved.
2. Compared with sodium bisulphite which can cause the increase of the safety risk of the lipoic acid injection, the oxidation resistance of the carnosine can not only effectively protect the lipoic acid from being oxidized at high temperature, but also play a role in treating mesoderm by cooperating with the lipoic acid for oxidation resistance, thereby greatly reducing the safety risk. Carnosine is used as a bioactive peptide and has the functions of buffering, regulating human body, scavenging free radicals, resisting oxidation, resisting aging and preventing metabolic disorder. The carnosine can be prepared into injections in clinic, such as cerebroside carnosine, which can treat injuries of cerebral nerves. Carnosine can also correct the energy metabolism disorder of the human body by scavenging oxygen free radicals. Sodium bisulphite is an acidic corrosive product, and excessive dosage can corrode eyes, skin and mucous membrane and has sensitization effect. The addition amount of the injection is as small as possible and is 0.01-0.2% in order to reduce the stimulation.
3. The lipoic acid injection disclosed by the application uses the carnosine and EDTA-2Na as stabilizers, the oxidation resistance of the carnosine is utilized to effectively protect the lipoic acid from being oxidized at a high temperature, meanwhile, the lipoic acid injection can be cooperated with the lipoic acid to resist oxidation to achieve the purpose of treating mesoderm, and the fading problem of the lipoic acid under illumination can be effectively solved by combining the carnosine and the EDTA-2 Na.
4. The lipoic acid injection is applied to mesoderm, and because mesoderm injection is different from intramuscular injection, substances with large irritation cannot be used, and the injection quantity is not too large, after carnosine and EDTA-2Na are added, the carnosine and the EDTA-2Na have the functions of antioxidation and stabilizing agents, so that the use quantity of cyclodextrin used for stabilizing lipoic acid can be reduced, the irritation caused by cyclodextrin is reduced, the stability of the lipoic acid injection cannot be influenced, and the lipoic acid injection is more suitable for mesoderm injection.
Detailed Description
Exemplary embodiments of the application are described below, including various details of embodiments of the application to facilitate understanding, which should be considered as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.
The application provides a lipoic acid injection composition applied to mesoderm, which comprises lipoic acid, cyclodextrin, a stabilizer, a regulator, a pH regulator and an osmotic pressure regulator.
In a preferred embodiment, the lipoic acid is 0.1 to 10 parts by weight, for example, 0.5 part by weight, 1 part by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, 5 parts by weight, 5.5 parts by weight, 6 parts by weight, 6.5 parts by weight, 7 parts by weight, 7.5 parts by weight, 8 parts by weight, 8.5 parts by weight, 9 parts by weight, 9.5 parts by weight, and more preferably 0.5 to 5.0 parts by weight, relative to 100 parts by weight of the composition.
In a preferred embodiment, the cyclodextrin is 0.05 to 5 parts by weight, for example, 0.1 part by weight, 0.15 part by weight, 0.2 part by weight, 0.25 part by weight, 0.3 part by weight, 0.35 part by weight, 0.4 part by weight, 0.45 part by weight, 0.5 part by weight, 1 part by weight, 1.5 part by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.1 to 1.5 parts by weight, based on 100 parts by weight of the composition.
In a preferred embodiment, the stabilizer is 0.02 to 5 parts by weight, for example, 0.04 parts by weight, 0.06 parts by weight, 0.08 parts by weight, 0.1 parts by weight, 0.15 parts by weight, 0.2 parts by weight, 0.25 parts by weight, 0.3 parts by weight, 0.35 parts by weight, 0.4 parts by weight, 0.45 parts by weight, 0.5 parts by weight, 1 parts by weight, 1.5 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.1 to 1.5 parts by weight, based on 100 parts by weight of the composition.
In a preferred embodiment, the regulator may be 0.05 to 5 parts by weight, for example, 0.1 part by weight, 0.15 part by weight, 0.2 part by weight, 0.25 part by weight, 0.3 part by weight, 0.35 part by weight, 0.4 part by weight, 0.45 part by weight, 0.5 part by weight, 1 part by weight, 1.5 part by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 parts by weight, 4.5 parts by weight, and more preferably 0.2 to 2.0 parts by weight, relative to 100 parts by weight of the composition.
In a preferred embodiment, the pH adjuster may be 0.001 to 1.0 part by weight, for example, 0.005 part by weight, 0.01 part by weight, 0.02 part by weight, 0.03 part by weight, 0.05 part by weight, 0.1 part by weight, 0.15 part by weight, 0.2 part by weight, 0.25 part by weight, 0.3 part by weight, 0.35 part by weight, 0.4 part by weight, 0.45 part by weight, 0.5 part by weight, 0.55 part by weight, 0.6 part by weight, 0.65 part by weight, 0.7 part by weight, 0.75 part by weight, 0.8 part by weight, and 0.9 part by weight, based on 100 parts by weight of the composition.
The lipoic acid injection composition is applied to injection of skin mesoderm, and the lipoic acid is poor in solubility, so that the lipoic acid is dissolved by using cyclodextrin, and meanwhile, the stability of the lipoic acid can be ensured.
The term "cyclodextrin" as used herein includes any of the known cyclodextrins, such as unsubstituted cyclodextrins containing 6-12 glucose units and/or derivatives thereof and/or mixtures thereof. Preferably, the cyclodextrin used in the present application is highly water-soluble α -cyclodextrin and/or its derivatives, β -cyclodextrin and/or its derivatives, and γ -cyclodextrin and/or its derivatives, and/or mixtures thereof. The cyclodextrin derivatives consist essentially of molecules in which some of the OH groups are converted to OR groups, where R is an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Further preferably, the cyclodextrin is beta-cyclodextrin, further preferably hydroxypropyl-beta-cyclodextrin.
However, since the dissolution of lipoic acid using cyclodextrin also increases the stimulus even more, and when used for injection into the mesoderm of the skin, causes a stimulus response such as pain to the user and gives discomfort to the user, the present application uses a regulator, which is not limited, but any regulator that can be applied to the mesoderm and can relieve the stimulus to the mesoderm of the composition, and in a preferred embodiment, the regulator is hyaluronic acid or a salt thereof, to alleviate the stimulus to the mesoderm of the composition.
The hyaluronic acid refers to a biopolymer material composed of repeating units of N-acetyl-D-glucosamine and D-glucuronic acid that are linearly linked. The hyaluronic acid or salt thereof includes hyaluronic acid itself, a salt thereof, or a combination thereof. Examples of hyaluronate salts include, but are not limited to, inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, gold hyaluronate, cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate. In the present application, hyaluronic acid itself or a salt thereof may be used alone, or a combination of two or more kinds of hyaluronic acid or a salt thereof may be used.
In a preferred embodiment, the hyaluronic acid salt is a water-soluble salt of hyaluronic acid, and more preferably one or more of sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, and calcium hyaluronate.
In a preferred embodiment, the molecular weight of the hyaluronic acid or salt thereof is 2500-3500kDa, for example 2600kDa, 2700kDa, 2800kDa, 2900kDa, 3000kDa, 3100kDa, 3200kDa, 3300kDa, 3400kDa, and preferably 3000kDa.
In a preferred embodiment, the mass ratio of the lipoic acid to the cyclodextrin to the regulator is 1 (0.05-0.5): 0.01-0.4, for example 1:0.05:0.01、1:0.1:0.01、1:0.2:0.01、1:0.3:0.01、1:0.4:0.01、1:0.05:0.02、1:0.05:0.02、1:0.1:0.02、1:0.2:0.02、1:0.3:0.02、1:0.4:0.02、1:0.05:0.02、1:0.05:0.1、1:0.1:0.1、1:0.2:0.1、1:0.3:0.1、1:0.4:0.1、1:0.5:0.1、1:0.05:0.2、1:0.1:0.2、1:0.2:0.2、1:0.3:0.2、1:0.4:0.2、1:0.5:0.2、1:0.05:0.3、1:0.1:0.3、1:0.2:0.3、1:0.3:0.3、1:0.4:0.3、1:0.5:0.3、1:0.05:0.4、1:0.1:0.4、1:0.2:0.4、1:0.3:0.4、1:0.4:0.4、1:0.5:0.4,, preferably 1 (0.1-0.3): 0.02-0.2.
In a preferred embodiment, the regulator is hyaluronic acid or a salt thereof, and the mass ratio of the lipoic acid, the cyclodextrin and the hyaluronic acid or the salt thereof is 1 (0.05-0.5): 0.01-0.4, for example 1:0.05:0.01、1:0.1:0.01、1:0.2:0.01、1:0.3:0.01、1:0.4:0.01、1:0.05:0.02、1:0.05:0.02、1:0.1:0.02、1:0.2:0.02、1:0.3:0.02、1:0.4:0.02、1:0.05:0.02、1:0.05:0.1、1:0.1:0.1、1:0.2:0.1、1:0.3:0.1、1:0.4:0.1、1:0.5:0.1、1:0.05:0.2、1:0.1:0.2、1:0.2:0.2、1:0.3:0.2、1:0.4:0.2、1:0.5:0.2、1:0.05:0.3、1:0.1:0.3、1:0.2:0.3、1:0.3:0.3、1:0.4:0.3、1:0.5:0.3、1:0.05:0.4、1:0.1:0.4、1:0.2:0.4、1:0.3:0.4、1:0.4:0.4、1:0.5:0.4, may be preferably 1 (0.1-0.3): 0.02-0.2.
The composition of the application is added with a pH regulator to regulate the pH value of the composition, is suitable for mesoderm injection, avoids discomfort and inadaptation of skin, and promotes the dissolution of lipoic acid to a certain extent. The pH adjustor is not limited, and any pH adjustor commonly used in the art may be used, and in a preferred embodiment the pH adjustor is selected from one or more of tromethamine, sodium hydroxide, potassium hydroxide or triethanolamine.
The composition of the present application incorporates an osmolality adjusting agent, which is not limited, and is commonly used in the art, and in a preferred embodiment, sodium chloride, to adjust the osmolality of the composition to accommodate injection of mesoderm to avoid discomfort and inadaptation of the skin.
To further alleviate the irritation of the composition of the present application, for better application to mesodermal injections, the present application adds another stabilizer, while reducing the conventional amount of cyclodextrin used while ensuring that the cyclodextrin is capable of dissolving the lipoic acid, and at the same time, using another stabilizer to ensure the stability of the lipoic acid. In a preferred embodiment, the mass ratio of the lipoic acid, the cyclodextrin and the stabilizer is 1 (0.1-0.5): 0.2-2, for example 1:0.1:0.2、1:0.2:0.2、1:0.3:0.2、1:0.4:0.2、1:0.5:0.2、1:0.1:0.3、1:0.2:0.3、1:0.3:0.3、1:0.4:0.3、1:0.5:0.3、1:0.1:0.5、1:0.2:0.5、1:0.3:0.5、1:0.4:0.5、1:0.5:0.5、1:0.1:1、1:0.2:1、1:0.3:1、1:0.4:1、1:0.5:1、1:0.1:1.5、1:0.2:1.5、1:0.3:1.5、1:0.4:1.5、1:0.5:1.5、1:0.1:2、1:0.2:2、1:0.3:2、1:0.4:2、1:0.5:2.
The stabilizer is not limited in kind and may be any one or more stabilizers commonly used in the art, and in a preferred embodiment, the stabilizer includes carnosine and EDTA-2Na, and carnosine is used as a bioactive peptide, and has functions of buffering, regulating human body, scavenging free radicals, resisting oxidation, resisting aging, and preventing metabolic disorders. The carnosine can be prepared into injections in clinic, such as cerebroside carnosine, which can treat injuries of cerebral nerves. Carnosine can also correct the energy metabolism disorder of the human body by scavenging oxygen free radicals. The application uses carnosine as a stabilizer, utilizes the oxidation resistance of the carnosine to effectively protect the lipoic acid from being oxidized at high temperature, can also cooperate with the lipoic acid to resist oxidation to play a role in treating mesoderm, and can effectively solve the problem of fading of the lipoic acid under illumination by combining with EDTA-2 Na.
In a preferred embodiment, the stabilizer is carnosine and EDTA-2Na, and the mass ratio of the lipoic acid, the cyclodextrin and the (carnosine and EDTA-2 Na) is 1 (0.1-0.5): 0.2-2, for example 1:0.1:0.2、1:0.2:0.2、1:0.3:0.2、1:0.4:0.2、1:0.5:0.2、1:0.1:0.3、1:0.2:0.3、1:0.3:0.3、1:0.4:0.3、1:0.5:0.3、1:0.1:0.5、1:0.2:0.5、1:0.3:0.5、1:0.4:0.5、1:0.5:0.5、1:0.1:1、1:0.2:1、1:0.3:1、1:0.4:1、1:0.5:1、1:0.1:1.5、1:0.2:1.5、1:0.3:1.5、1:0.4:1.5、1:0.5:1.5、1:0.1:2、1:0.2:2、1:0.3:2、1:0.4:2、1:0.5:2.
In a preferred embodiment, the mass ratio of carnosine to EDTA-2Na is 1 (0.5-2), for example, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9.
The application also provides a method for preparing the injection composition applied to mesoderm, which comprises the steps of dissolving cyclodextrin in injection water, adding lipoic acid, stirring until the solution is clear and transparent, regulating the pH value of the solution by using a pH regulator, regulating the osmotic pressure by using an osmotic pressure regulator, adding the regulator after sterile filtration, stirring uniformly, and sterilizing to obtain the injection composition.
In a preferred embodiment of the above preparation method, the preparation method is performed at 40 to 50 ℃, for example, 41 ℃, 42 ℃, 43 ℃, 44 ℃,45 ℃, 46 ℃, 47 ℃, 48 ℃ and 49 ℃.
In a preferred embodiment of the above preparation method, the pH of the solution is adjusted to a pH value in the range of 8.5 to 9.5 with a pH adjuster, for example, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4.
In a preferred embodiment of the above preparation method, the pH of the injection composition obtained after sterilization is in the range of 7.0 to 7.3, for example, 7.1 and 7.2, and the osmotic pressure is 230 to 330mOsmol/kg, for example 240mOsmol/kg、250mOsmol/kg、260mOsmol/kg、270mOsmol/kg、280mOsmol/kg、290mOsmol/kg、300mOsmol/kg、310mOsmol/kg、320mOsmol/kg.
The application provides the application of the mesoderm injection composition disclosed by the application or the mesoderm injection composition prepared by any preparation method for preparing the mesoderm injection composition disclosed by the application in the aspects of resisting skin oxidization, reducing skin pigment, relieving skin roughness or relieving skin treatment pain.
The application also provides the use of hyaluronic acid or a salt thereof for alleviating the irritation of cyclodextrin.
The application further provides the use of carnosine and EDTA-2Na for stabilizing lipoic acid.
The application further provides the use of carnosine and EDTA-2Na to prevent oxidation of lipoic acid.
The application further provides the use of carnosine and EDTA-2Na to prevent the discoloration of lipoic acid.
The lipoic acid injection composition applied to mesoderm provided by the application ensures the stability of lipoic acid, and has no obvious change in appearance, yellowish transparent liquid, pH value and osmotic pressure within a standard range, no obvious reduction in the content of lipoic acid within the standard range and very good stability under the condition that 50 ℃ is accelerated for 6 months, and also ensures that the composition can normally exert the effects of resisting skin oxidation, reducing skin pigment, relieving skin roughness or relieving skin treatment pain.
The human body experiment shows that the lipoic acid injection composition has obvious effect of improving the dark, yellow, dry and matt complexion of the subject, and the composition has no obvious irritation and good comfort degree through feedback of the subject.
Examples
Examples 1 to 8 and comparative examples 1 and 2 lipoic acid injections were prepared as follows, and parameters such as kinds and amounts of raw materials are shown in Table 1.
1) At the temperature of 40-50 ℃, firstly, rapidly dissolving hydroxypropyl-beta-cyclodextrin, then adding lipoic acid, stirring until the solution is clear and transparent, regulating the pH range to 8.5-9.5 by using a pH regulator, subsequently adding a stabilizer and an osmotic pressure regulator, and uniformly stirring;
2) Adding regulator and supplementary solvent after aseptic filtration, stirring, sterilizing, and sterilizing to pH 7.0-7.3 and osmotic pressure 230-330mOsmol/kg.
In the preparation process, the impurities and bacteria possibly introduced by the micromolecular substances are removed by adopting a sterile filtration mode, and the filtration is carried out by adopting a 0.22-0.45um filter membrane. Considering that the regulator is macromolecular polymer (hyaluronic acid and salts thereof) and cannot pass through the pore diameter of 0.22-0.45um, the product is sterilized by adopting a damp-heat sterilization method. In order to maintain the effective activity of the injection to the maximum extent, the sterilization condition required by biological load is adopted, wherein the sterilization condition is 121 ℃,8min or 115 ℃ for 30min
Table 1 raw materials and amounts of examples and comparative examples
Test example 1 evaluation of stabilization Effect
The stability of the injection at the later stage of the accelerating condition of 50 ℃ is evaluated, and according to the requirements of four-9001 raw material medicaments and preparation stability test guidance principles of the "passive implantable medical device shelf life registration declaration data guide principle" and the "Chinese pharmacopoeia of the people's republic of China" 2020 edition, the stability test research is carried out on three groups of products, and the quality requirement change under different temperature environment conditions in the storage process is evaluated. The quality evaluation is referred to the quality evaluation study of lipoic acid injection preparation.
Table 2 data comparison of example 2 and control
According to the requirements of four-9001 raw material medicines and preparation stability test guidelines in the pharmacopoeia of the people's republic of China, the preparation is accelerated for 4 months at 50 ℃, the time is approximately equal to the placement time of 2 years at normal temperature (25 ℃), and the preparation is accelerated for 6 months at 50 ℃, and the placement time is approximately equal to the placement time of 3 years at normal temperature (25 ℃). As can be seen from table 2, in example 2 of the present application, each index is qualified within 6 months of the acceleration time, that is, the index meets the standard within the shelf life of 3 years, while in comparative example 1, no stabilizer carnosine and disodium ethylenediamine tetraacetate are added, the shelf life of 3 years cannot be achieved (appearance is not qualified, lipoic acid content is not qualified, and pH is not qualified), in comparative example 2, the stabilizer is replaced by sodium bisulphite, and the shelf life of 3 years cannot be achieved, which indicates that the addition of the stabilizer of the present application can further assist cyclodextrin to ensure the stability of the product in the later period. Whereas the stabilizer of example 8 was added with only carnosine and no disodium edetate, the accelerated stability was slightly inferior, indicating that in the present application, the simultaneous addition of the stabilizer carnosine and disodium edetate gave a better stabilizing effect on the composition, with a synergistic effect, over the use of the stabilizer alone (carnosine).
Test example 2 evaluation of human safety and efficacy
60 Volunteers were selected, and by comparing example 3 with example 4, example 3 with example 5, 60 volunteers were selected, and the ages were between 20 and 55 years, and divided into two groups. Volunteers were asked to darken, yellow, dry and matt skin tone. The right and left faces were injected with a Dema 2-substituted water light injector (nine needles), respectively, one set of injection example 3 (left face) and example 4 (right face), and the other set of injection example 3 (left face) and example 5 (right face), with an injection depth of 0.8-1.2mm. The composition of the invention of the examples was injected aseptically by washing the face prior to injection to take a photograph of VISA (Canfiled company sixth generation VISIA), then applying a layer of the facial plaster, removing the plaster after 30 minutes. And (5) applying a refrigerated sterile mechanical word size surface film for 20-30min after injection.
The observation index is that the skin color improvement is classified into five grades, namely obvious improvement, more obvious improvement, no obvious improvement, more obvious deterioration and obvious deterioration. The products were classified into four classes, very satisfactory, general, unsatisfactory, by the comfort of the injection.
Two weeks later, the VISA was taken by washing the face, and the skin tone was improved as compared with the VISA photograph before the treatment, and the results are shown in table 3. The volunteers were simultaneously allowed to self-evaluate in terms of both skin tone improvement and comfort (pain) and the evaluation results are shown in table 4.
TABLE 3VISA taken skin color improvement results
Table 4 volunteer self-evaluation
As can be seen from tables 3 and 4, example 3 is better than that of example 4 in effect, and scores high in satisfaction (pain), demonstrating that hyaluronic acid has a regulating effect on skin texture in addition to alleviating the irritation of hydroxypropyl- β -cyclodextrin. Example 5 is better than example 3, but brings about irritation at the same time, and has a lower comfort than example 3, but also has a satisfaction of 96% or more. No adverse reaction related to the product is generated, and the safety is good.
Although the embodiments of the present application have been described above in connection with the above, the present application is not limited to the above-described specific embodiments and fields of application, which are merely illustrative, instructive, and not restrictive. Those skilled in the art, having the benefit of this disclosure, may effect numerous forms of the application without departing from the scope of the application as claimed.
Claims (21)
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| CN202510091870.2A CN119818436A (en) | 2023-02-15 | 2023-02-15 | Lipoic acid injection composition applied to mesoderm and preparation method thereof |
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| CN1947716A (en) * | 2005-10-14 | 2007-04-18 | 车瓯 | Clathrate compound of alpha-lipoic acid-cyclodextrin derivatives, and its prepn. method |
| CN104840415A (en) * | 2014-02-19 | 2015-08-19 | 香港浸会大学 | Long-acting controlled-release liposome gel composition containing hypoglycemic active ingredient and preparation method thereof |
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| PT95826B (en) * | 1989-11-09 | 1997-11-28 | Asta Medica Ag | PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS CONTAINING AS ACTIVE INGREDIENT R-ALPHA-LIPONIC ACID OR S-ALPHA-LIPONIC ACID |
| CN102172352B (en) * | 2011-03-28 | 2013-05-08 | 江苏奥赛康药业股份有限公司 | Lipoic acid composition for injection and preparation method thereof |
| US20200383946A1 (en) * | 2019-05-07 | 2020-12-10 | Aciont Inc. | Lipoic acid formulations |
| CN110237229A (en) * | 2019-07-31 | 2019-09-17 | 孟雨 | A kind of pharmaceutical composition of mesotherapy and preparation method thereof for reducing skin pigment and treating pain degree |
| IT201900017387A1 (en) * | 2019-09-27 | 2021-03-27 | Bmg Pharma S P A | HYDROGEL BASED ON ZINC GLUCONATE AND ESTERS OF HYALURONIC ACID |
| CN113117143B (en) * | 2020-01-14 | 2023-11-28 | 渼颜空间(河北)生物科技有限公司 | Use of hyaluronic acid for producing biodegradable polymer microparticle formulations |
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| CN1947716A (en) * | 2005-10-14 | 2007-04-18 | 车瓯 | Clathrate compound of alpha-lipoic acid-cyclodextrin derivatives, and its prepn. method |
| CN104840415A (en) * | 2014-02-19 | 2015-08-19 | 香港浸会大学 | Long-acting controlled-release liposome gel composition containing hypoglycemic active ingredient and preparation method thereof |
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