WO2022105225A1 - Azelaic acid gel, preparation method therefor and application thereof - Google Patents
Azelaic acid gel, preparation method therefor and application thereof Download PDFInfo
- Publication number
- WO2022105225A1 WO2022105225A1 PCT/CN2021/101503 CN2021101503W WO2022105225A1 WO 2022105225 A1 WO2022105225 A1 WO 2022105225A1 CN 2021101503 W CN2021101503 W CN 2021101503W WO 2022105225 A1 WO2022105225 A1 WO 2022105225A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- azelaic acid
- parts
- carbitol
- gel according
- acid
- Prior art date
Links
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 title claims abstract description 298
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 9
- 206010000496 acne Diseases 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 208000012641 Pigmentation disease Diseases 0.000 claims abstract description 7
- 239000012535 impurity Substances 0.000 claims abstract description 4
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 16
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 15
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 15
- 229920000058 polyacrylate Polymers 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- 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
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000000284 extract Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 240000006053 Garcinia mangostana Species 0.000 claims description 6
- 235000017048 Garcinia mangostana Nutrition 0.000 claims description 6
- 240000004670 Glycyrrhiza echinata Species 0.000 claims description 6
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 claims description 6
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 claims description 6
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 claims description 6
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 6
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 6
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 claims description 6
- 150000004676 glycans Chemical class 0.000 claims description 6
- BJRNKVDFDLYUGJ-RMPHRYRLSA-N hydroquinone O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-RMPHRYRLSA-N 0.000 claims description 6
- 229940010454 licorice Drugs 0.000 claims description 6
- 230000003020 moisturizing effect Effects 0.000 claims description 6
- 229920001282 polysaccharide Polymers 0.000 claims description 6
- 239000005017 polysaccharide Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 150000003751 zinc Chemical class 0.000 claims description 6
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 5
- 230000003255 anti-acne Effects 0.000 claims description 5
- 229920005862 polyol Polymers 0.000 claims description 5
- 150000003077 polyols Chemical class 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 4
- 108010012715 Superoxide dismutase Proteins 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- -1 isopentyl glycol Chemical compound 0.000 claims description 4
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- 230000035515 penetration Effects 0.000 claims description 4
- 239000000419 plant extract Substances 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- WTVHAMTYZJGJLJ-UHFFFAOYSA-N (+)-(4S,8R)-8-epi-beta-bisabolol Natural products CC(C)=CCCC(C)C1(O)CCC(C)=CC1 WTVHAMTYZJGJLJ-UHFFFAOYSA-N 0.000 claims description 3
- RGZSQWQPBWRIAQ-CABCVRRESA-N (-)-alpha-Bisabolol Chemical compound CC(C)=CCC[C@](C)(O)[C@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-CABCVRRESA-N 0.000 claims description 3
- 229940043375 1,5-pentanediol Drugs 0.000 claims description 3
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims description 3
- AJBZENLMTKDAEK-UHFFFAOYSA-N 3a,5a,5b,8,8,11a-hexamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-4,9-diol Chemical compound CC12CCC(O)C(C)(C)C1CCC(C1(C)CC3O)(C)C2CCC1C1C3(C)CCC1C(=C)C AJBZENLMTKDAEK-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 244000144927 Aloe barbadensis Species 0.000 claims description 3
- 235000002961 Aloe barbadensis Nutrition 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- 235000007319 Avena orientalis Nutrition 0.000 claims description 3
- 241000209763 Avena sativa Species 0.000 claims description 3
- 235000007558 Avena sp Nutrition 0.000 claims description 3
- 235000003880 Calendula Nutrition 0.000 claims description 3
- 240000001432 Calendula officinalis Species 0.000 claims description 3
- 244000146462 Centella asiatica Species 0.000 claims description 3
- 235000004032 Centella asiatica Nutrition 0.000 claims description 3
- 235000007866 Chamaemelum nobile Nutrition 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- 239000005639 Lauric acid Substances 0.000 claims description 3
- BNMGUJRJUUDLHW-HCZMHFOYSA-N Madecassoside Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)OC[C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)OC(=O)[C@]12CC[C@H]([C@@H]([C@H]1C=1[C@@]([C@@]3(C[C@@H](O)[C@H]4[C@](C)(CO)[C@@H](O)[C@H](O)C[C@]4(C)[C@H]3CC=1)C)(C)CC2)C)C)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O BNMGUJRJUUDLHW-HCZMHFOYSA-N 0.000 claims description 3
- BNMGUJRJUUDLHW-HLUHVYOBSA-N Madecassoside Natural products C[C@@H]1CC[C@@]2(CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5[C@H](O)C[C@@]34C)[C@@H]2[C@H]1C)C(=O)O[C@@H]6O[C@H](CO[C@@H]7O[C@H](CO)[C@@H](O[C@@H]8O[C@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@@H](O)[C@H](O)[C@H]6O BNMGUJRJUUDLHW-HLUHVYOBSA-N 0.000 claims description 3
- 244000042664 Matricaria chamomilla Species 0.000 claims description 3
- 235000007232 Matricaria chamomilla Nutrition 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 244000234609 Portulaca oleracea Species 0.000 claims description 3
- 235000001855 Portulaca oleracea Nutrition 0.000 claims description 3
- 244000181025 Rosa gallica Species 0.000 claims description 3
- 235000011402 Rosa x damascena Nutrition 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 3
- 235000011399 aloe vera Nutrition 0.000 claims description 3
- RGZSQWQPBWRIAQ-LSDHHAIUSA-N alpha-Bisabolol Natural products CC(C)=CCC[C@@](C)(O)[C@@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-LSDHHAIUSA-N 0.000 claims description 3
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 229960000271 arbutin Drugs 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- QCYLIQBVLZBPNK-UHFFFAOYSA-N asiaticoside A Natural products O1C(C(=O)C(C)C)=CC(C)C(C2(C(OC(C)=O)CC34C5)C)C1CC2(C)C3CCC(C1(C)C)C45CCC1OC1OCC(O)C(O)C1O QCYLIQBVLZBPNK-UHFFFAOYSA-N 0.000 claims description 3
- 229940036350 bisabolol Drugs 0.000 claims description 3
- HHGZABIIYIWLGA-UHFFFAOYSA-N bisabolol Natural products CC1CCC(C(C)(O)CCC=C(C)C)CC1 HHGZABIIYIWLGA-UHFFFAOYSA-N 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 3
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 3
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 3
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 3
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 3
- 229930003935 flavonoid Natural products 0.000 claims description 3
- 150000002215 flavonoids Chemical class 0.000 claims description 3
- 235000017173 flavonoids Nutrition 0.000 claims description 3
- 229960005150 glycerol Drugs 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229960004488 linolenic acid Drugs 0.000 claims description 3
- 229940090813 madecassoside Drugs 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003961 penetration enhancing agent Substances 0.000 claims description 3
- WCVRQHFDJLLWFE-UHFFFAOYSA-N pentane-1,2-diol Chemical compound CCCC(O)CO WCVRQHFDJLLWFE-UHFFFAOYSA-N 0.000 claims description 3
- 229960005323 phenoxyethanol Drugs 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical class 0.000 claims description 3
- 230000002207 retinal effect Effects 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 229960002920 sorbitol Drugs 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical group NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 2
- 150000001277 beta hydroxy acids Chemical class 0.000 claims description 2
- 239000002537 cosmetic Substances 0.000 claims description 2
- 229960003966 nicotinamide Drugs 0.000 claims description 2
- 235000005152 nicotinamide Nutrition 0.000 claims description 2
- 239000011570 nicotinamide Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 2
- 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 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims 2
- 235000009024 Ceanothus sanguineus Nutrition 0.000 claims 1
- 240000003553 Leptospermum scoparium Species 0.000 claims 1
- 235000015459 Lycium barbarum Nutrition 0.000 claims 1
- 229940093476 ethylene glycol Drugs 0.000 claims 1
- 229960003080 taurine Drugs 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 45
- 239000000047 product Substances 0.000 description 34
- 210000003491 skin Anatomy 0.000 description 19
- 239000003349 gelling agent Substances 0.000 description 18
- 239000006071 cream Substances 0.000 description 11
- 239000002994 raw material Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000035699 permeability Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000004584 polyacrylic acid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940061720 alpha hydroxy acid Drugs 0.000 description 2
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
- 229960003473 androstanolone Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 235000020945 retinal Nutrition 0.000 description 2
- 230000037384 skin absorption Effects 0.000 description 2
- 231100000274 skin absorption Toxicity 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940111630 tea tree oil Drugs 0.000 description 2
- 239000010677 tea tree oil Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- 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 group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- XHZPRMZZQOIPDS-UHFFFAOYSA-N 2-Methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(C)(C)NC(=O)C=C XHZPRMZZQOIPDS-UHFFFAOYSA-N 0.000 description 1
- XVPBINOPNYFXID-JARXUMMXSA-N 85u4c366qs Chemical compound C([C@@H]1CCC[N@+]2(CCC[C@H]3[C@@H]21)[O-])N1[C@@H]3CCCC1=O XVPBINOPNYFXID-JARXUMMXSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010064503 Excessive skin Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 1
- 229960002916 adapalene Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- BQMNFPBUAQPINY-UHFFFAOYSA-N azane;2-methyl-2-(prop-2-enoylamino)propane-1-sulfonic acid Chemical compound [NH4+].[O-]S(=O)(=O)CC(C)(C)NC(=O)C=C BQMNFPBUAQPINY-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229930015582 oxymatrine Natural products 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N retinal group Chemical group C\C(=C/C=O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/362—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Definitions
- the invention relates to azelaic acid gel, a preparation method and application thereof, and belongs to the technical field of skin external medicines.
- Azelaic acid also known as azelaic acid, appears as white to yellowish monoclinic prisms, needle-like crystals or powder. With antibacterial effect, it can directly inhibit and kill bacteria on the skin surface and in hair follicles; competitively inhibit the enzymatic process of producing dihydrotestosterone, reduce excessive skin oil caused by dihydrotestosterone factors; inhibit the production of active oxygen free radicals and role, is conducive to anti-inflammatory.
- the invention patent with the application number 201610786026.2 discloses an acne cream and a preparation method thereof, which consists of a morning cream and a night cream, wherein the night cream includes a second raw material and a cream base, and the second raw material is composed of the following substances Composition: 10% azelaic acid, 0.1% adapalene, 1% clindamycin, 1% salicylic acid, 1.5% oleaginous azone and 0.2% nepalin.
- the invention patent with the application number 201210230433.7 discloses an ointment for treating acne, which consists of oxymatrine 3%, vitamin E 1%, azelaic acid 2%, menthol 0.5%, 2901 5% by mass percentage, 3% of boric acid, 2% of azone and 83.5% by mass of cream base were mixed to prepare an ointment.
- these ointments use oily raw materials to dissolve azelaic acid, and at the same time add a penetrant (usually oily raw materials) to promote its penetration in the skin, so that the products can only be oily creams or lotions. If the dosage of azelaic acid is large, the amount of oily raw materials will be large, and the dosage of strong permeability will be larger, and the side effects will be greater. Therefore, cream-type azelaic acid is relatively oily, has poor air permeability, and has large side effects.
- the Chinese invention patent with the application number of CN2018108258077 discloses an azelaic acid gel, which uses 1,3-propanediol mixed with water as a solvent, and the azelaic acid is made into a gel, which can change the greasy feeling of the cream and does not It will increase the burden on the skin and block the pores, so as to avoid the corresponding side effects caused by the excessive introduction of oily substances.
- the content of azelaic acid in the gel can only reach about 18%, and the permeability of the gel is not enough. The skin absorption effect also needs to be further improved.
- the technical problem solved by the present invention is to provide a gelling agent of azelaic acid with better absorption.
- the azelaic acid gel of the present invention has a gel component comprising azelaic acid, a pharmaceutically acceptable gel excipient, and inevitable impurities; wherein the pharmaceutically acceptable gel excipient comprises Carbitol.
- the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents.
- the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase, ascorbic acid and arbutin;
- the preservative is ethylene glycol, pentylene glycol , at least one in phenoxyethanol, glycerin, sorbitol, paraben and cymene-5-ol;
- the penetration enhancer is at least one in polyol and azone;
- the moisturizing agent is hyaluronic acid At least one of sodium and polysaccharide, the polysaccharide includes dextran;
- the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and ammonium acryloyldimethyltaurate;
- the pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine;
- the exfoliating agent is at least one of ⁇ -hydroxy acid and ⁇ -
- the anti-inflammatory agent is at least one of nicotinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salt, bisabolol and plant extracts, and the plant
- the extract is extracted from at least one of purslane, tea tree oil, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile, and mangosteen.
- the weight ratio of azelaic acid to carbitol is 1:1-10. In a specific embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:2-10.
- the content of azelaic acid in the gelling agent is 10-30 wt %. In a specific embodiment, the content of azelaic acid is 15-25 wt %. In a more specific embodiment, the content of azelaic acid is 18-25 wt %.
- the azelaic acid gelling agent comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylate Cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- the azelaic acid gelling agent comprises the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; polyacrylic acid Ester cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- the azelaic acid gelling agent comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propanediol; 7 parts of water; polyacrylate cross-linked polymer- 63 servings; 60 servings of carbitol.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylic acid Ester cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Acrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; polyacrylate cross-linked polymer -6 3 servings; Carbitol 60 servings.
- the invention also provides a preparation method of azelaic acid gel.
- the preparation method of azelaic acid gel of the present invention comprises the following steps:
- the temperature after heating is preferably lower than 65°C.
- the present invention also provides the use of the azelaic acid gel of the present invention for preparing medicines, cosmetics or skin care products for treating anti-inflammatory, acne or pigmentation disorders.
- the azelaic acid gel of the present invention uses azelaic acid as an active ingredient, and can be used for treating anti-inflammatory, acne or pigmentation disorders. When used, it can be applied directly to the skin.
- the present invention has the following beneficial effects:
- the present invention finds for the first time that the use of carbitol in azelaic acid gel can promote the transdermal absorption of azelaic acid in the skin, and can increase the concentration of azelaic acid in the product, improve the skin feel of the product, and thereby improve the curative effect.
- the azelaic acid gel of the invention has good absorption and good curative effect, and can be used for preparing medicines for treating anti-inflammatory, acne or pigmentation disorders.
- the azelaic acid gel of the present invention has a gel component comprising azelaic acid, a pharmaceutically acceptable gel excipient, and inevitable impurities; wherein the pharmaceutically acceptable gel excipient comprises Carbitol.
- Carbitol also known as diethylene glycol monoethyl ether and diethylene glycol ethyl ether, is a colorless, water-absorptive and stable liquid. It is often used as a solvent for nitrocellulose, resins, spray paints, dyes, etc. It is a high boiling point solvent. Studies have found that carbitol can not only dissolve azelaic acid so that it can be prepared into a gel, but also promote the transdermal absorption of azelaic acid. When it is used in azelaic acid gel, it can promote skin absorption of azelaic acid. diacids, thereby enhancing the efficacy of the gel.
- the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents.
- the addition amount of these gelling adjuvants can be the conventional amount in the field.
- the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase (SOD), ascorbic acid and arbutin;
- the preservative is ethyl acetate at least one of glycol, pentylene glycol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-ol;
- the penetration enhancer is at least one of polyol and azone;
- the The moisturizing agent is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide includes dextran;
- the stabilizer is carbomer, poloxamer, hydroxyethyl cellulose and acryloyldimethyltaurine At least one of ammonium;
- the pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine;
- the exfoliating agent is ⁇ -
- the medium-chain fatty acid of the present invention is a kind of compound composed of carbon, hydrogen and oxygen, and is a fatty acid with 8-10 carbon atoms in the carbon chain.
- the weight ratio of azelaic acid to carbitol is 1:1-10. It was found that the solubility of azelaic acid in carbitol increased with increasing temperature. In the production of gelling agents, in order to increase the content of azelaic acid, the temperature is generally increased. However, when the temperature exceeds 65 °C, the color of the product will deepen. Therefore, in order to ensure the better properties of the product, the general production The system temperature was maintained at 60°C. At this temperature, the solubility of azelaic acid in carbitol is 52.71 g. Therefore, the weight ratio of azelaic acid to carbitol is preferably 1:2 or less.
- azelaic acid is The weight ratio of acid to carbitol is 1:2-10.
- the azelaic acid content in the azelaic acid gel can be adjusted as required.
- the content of azelaic acid in the gelling agent is 10-30 wt %.
- the content of azelaic acid is 15-25 wt %.
- the content of azelaic acid is 18-25 wt %.
- the content of azelaic acid may be 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25%, and the like.
- the azelaic acid gelling agent comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylate Cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- the azelaic acid gelling agent comprises the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; polyacrylic acid Ester cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- the azelaic acid gelling agent comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propanediol; 7 parts of water; polyacrylate cross-linked polymer- 63 servings; 60 servings of carbitol.
- ZEN Polyacrylate cross-linked polymer-6, abbreviated as ZEN, is produced by French company SepiMAX under the trade name SepiMAX ZEN.
- ZEN is an associative polymer with excellent resistance to electrolysis. It can resist the damage caused by electrolytes to the formula to the greatest extent, and at the same time, it also has good suspension stability, and can produce transparent hydrogel products with a moist and elegant touch and a velvety texture.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylic acid Ester cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Acrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- the azelaic acid gelling agent is composed of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; polyacrylate cross-linked polymer -6 3 servings; Carbitol 60 servings.
- the preparation method of azelaic acid gel of the present invention comprises the following steps:
- step a may be performed first and then step b, or step b may be performed first and then step a, or step a and step b may be performed simultaneously. Just mix solution A and solution B at the end and stir well.
- step b the heating temperature is based on the dissolution of azelaic acid until transparent. Experimental studies have shown that azelaic acid is insoluble in water, oil and polyol at room temperature, and the temperature needs to be raised to 55°C during product preparation, and when it exceeds 65°C, the product will appear darker in color. Therefore, in step b, The temperature after heating is preferably lower than 65°C.
- the temperature of step b is 60°C.
- the solubility of azelaic acid in carbitol is 52.71g, which is higher than that of 1,3 propylene glycol (40.33g), which can effectively increase the content of azelaic acid in the product.
- the azelaic acid gel of the present invention uses azelaic acid as an active ingredient, and can be used for treating anti-inflammatory, acne or pigmentation disorders. When used, it can be applied directly to the skin.
- the raw materials used in the examples are:
- Azelaic acid purchased from Shanghai Linen Technology Development Co., Ltd.;
- Carbitol purchased from Shanghai McLean Biochemical Technology Co., Ltd.;
- 1,3-Propanediol corn source, purchased from DuPont, USA;
- Water Homemade deionized water.
- Azelaic acid gel formulated as:
- Liquid A ZEN 3%; Carbitol 10%; Water 7%.
- Liquid B azelaic acid 20%; 1,3 propylene glycol 10%; carbitol 50%.
- Azelaic acid gel formulated as:
- Liquid A ZEN 2%; Carbitol 10%; Water 13%.
- Liquid B azelaic acid 15%; 1,3 propylene glycol 10%; carbitol 50%.
- Product No. 1 the product of Example 2, its formula is: azelaic acid 15%, ZEN 2%, carbitol 60%, 1,3-propanediol 10%, water 13%.
- Product No. 2 the product in the patent CN2018108258077, its formula is: azelaic acid 15%, ZEN 2%, 1,3-propanediol 70%, water 13%.
- Azelaic acid cream Reference substance AZECLEAR Cream, HK-59866, batch number R595, Australia Frunkang Pharmaceutical Co., Ltd., the content of azelaic acid is 20%;
- Base fluid colorless, transparent gel, free of azelaic acid, consisting only of carbitol, ZEN, 1,3-propanediol and water.
- SPF barrier system Institute of Pharmacology and Toxicology, Sichuan Academy of Traditional Chinese Medicine.
- the indoor temperature is 20 ⁇ 22°C
- the relative humidity is 40% ⁇ 70%
- the light and dark are alternately illuminated for 12 hours.
- the license number is SYXK (Chuan) 2018-19. Free access to water. Standard feed was provided by the Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine.
- mice 48 KM mice, half male and half male, were divided into 4 groups with 12 mice in each group, namely No. 1 product group, No. 2 product group, No. 3 product group and matrix liquid group.
- Depilatory cream was used to remove the abdominal hair of mice, and the test sample solution was applied to the depilation site, with 0.5g/kg applied to each part, and the smeared area was about 3.0 ⁇ 3.0cm 2 .
- the animals were euthanized by cervical dislocation 1 hour after application, and the skin of the application site was taken and removed.
- Deep muscle tissue weigh 0.1 g of skin, cut into pieces, homogenize with 1 ml of 70% methanol, shake and soak for 2 h, centrifuge at 3000 r/min for 10 min, take the supernatant, and measure the absorbance at 450 nm according to the instructions of the ELISA kit.
- the azelaic acid concentration was calculated according to the standard curve, see Table 1.
- the azelaic acid gel was prepared according to the method described in Example 1, wherein the total consumption of each raw material is shown in Table 2, and the properties of the prepared gel are also shown in Table 2.
- the gel is prepared according to the product formula in the patent CN2018108258077, and its specific formula is: azelaic acid 20%, ZEN 3%, 1,3-propanediol 70%, water 7%.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Abstract
An azelaic acid gel and a preparation method therefor, which are characterized in that: components of the gel comprise azelaic acid and a pharmaceutically acceptable gel excipient and inevitable impurities, the pharmaceutically acceptable gel excipient comprising carbitol. The gel can be used for anti-inflammation and the treatment of acne or pigmentation disorders.
Description
本发明涉及壬二酸凝胶剂及其制备方法和应用，属于皮肤外用药物技术领域。The invention relates to azelaic acid gel, a preparation method and application thereof, and belongs to the technical field of skin external medicines.
壬二酸，又名杜鹃花酸，外观为白色至微黄色单斜棱晶、针状结晶或粉末。具有抗菌的作用，可以直接抑制和杀灭皮肤表面和毛囊内的细菌；竞争性抑制产生二氢睾酮的酶过程，减少二氢睾酮因素诱发的皮肤油脂过多；抑制活性氧自由基的产生和作用，有利于抗炎。常用于痤疮、玫瑰痤疮，色素沉着紊乱等的治疗。对皮肤有较好的渗透性，可增加皮肤的吸收功能。但受高温易分解，因此，在使用时不宜高温加入。易溶于热水、酒精及部分多元醇，微溶于冷水、醚和苯。Azelaic acid, also known as azelaic acid, appears as white to yellowish monoclinic prisms, needle-like crystals or powder. With antibacterial effect, it can directly inhibit and kill bacteria on the skin surface and in hair follicles; competitively inhibit the enzymatic process of producing dihydrotestosterone, reduce excessive skin oil caused by dihydrotestosterone factors; inhibit the production of active oxygen free radicals and role, is conducive to anti-inflammatory. Commonly used in the treatment of acne, rosacea, pigmentation disorders, etc. It has good permeability to the skin and can increase the absorption function of the skin. However, it is easily decomposed by high temperature, so it should not be added at high temperature during use. Soluble in hot water, alcohol and some polyols, slightly soluble in cold water, ether and benzene.
目前，对于壬二酸产品，常做成膏剂，目的是为增加其溶解性和渗透性。比如，申请号为201610786026.2的发明专利公开了一种痤疮膏及其制备方法，由早用膏剂和晚用膏剂组成，其中的晚用膏剂包括第二原料和乳膏基质，第二原料由以下物质组成：10％壬二酸，0.1％阿达帕林，1％克林霉素，1％水杨酸，1.5％油脂性氮酮和0.2％尼泊尔金甲酯。又如，申请号为201210230433.7的发明专利公开了一种治疗痤疮的药膏，按质量百分比由氧化苦参碱3％，维生素E 1％，壬二酸2％，薄荷脑0.5％，2901 5％，硼酸3％，氮酮2％与乳膏基质83.5％质量百分比混合制成膏剂。Currently, azelaic acid products are often made into ointments in order to increase their solubility and permeability. For example, the invention patent with the application number 201610786026.2 discloses an acne cream and a preparation method thereof, which consists of a morning cream and a night cream, wherein the night cream includes a second raw material and a cream base, and the second raw material is composed of the following substances Composition: 10% azelaic acid, 0.1% adapalene, 1% clindamycin, 1% salicylic acid, 1.5% oleaginous azone and 0.2% nepalin. Another example, the invention patent with the application number 201210230433.7 discloses an ointment for treating acne, which consists of oxymatrine 3%, vitamin E 1%, azelaic acid 2%, menthol 0.5%, 2901 5% by mass percentage, 3% of boric acid, 2% of azone and 83.5% by mass of cream base were mixed to prepare an ointment.
但是，这些膏剂均是通过油性的原料来溶解壬二酸，同时加入助渗透剂(一般为油性原料)促进它在皮肤中的渗透，这样就使得产品只能是含油的膏霜或者乳液。壬二酸的用量大则油性原料用量则多，渗透性强助渗剂量也越大，副作用也越大。因此，膏霜型的壬二酸相对油感厚重，透气性差，副作用较大。However, these ointments use oily raw materials to dissolve azelaic acid, and at the same time add a penetrant (usually oily raw materials) to promote its penetration in the skin, so that the products can only be oily creams or lotions. If the dosage of azelaic acid is large, the amount of oily raw materials will be large, and the dosage of strong permeability will be larger, and the side effects will be greater. Therefore, cream-type azelaic acid is relatively oily, has poor air permeability, and has large side effects.
申请号为CN2018108258077的中国发明专利公开了一种壬二酸凝胶剂，采用1,3-丙二醇和水混合作为溶剂，将壬二酸做成凝胶剂，可以改变膏霜的油腻感，不会增加皮肤上的负担和堵塞毛孔，从而避免因油性物质过度引入而产生相应的副作用，但是，该凝胶剂中的壬二酸的含量仅能达到18％左右，且该凝胶剂的透皮吸收效果也有待进一步提高。The Chinese invention patent with the application number of CN2018108258077 discloses an azelaic acid gel, which uses 1,3-propanediol mixed with water as a solvent, and the azelaic acid is made into a gel, which can change the greasy feeling of the cream and does not It will increase the burden on the skin and block the pores, so as to avoid the corresponding side effects caused by the excessive introduction of oily substances. However, the content of azelaic acid in the gel can only reach about 18%, and the permeability of the gel is not enough. The skin absorption effect also needs to be further improved.
发明内容SUMMARY OF THE INVENTION
为了克服以上缺陷，本发明解决的技术问题是提供一种吸收较好的壬二酸凝胶剂。In order to overcome the above defects, the technical problem solved by the present invention is to provide a gelling agent of azelaic acid with better absorption.
本发明壬二酸凝胶剂，其凝胶剂组分包含壬二酸和药学上可接受的凝胶剂辅料，以及不可避免的杂质；其中，所述药学上可接受的凝胶剂辅料包含卡必醇。The azelaic acid gel of the present invention has a gel component comprising azelaic acid, a pharmaceutically acceptable gel excipient, and inevitable impurities; wherein the pharmaceutically acceptable gel excipient comprises Carbitol.
在本发明的一个实施方式中，所述药学上可接受的凝胶剂辅料还包括抗氧化剂、防腐剂、促透剂、保湿剂、稳定剂、去角质剂、pH调节剂、抗菌剂和抗炎剂中的至少一种。In one embodiment of the present invention, the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents.
在本发明的一个实施方式中，所述抗氧化剂为甘草黄酮、积雪草苷、超氧化物歧化酶、抗坏血酸和熊果苷中至少一种；所述防腐剂为乙二醇、戊二醇、苯氧乙醇、甘油、山梨醇、尼泊金酯和伞花烃-5-醇中至少一种；所述促透剂为多元醇和氮酮中至少一种；所述保湿剂为透明质酸钠和多糖中至少一种，所述多糖包括葡聚糖；所述稳定剂为卡波姆、泊洛沙姆、羟乙基纤维素和丙烯酰二甲基牛磺酸铵中至少一种；所述pH调节剂为氢氧化钾、氢氧化钠、磷酸氢二钠、三乙醇胺和精氨酸中至少一种；所述去角质剂为a-羟基酸和β-羟基酸中至少一种；所述抗菌剂为季铵盐-73、水杨酸、异戊二醇、滇重楼提取物、锌盐、月桂酸、月桂酸乙酯、中链脂肪酸、视网醛和山竹提取物中至少一种；所述抗炎剂为烟酰胺、α-亚麻酸、二十碳五烯酸、二十二碳六烯酸、锌盐、没红药醇和植物提取物中至少一种，所述植物提取物提取自马齿苋、茶树油、燕麦、芦荟、金盏花、积雪草、甘草、大马士革玫瑰、西洋甘菊和山竹中至少一种。In one embodiment of the present invention, the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase, ascorbic acid and arbutin; the preservative is ethylene glycol, pentylene glycol , at least one in phenoxyethanol, glycerin, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one in polyol and azone; the moisturizing agent is hyaluronic acid At least one of sodium and polysaccharide, the polysaccharide includes dextran; the stabilizer is at least one of carbomer, poloxamer, hydroxyethyl cellulose and ammonium acryloyldimethyltaurate; The pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is at least one of α-hydroxy acid and β-hydroxy acid; Described antibacterial agent is at least among quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, retinal and mangosteen extract. One; the anti-inflammatory agent is at least one of nicotinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salt, bisabolol and plant extracts, and the plant The extract is extracted from at least one of purslane, tea tree oil, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile, and mangosteen.
在本发明的一个实施方式中，壬二酸与卡必醇的重量比为1:1～10。在本发明的一个具体实施方式中，壬二酸与卡必醇的重量比为1:2～10。In one embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:1-10. In a specific embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:2-10.
在本发明的一个实施方式中，凝胶剂中的壬二酸的含量为10～30wt％。在一个具体的实施方式中，壬二酸的含量为15～25wt％。在一个更具体的实施方式中，壬二酸的含量为18～25wt％。In one embodiment of the present invention, the content of azelaic acid in the gelling agent is 10-30 wt %. In a specific embodiment, the content of azelaic acid is 15-25 wt %. In a more specific embodiment, the content of azelaic acid is 18-25 wt %.
在本发明的一个实施方式中，壬二酸凝胶剂包含以下重量份的组分：壬二酸10～30份；1,3-丙二醇0～30份；水1～20份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。In one embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylate Cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
在本发明的一个具体实施方式中，壬二酸凝胶剂包含以下重量份的组分：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; polyacrylic acid Ester cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
在本发明的一个具体实施例中，壬二酸凝胶剂包含以下重量份的组分：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propanediol; 7 parts of water; polyacrylate cross-linked polymer- 63 servings; 60 servings of carbitol.
在本发明的一个实施方式中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸10～30份；1,3-丙二醇0～30份；水1～20份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。In one embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylic acid Ester cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
在本发明的一个具体实施方式中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Acrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
在本发明的一个具体实施例中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; polyacrylate cross-linked polymer -6 3 servings; Carbitol 60 servings.
本发明还提供一种壬二酸凝胶剂的制备方法。The invention also provides a preparation method of azelaic acid gel.
本发明壬二酸凝胶剂的制备方法，包括以下步骤：The preparation method of azelaic acid gel of the present invention comprises the following steps:
a、将聚丙烯酸酯交联聚合物-6均匀分散于卡必醇中后，再与水混合均匀，得到溶液A；a. After the polyacrylate cross-linked polymer-6 is uniformly dispersed in the carbitol, it is mixed with water to obtain solution A;
b、将壬二酸均匀分散于卡必醇和1,3-丙二醇中，加热至透明，得到溶液B；b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;
c、将溶液A、溶液B混合，搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
步骤b中，优选加热后的温度低于65℃。In step b, the temperature after heating is preferably lower than 65°C.
本发明还提供本发明所述的壬二酸凝胶剂用于制备治疗抗炎、痤疮或色素沉着紊乱的药物、化妆品或护肤品中的用途。The present invention also provides the use of the azelaic acid gel of the present invention for preparing medicines, cosmetics or skin care products for treating anti-inflammatory, acne or pigmentation disorders.
本发明的壬二酸凝胶剂，以壬二酸为有效成分，能够用于治疗抗炎、痤疮或色素沉着紊乱。其使用时，可直接涂抹在皮肤上。The azelaic acid gel of the present invention uses azelaic acid as an active ingredient, and can be used for treating anti-inflammatory, acne or pigmentation disorders. When used, it can be applied directly to the skin.
与现有技术相比，本发明具有如下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明首次发现将卡必醇用于壬二酸凝胶剂中，可以促进壬二酸在皮肤中的透皮吸收，且能够提高产品中壬二酸的浓度，改善产品的肤感，从而提高疗效。本发明的壬二酸凝胶剂，吸收好，疗效佳，可用于制备治疗抗炎、痤疮或色素沉着紊乱的药物中。The present invention finds for the first time that the use of carbitol in azelaic acid gel can promote the transdermal absorption of azelaic acid in the skin, and can increase the concentration of azelaic acid in the product, improve the skin feel of the product, and thereby improve the curative effect. The azelaic acid gel of the invention has good absorption and good curative effect, and can be used for preparing medicines for treating anti-inflammatory, acne or pigmentation disorders.
本发明壬二酸凝胶剂，其凝胶剂组分包含壬二酸和药学上可接受的凝胶剂辅料，以及不可避免的杂质；其中，所述药学上可接受的凝胶剂辅料包含卡必醇。The azelaic acid gel of the present invention has a gel component comprising azelaic acid, a pharmaceutically acceptable gel excipient, and inevitable impurities; wherein the pharmaceutically acceptable gel excipient comprises Carbitol.
卡必醇，又名二甘醇单***、二乙二醇***，为无色、吸水性稳定的液体，常用作硝酸纤维素、树脂、喷漆、染料等的溶剂，是高沸点溶剂。研究发现，卡必醇不仅 可以溶解壬二酸，使其能够制备成凝胶剂，还能促进壬二酸的透皮吸收，将其用在壬二酸凝胶剂中，能够促进皮肤吸收壬二酸，从而提高凝胶剂的疗效。Carbitol, also known as diethylene glycol monoethyl ether and diethylene glycol ethyl ether, is a colorless, water-absorptive and stable liquid. It is often used as a solvent for nitrocellulose, resins, spray paints, dyes, etc. It is a high boiling point solvent. Studies have found that carbitol can not only dissolve azelaic acid so that it can be prepared into a gel, but also promote the transdermal absorption of azelaic acid. When it is used in azelaic acid gel, it can promote skin absorption of azelaic acid. diacids, thereby enhancing the efficacy of the gel.
此外，在现有CN2018108258077的凝胶剂体系中，用水和1,3丙二醇为溶剂，受壬二酸在1,3丙二醇中溶解度的影响，该凝胶剂中壬二酸的含量最多可以达到18％，如果再增多，将面临着出现结晶、产品不稳定等缺陷。而发明人发现，在凝胶剂体系中添加卡必醇，以卡必醇为溶剂，壬二酸的溶解度提高，在将其制备成凝胶剂时，能够提高产品中的壬二酸含量，从而提高产品的有效成分浓度。In addition, in the existing gel system of CN2018108258077, water and 1,3 propylene glycol are used as solvents, and due to the influence of the solubility of azelaic acid in 1,3 propylene glycol, the content of azelaic acid in the gel can reach up to 18 %, if it increases, it will face defects such as crystallization and product instability. The inventor found that adding carbitol to the gel system and using carbitol as a solvent improves the solubility of azelaic acid. When it is prepared into a gel, the content of azelaic acid in the product can be increased. Thereby increasing the active ingredient concentration of the product.
在本发明的一个实施方式中，所述药学上可接受的凝胶剂辅料还包括抗氧化剂、防腐剂、促透剂、保湿剂、稳定剂、去角质剂、pH调节剂、抗菌剂和抗炎剂中的至少一种。这些凝胶剂辅料的添加量可以为本领域常规用量。In one embodiment of the present invention, the pharmaceutically acceptable adjuvants for gelling agents further include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants, pH adjusters, antibacterial agents and antibacterial agents. at least one of the inflammatory agents. The addition amount of these gelling adjuvants can be the conventional amount in the field.
在本发明的一个实施方式中，所述抗氧化剂为甘草黄酮、积雪草苷、超氧化物歧化酶(Superoxide dismutase，SOD)、抗坏血酸和熊果苷中至少一种；所述防腐剂为乙二醇、戊二醇、苯氧乙醇、甘油、山梨醇、尼泊金酯和伞花烃-5-醇中至少一种；所述促透剂为多元醇和氮酮中至少一种；所述保湿剂为透明质酸钠和多糖中至少一种，所述多糖包括葡聚糖；所述稳定剂为卡波姆、泊洛沙姆、羟乙基纤维素和丙烯酰二甲基牛磺酸铵中至少一种；所述pH调节剂为氢氧化钾、氢氧化钠、磷酸氢二钠、三乙醇胺和精氨酸中至少一种；所述去角质剂为a-羟基酸和β-羟基酸中至少一种；所述抗菌剂为季铵盐-73、水杨酸、异戊二醇、滇重楼提取物、锌盐、月桂酸、月桂酸乙酯、中链脂肪酸、视网醛和山竹提取物中至少一种；所述抗炎剂为烟酰胺、α-亚麻酸、二十碳五烯酸、二十二碳六烯酸、锌盐、没红药醇和植物提取物中至少一种，所述植物提取物提取自马齿苋、茶树油、燕麦、芦荟、金盏花、积雪草、甘草、大马士革玫瑰、西洋甘菊和山竹中至少一种。In one embodiment of the present invention, the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase (SOD), ascorbic acid and arbutin; the preservative is ethyl acetate at least one of glycol, pentylene glycol, phenoxyethanol, glycerol, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one of polyol and azone; the The moisturizing agent is at least one of sodium hyaluronate and polysaccharide, and the polysaccharide includes dextran; the stabilizer is carbomer, poloxamer, hydroxyethyl cellulose and acryloyldimethyltaurine At least one of ammonium; the pH adjusting agent is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is α-hydroxy acid and β-hydroxy At least one in acid; Described antibacterial agent is quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, retinal aldehyde and at least one of mangosteen extracts; the anti-inflammatory agent is at least one of niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salts, bisabolol and plant extracts One, the plant extract is extracted from at least one of purslane, tea tree oil, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile and mangosteen.
本发明所述中链脂肪酸是一类由碳、氢、氧三种元素构成的化合物，为碳链中含碳原子数在8～10个的脂肪酸。The medium-chain fatty acid of the present invention is a kind of compound composed of carbon, hydrogen and oxygen, and is a fatty acid with 8-10 carbon atoms in the carbon chain.
在本发明的一个实施方式中，壬二酸与卡必醇的重量比为1:1～10。研究发现，壬二酸在卡必醇中的溶解度随着温度的升高而加大。而在生产凝胶剂时，为了加大壬二酸的含量，一般会升温，但是，当温度超过65℃时，产品会出现颜色加深的状况，因此，为了保证产品较好的性状，一般生产时会将体系温度维持在60℃。在此温度下，壬二酸在卡必醇中的溶解度为52.71g。因此，壬二酸与卡必醇的重量比优选在1:2以 下。如果壬二酸与卡必醇的重量比太小，即卡必醇用量太多，将会造成凝胶剂中壬二酸含量太低，甚至达不到有效浓度，因此，优选的，壬二酸与卡必醇的重量比为1:2～10。In one embodiment of the present invention, the weight ratio of azelaic acid to carbitol is 1:1-10. It was found that the solubility of azelaic acid in carbitol increased with increasing temperature. In the production of gelling agents, in order to increase the content of azelaic acid, the temperature is generally increased. However, when the temperature exceeds 65 °C, the color of the product will deepen. Therefore, in order to ensure the better properties of the product, the general production The system temperature was maintained at 60°C. At this temperature, the solubility of azelaic acid in carbitol is 52.71 g. Therefore, the weight ratio of azelaic acid to carbitol is preferably 1:2 or less. If the weight ratio of azelaic acid to carbitol is too small, that is, the amount of carbitol is too much, the content of azelaic acid in the gel will be too low, or even fail to reach an effective concentration. Therefore, preferably, azelaic acid is The weight ratio of acid to carbitol is 1:2-10.
壬二酸凝胶剂中的壬二酸含量可根据需要进行调整。在本发明的一个实施方式中，凝胶剂中的壬二酸的含量为10～30wt％。在一个具体的实施方式中，壬二酸的含量为15～25wt％。在一个更具体的实施方式中，壬二酸的含量为18～25wt％。在具体的实施例中，壬二酸的含量可以为10％、12％、15％、16％、18％、20％、21％、23％、25％等。The azelaic acid content in the azelaic acid gel can be adjusted as required. In one embodiment of the present invention, the content of azelaic acid in the gelling agent is 10-30 wt %. In a specific embodiment, the content of azelaic acid is 15-25 wt %. In a more specific embodiment, the content of azelaic acid is 18-25 wt %. In a specific embodiment, the content of azelaic acid may be 10%, 12%, 15%, 16%, 18%, 20%, 21%, 23%, 25%, and the like.
在本发明的一个实施方式中，壬二酸凝胶剂包含以下重量份的组分：壬二酸10～30份；1,3-丙二醇0～30份；水1～20份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。In one embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylate Cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
在本发明的一个具体实施方式中，壬二酸凝胶剂包含以下重量份的组分：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; polyacrylic acid Ester cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
在本发明的一个具体实施例中，壬二酸凝胶剂包含以下重量份的组分：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。In a specific embodiment of the present invention, the azelaic acid gelling agent comprises the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propanediol; 7 parts of water; polyacrylate cross-linked polymer- 63 servings; 60 servings of carbitol.
聚丙烯酸酯交联聚合物-6，简写为ZEN，为法国赛比克公司生产，商品名为SepiMAX ZEN。ZEN是一种具有优良耐电解能力的缔合聚合物。可以最大程度的抵御电解质给配方带来的破坏，同时，还具有很好的悬浮稳定能力，可以生产具有滋润优雅触感，赋予天鹅绒质感的透明水凝胶产品。Polyacrylate cross-linked polymer-6, abbreviated as ZEN, is produced by French company SepiMAX under the trade name SepiMAX ZEN. ZEN is an associative polymer with excellent resistance to electrolysis. It can resist the damage caused by electrolytes to the formula to the greatest extent, and at the same time, it also has good suspension stability, and can produce transparent hydrogel products with a moist and elegant touch and a velvety texture.
在本发明的一个实施方式中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸10～30份；1,3-丙二醇0～30份；水1～20份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。In one embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; polyacrylic acid Ester cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
在本发明的一个具体实施方式中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Acrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
在本发明的一个具体实施例中，壬二酸凝胶剂由以下重量份的组分组成：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。In a specific embodiment of the present invention, the azelaic acid gelling agent is composed of the following components in parts by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; polyacrylate cross-linked polymer -6 3 servings; Carbitol 60 servings.
本发明壬二酸凝胶剂的制备方法，包括以下步骤：The preparation method of azelaic acid gel of the present invention comprises the following steps:
a、将聚丙烯酸酯交联聚合物-6均匀分散于卡必醇中后，再与水混合均匀，得到溶液A；a. After the polyacrylate cross-linked polymer-6 is uniformly dispersed in the carbitol, it is mixed with water to obtain solution A;
b、将壬二酸均匀分散于卡必醇和1,3-丙二醇中，加热至透明，得到溶液B；b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;
c、将溶液A、溶液B混合，搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
其中，步骤a和步骤b之间没有时间顺序，可以先进行步骤a再进行步骤b，也可以先进行步骤b再进行步骤a，也可以步骤a和步骤b同时进行。仅需在最后将溶液A和溶液B混合搅匀即可。Wherein, there is no time sequence between step a and step b, step a may be performed first and then step b, or step b may be performed first and then step a, or step a and step b may be performed simultaneously. Just mix solution A and solution B at the end and stir well.
步骤b中，加热的温度以壬二酸溶解至透明为准。实验研究表明壬二酸在室温时不溶于水、油及多元醇，在产品制备时需将温度提升至55℃，而超过65℃时，产品会出现颜色加深的状况，因此，步骤b中，优选加热后的温度低于65℃。In step b, the heating temperature is based on the dissolution of azelaic acid until transparent. Experimental studies have shown that azelaic acid is insoluble in water, oil and polyol at room temperature, and the temperature needs to be raised to 55°C during product preparation, and when it exceeds 65°C, the product will appear darker in color. Therefore, in step b, The temperature after heating is preferably lower than 65°C.
在本发明的一个实施方式中，步骤b的温度为60℃。在此温度下，壬二酸在卡必醇中溶解度为52.71g，高于1,3丙二醇的溶解度(40.33g)，可有效提升产品中的壬二酸含量。In one embodiment of the present invention, the temperature of step b is 60°C. At this temperature, the solubility of azelaic acid in carbitol is 52.71g, which is higher than that of 1,3 propylene glycol (40.33g), which can effectively increase the content of azelaic acid in the product.
本发明的壬二酸凝胶剂，以壬二酸为有效成分，能够用于治疗抗炎、痤疮或色素沉着紊乱。其使用时，可直接涂抹在皮肤上。The azelaic acid gel of the present invention uses azelaic acid as an active ingredient, and can be used for treating anti-inflammatory, acne or pigmentation disorders. When used, it can be applied directly to the skin.
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。The specific embodiments of the present invention will be further described below with reference to the examples, but the present invention is not limited to the scope of the described examples.
实施例中所用原料为：The raw materials used in the examples are:
ZEN：购自法国赛比克；ZEN: purchased from France Saibiq;
壬二酸：购自上海凛恩科技发展有限公司；Azelaic acid: purchased from Shanghai Linen Technology Development Co., Ltd.;
卡必醇：购自上海麦克林生化科技有限公司；Carbitol: purchased from Shanghai McLean Biochemical Technology Co., Ltd.;
1,3-丙二醇：玉米来源，购自美国杜邦公司；1,3-Propanediol: corn source, purchased from DuPont, USA;
水：自制去离子水。Water: Homemade deionized water.
实施例1Example 1
壬二酸凝胶剂，配方为：Azelaic acid gel, formulated as:
A液：ZEN 3％；卡必醇10％；水7％。Liquid A: ZEN 3%; Carbitol 10%; Water 7%.
B液：壬二酸20％；1,3丙二醇10％；卡必醇50％。Liquid B: azelaic acid 20%; 1,3 propylene glycol 10%; carbitol 50%.
按如下步骤进行制备：Prepare as follows:
a、将ZEN均匀分散于卡必醇中后再与水混合均匀，得到溶液A；a. Disperse ZEN evenly in carbitol and then mix with water to obtain solution A;
b、将壬二酸均匀分散于卡必醇和1,3-丙二醇中，加热至透明，得到溶液B；b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;
c、将溶液A、溶液B混合，搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
实施例2Example 2
壬二酸凝胶剂，配方为：Azelaic acid gel, formulated as:
A液：ZEN 2％；卡必醇10％；水13％。Liquid A: ZEN 2%; Carbitol 10%; Water 13%.
B液：壬二酸15％；1,3丙二醇10％；卡必醇50％。Liquid B: azelaic acid 15%; 1,3 propylene glycol 10%; carbitol 50%.
按如下步骤进行制备：Prepare as follows:
a、将ZEN均匀分散于卡必醇中后再与水混合均匀，得到溶液A；a. Disperse ZEN evenly in carbitol and then mix with water to obtain solution A;
b、将壬二酸均匀分散于卡必醇和1,3-丙二醇中，加热至透明，得到溶液B；b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;
c、将溶液A、溶液B混合，搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
试验例1 透皮吸收实验Test Example 1 Transdermal absorption test
1、实验药物：1. Experimental drug:
1号产品：实施例2产品，其配方为：壬二酸15％，ZEN 2％，卡必醇60％，1,3-丙二醇10％，水13％。Product No. 1: the product of Example 2, its formula is: azelaic acid 15%, ZEN 2%, carbitol 60%, 1,3-propanediol 10%, water 13%.
2号产品：专利CN2018108258077中的产品，其配方为：壬二酸15％，ZEN 2％，1,3-丙二醇70％，水13％。Product No. 2: the product in the patent CN2018108258077, its formula is: azelaic acid 15%, ZEN 2%, 1,3-propanediol 70%, water 13%.
3号产品：壬二酸霜剂对照品：AZECLEAR Cream,HK-59866，批号R595，澳洲肤润康药业有限公司，其中的壬二酸含量为20％；Product No. 3: Azelaic acid cream Reference substance: AZECLEAR Cream, HK-59866, batch number R595, Australia Frunkang Pharmaceutical Co., Ltd., the content of azelaic acid is 20%;
基质液：无色透明凝胶，不含壬二酸，仅由卡必醇、ZEN、1,3-丙二醇和水组成。Base fluid: colorless, transparent gel, free of azelaic acid, consisting only of carbitol, ZEN, 1,3-propanediol and water.
2、实验动物2. Experimental animals
昆明种(KM)小鼠，SPF级，体重20～24g；由四川省中医药科学院实验动物中心提供，动物合格证编号：SCXK(川)2018-19。Kunming (KM) mice, SPF grade, weighing 20-24g; provided by the Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine, animal certificate number: SCXK (Chuan) 2018-19.
3、主要仪器3. Main instruments
电子天平：JA1003A，d＝1mg，e＝10d，上海精天电子仪器有限公司。电子天平：LD3100-1，d＝0.1g,e＝1g,沈阳龙腾电子有限公司。MagNA LYSer匀浆机41440103，Made in Germany；全波长多功能酶标仪：VARIOSKAN FLASH，Thermo Scientific,USA.Electronic balance: JA1003A, d=1mg, e=10d, Shanghai Jingtian Electronic Instrument Co., Ltd. Electronic balance: LD3100-1, d=0.1g, e=1g, Shenyang Longteng Electronics Co., Ltd. MagNA LYSer homogenizer 41440103, Made in Germany; full-wavelength multi-function microplate reader: VARIOSKAN FLASH, Thermo Scientific, USA.
4、实验环境4. Experimental environment
四川省中医药科学院药理毒理研究所SPF屏障***。室内温度20～22℃，相对湿度40％～70％，12小时明暗交替照明。使用许可证号为SYXK(川)2018-19。自由饮水。 标准饲料由四川省中医药科学院实验动物中心提供。SPF barrier system, Institute of Pharmacology and Toxicology, Sichuan Academy of Traditional Chinese Medicine. The indoor temperature is 20~22℃, the relative humidity is 40%~70%, and the light and dark are alternately illuminated for 12 hours. The license number is SYXK (Chuan) 2018-19. Free access to water. Standard feed was provided by the Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine.
5、实验方法5. Experimental method
取KM种小鼠48只，雌雄各半，分为4组，每组12只，即1号产品组，2号产品组，3号产品组及基质液组，试验前一天用电动理发器和脱毛膏去除小鼠腹部毛发，将受试样品溶液涂抹于脱毛部位，每部位涂0.5g/kg，涂抹范围约3.0×3.0cm
2，涂抹后1h颈椎脱臼安乐死动物，取涂抹部位皮肤，去除深部肌肉组织，称取0.1克皮肤，剪碎，用1ml70％甲醇匀浆，震摇浸泡2h后,3000r/min，离心10min，取上清液，根据ELISA试剂盒说明书在450nm处测吸光度值，根据标准曲线计算出壬二酸浓度，见表1。
48 KM mice, half male and half male, were divided into 4 groups with 12 mice in each group, namely No. 1 product group, No. 2 product group, No. 3 product group and matrix liquid group. Depilatory cream was used to remove the abdominal hair of mice, and the test sample solution was applied to the depilation site, with 0.5g/kg applied to each part, and the smeared area was about 3.0×3.0cm 2 . The animals were euthanized by cervical dislocation 1 hour after application, and the skin of the application site was taken and removed. Deep muscle tissue, weigh 0.1 g of skin, cut into pieces, homogenize with 1 ml of 70% methanol, shake and soak for 2 h, centrifuge at 3000 r/min for 10 min, take the supernatant, and measure the absorbance at 450 nm according to the instructions of the ELISA kit. The azelaic acid concentration was calculated according to the standard curve, see Table 1.
6、实验结果6. Experimental results
实验结果见表1。The experimental results are shown in Table 1.
表1 小鼠皮肤中壬二酸的含量
Table 1 Content of azelaic acid in mouse skin
注：a：与3号产品比较显著性P<0.01，b：与2号产品比较显著性P<0.05。Note: a: Significant P<0.01 compared with No. 3 product, b: Significant P<0.05 compared with No. 2 product.
从表1可见，小鼠皮肤涂抹几种壬二酸产品后，凝胶剂产品(即1号产品和2号产品)中壬二酸含量明显高于壬二酸霜剂对照组(即3号产品)，具有统计学差异；同时1号产品皮肤中壬二酸含量明显高于2号产品皮肤中含量。由此可见，相同剂量涂抹小鼠皮肤，凝胶产品在皮肤中壬二酸含量更高，且本发明产品中的壬二酸含量更为显著增高。As can be seen from Table 1, after smearing several azelaic acid products on the mouse skin, the content of azelaic acid in the gel products (namely product No. 1 and product No. 2) was significantly higher than that in the azelaic acid cream control group (namely, product No. 3). , with a statistical difference; at the same time, the content of azelaic acid in the skin of product No. 1 was significantly higher than that in the skin of product No. 2. It can be seen that when the same dose is applied to the skin of mice, the gel product has a higher azelaic acid content in the skin, and the azelaic acid content in the product of the present invention is significantly increased.
实施例3Example 3
按照实施例1所述的方法制备得到壬二酸凝胶剂，其中，各原料的总用量见表2，制备得到的凝胶剂性状也见表2。The azelaic acid gel was prepared according to the method described in Example 1, wherein the total consumption of each raw material is shown in Table 2, and the properties of the prepared gel are also shown in Table 2.
表2Table 2
实施例4Example 4
改变壬二酸凝胶剂的配方，其中，各原料的用量见表3，制备得到的凝胶剂性状也见表3。Change the formula of azelaic acid gel, wherein, the consumption of each raw material is shown in Table 3, and the properties of the prepared gel are also shown in Table 3.
表3table 3
对比例1Comparative Example 1
按照专利CN2018108258077中的产品配方配制凝胶剂，其具体配方为：壬二酸20％，ZEN 3％，1,3-丙二醇70％，水7％。The gel is prepared according to the product formula in the patent CN2018108258077, and its specific formula is: azelaic acid 20%, ZEN 3%, 1,3-propanediol 70%, water 7%.
按如下步骤制备：Prepare as follows:
a、将ZEN均匀分散于1,3-丙二醇中后再与水混合均匀，得到溶液A；a. Disperse ZEN evenly in 1,3-propanediol and then mix with water to obtain solution A;
b、将壬二酸均匀分散于1,3-丙二醇中，加热至75℃，搅拌至透明，得到溶液B；b. Uniformly disperse azelaic acid in 1,3-propanediol, heat to 75°C, and stir until transparent to obtain solution B;
c、将溶液A和溶液B，60℃搅拌混匀，然后冷却至室温。c. Stir and mix solution A and solution B at 60°C, and then cool to room temperature.
发现，采用该配方，冷却后，壬二酸晶体会逐渐析出，有明显颗粒感，凝胶流动性逐步变差，2周后成为固态。It was found that with this formula, after cooling, crystals of azelaic acid would gradually separate out, with obvious graininess, and the fluidity of the gel would gradually deteriorate, and it would become solid after 2 weeks.
Claims (17)
- 壬二酸凝胶剂，其特征在于：凝胶剂组分包含壬二酸和药学上可接受的凝胶剂辅料，以及不可避免的杂质；其中，所述药学上可接受的凝胶剂辅料包含卡必醇。Azelaic acid gel, characterized in that: the gel component comprises azelaic acid and pharmaceutically acceptable gel excipients, and inevitable impurities; wherein, the pharmaceutically acceptable gel excipients Contains carbitol.
- 根据权利要求1所述的壬二酸凝胶剂，其特征在于：所述药学上可接受的凝胶剂辅料还包括抗氧化剂、防腐剂、促透剂、保湿剂、稳定剂、去角质剂、pH调节剂、抗菌剂和抗炎剂中至少一种。The azelaic acid gel according to claim 1, characterized in that: the pharmaceutically acceptable adjuvants for the gel also include antioxidants, preservatives, penetration enhancers, moisturizing agents, stabilizers, exfoliants , at least one of a pH adjusting agent, an antibacterial agent and an anti-inflammatory agent.
- 根据权利要求2所述的壬二酸凝胶剂，其特征在于：所述抗氧化剂为甘草黄酮、积雪草苷、超氧化物歧化酶、抗坏血酸和熊果苷中至少一种；所述防腐剂为乙二醇、戊二醇、苯氧乙醇、甘油、山梨醇、尼泊金酯和伞花烃-5-醇中至少一种；所述促透剂为多元醇和氮酮中至少一种；所述保湿剂为透明质酸钠和多糖中至少一种，所述多糖包括葡聚糖；所述稳定剂为卡波姆、泊洛沙姆、羟乙基纤维素和丙烯酰二甲基牛磺酸铵中至少一种；所述pH调节剂为氢氧化钾、氢氧化钠、磷酸氢二钠、三乙醇胺和精氨酸中至少一种；所述去角质剂为a-羟基酸和β-羟基酸中至少一种；所述抗菌剂为季铵盐-73、水杨酸、异戊二醇、滇重楼提取物、锌盐、月桂酸、月桂酸乙酯、中链脂肪酸、视网醛和山竹提取物中至少一种；所述抗炎剂为烟酰胺、α-亚麻酸、二十碳五烯酸、二十二碳六烯酸、锌盐、没红药醇、茶树油和植物提取物中至少一种，所述植物提取物提取自马齿苋、燕麦、芦荟、金盏花、积雪草、甘草、大马士革玫瑰、西洋甘菊和山竹中至少一种。The azelaic acid gel according to claim 2, wherein the antioxidant is at least one of licorice flavonoids, madecassoside, superoxide dismutase, ascorbic acid and arbutin; The agent is at least one in ethylene glycol, pentylene glycol, phenoxyethanol, glycerin, sorbitol, paraben and cymene-5-ol; the penetration enhancer is at least one in polyol and azone ; Described moisturizing agent is at least one in sodium hyaluronate and polysaccharide, and described polysaccharide includes dextran; Described stabilizer is carbomer, poloxamer, hydroxyethyl cellulose and acryloyl dimethyl At least one of ammonium taurine; the pH adjuster is at least one of potassium hydroxide, sodium hydroxide, disodium hydrogen phosphate, triethanolamine and arginine; the exfoliating agent is a-hydroxy acid and At least one in β-hydroxy acid; Described antibacterial agent is quaternary ammonium salt-73, salicylic acid, isopentyl glycol, Dianzhonglou extract, zinc salt, lauric acid, ethyl laurate, medium chain fatty acid, At least one of retinal and mangosteen extract; the anti-inflammatory agent is niacinamide, alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, zinc salt, bisabolol, tea tree At least one of an oil and a plant extract extracted from at least one of purslane, oat, aloe vera, calendula, centella asiatica, licorice, damask rose, chamomile, and mangosteen.
- 根据权利要求1所述的壬二酸凝胶剂，其特征在于：壬二酸与卡必醇的重量比为1:1～10。The azelaic acid gel according to claim 1 is characterized in that: the weight ratio of azelaic acid to carbitol is 1:1-10.
- 根据权利要求4所述的壬二酸凝胶剂，其特征在于：壬二酸与卡必醇的重量比为1:2～10。The azelaic acid gel according to claim 4 is characterized in that: the weight ratio of azelaic acid to carbitol is 1:2-10.
- 根据权利要求1～5任一项所述的壬二酸凝胶剂，其特征在于：壬二酸的含量为10～30wt％。The azelaic acid gel according to any one of claims 1 to 5, wherein the content of azelaic acid is 10 to 30 wt %.
- 根据权利要求6所述的壬二酸凝胶剂，其特征在于：壬二酸的含量为15～25wt％。The azelaic acid gel according to claim 6, wherein the content of azelaic acid is 15-25 wt%.
- 根据权利要求7所述的壬二酸凝胶剂，其特征在于：壬二酸的含量为18～25wt％。The azelaic acid gel according to claim 7, wherein the content of azelaic acid is 18-25 wt%.
- 根据权利要求1所述的壬二酸凝胶剂，其特征在于：包含以下重量份的组分： 壬二酸10～30份；1,3-丙二醇0～30份；水1～20份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。The azelaic acid gel according to claim 1 is characterized in that: it comprises the following components by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-20 parts of water; Polyacrylate cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- 根据权利要求9所述的壬二酸凝胶剂，其特征在于：包含以下重量份的组分：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。The azelaic acid gel according to claim 9, characterized in that: it comprises the following components by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water; Polyacrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- 根据权利要求10所述的壬二酸凝胶剂，其特征在于：包含以下重量份的组分：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。The azelaic acid gel according to claim 10 is characterized in that: it comprises the following components by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; Matter-6 3 copies; Carbitol 60 copies.
- 根据权利要求1所述的壬二酸凝胶剂，其特征在于：由以下重量份的组分组成：壬二酸10～30份；1,3-丙二醇0～30份；水1～10份；聚丙烯酸酯交联聚合物-6 2～5份；卡必醇30～80份。The azelaic acid gel according to claim 1 is characterized in that: it is composed of the following components by weight: 10-30 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 1-10 parts of water ; Polyacrylate cross-linked polymer-6 2-5 parts; Carbitol 30-80 parts.
- 根据权利要求12所述的壬二酸凝胶剂，其特征在于：由以下重量份的组分组成：壬二酸10～25份；1,3-丙二醇0～30份；水5～16份；聚丙烯酸酯交联聚合物-6 3～3.5份；卡必醇40～70份。The azelaic acid gel according to claim 12 is characterized in that: it is composed of the following components by weight: 10-25 parts of azelaic acid; 0-30 parts of 1,3-propylene glycol; 5-16 parts of water ; Polyacrylate cross-linked polymer-6 3-3.5 parts; Carbitol 40-70 parts.
- 根据权利要求13所述的壬二酸凝胶剂，其特征在于：由以下重量份的组分组成：壬二酸20份；1,3-丙二醇10份；水7份；聚丙烯酸酯交联聚合物-6 3份；卡必醇60份。The azelaic acid gel according to claim 13 is characterized in that: it is composed of the following components by weight: 20 parts of azelaic acid; 10 parts of 1,3-propylene glycol; 7 parts of water; Polymer - 6 3 parts; Carbitol 60 parts.
- 一种壬二酸凝胶剂的制备方法，其特征在于，包括以下步骤：A kind of preparation method of azelaic acid gel, is characterized in that, comprises the following steps:a、将聚丙烯酸酯交联聚合物-6均匀分散于卡必醇中后，再与水混合均匀，得到溶液A；a. After the polyacrylate cross-linked polymer-6 is uniformly dispersed in the carbitol, it is mixed with water to obtain solution A;b、将壬二酸均匀分散于卡必醇和1,3-丙二醇中，加热至透明，得到溶液B；b. Uniformly disperse azelaic acid in carbitol and 1,3-propanediol, and heat until transparent to obtain solution B;c、将溶液A、溶液B混合，搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。c. Mix solution A and solution B, stir and mix well, and then cool to room temperature to obtain azelaic acid gel.
- 根据权利要求15所述的壬二酸凝胶剂的制备方法，其特征在于：步骤b中，加热后的温度低于65℃。The method for preparing azelaic acid gel according to claim 15, wherein in step b, the temperature after heating is lower than 65°C.
- 权利要求1～14任一项所述的壬二酸凝胶剂用于制备治疗抗炎、痤疮或色素沉着紊乱的药物、化妆品或护肤品中的用途。Use of the azelaic acid gel according to any one of claims 1 to 14 for preparing a drug, cosmetic or skin care product for treating anti-inflammatory, acne or pigmentation disorders.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011295511.2 | 2020-11-18 | ||
| CN202011295511.2A CN112220741A (en) | 2020-11-18 | 2020-11-18 | Azelaic acid gel and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022105225A1 true WO2022105225A1 (en) | 2022-05-27 |
Family
ID=74123723
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/101503 WO2022105225A1 (en) | 2020-11-18 | 2021-06-22 | Azelaic acid gel, preparation method therefor and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112220741A (en) |
| WO (1) | WO2022105225A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115252449A (en) * | 2022-08-17 | 2022-11-01 | 上海臻臣化妆品有限公司 | Azelaic acid aqueous solution, preparation method thereof and cosmetic composition |
| CN116370325A (en) * | 2023-03-23 | 2023-07-04 | 上海科黛生物科技有限公司 | Transparent azelaic acid gel and preparation method and application thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114306106B (en) * | 2020-10-09 | 2023-03-31 | 铂曼(浙江)生物科技有限公司 | Composition for skin and use thereof |
| CN112220741A (en) * | 2020-11-18 | 2021-01-15 | 成都卓阳生物科技有限公司 | Azelaic acid gel and preparation method and application thereof |
| CN113520890B (en) * | 2021-06-29 | 2023-02-17 | 上海瑞叶生物科技有限公司 | Azelaic acid dispersion and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108553411A (en) * | 2018-07-25 | 2018-09-21 | 成都卓阳生物科技有限公司 | Azelaic acid gelling agent and its preparation method and application |
| CN112220741A (en) * | 2020-11-18 | 2021-01-15 | 成都卓阳生物科技有限公司 | Azelaic acid gel and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111374938B (en) * | 2020-03-19 | 2020-12-22 | 广州杨森药业有限公司 | Oil-free gel containing azelaic acid and preparation method thereof |
-
2020
- 2020-11-18 CN CN202011295511.2A patent/CN112220741A/en active Pending
-
2021
- 2021-06-22 WO PCT/CN2021/101503 patent/WO2022105225A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108553411A (en) * | 2018-07-25 | 2018-09-21 | 成都卓阳生物科技有限公司 | Azelaic acid gelling agent and its preparation method and application |
| CN112220741A (en) * | 2020-11-18 | 2021-01-15 | 成都卓阳生物科技有限公司 | Azelaic acid gel and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| WU YING, ZHONG TIANGENG, MA SHUREN: "Application and Mechanism of Transcutol as Enhancer for Percutaneous Absorption", CHINESE JOURNAL OF MODERN APPLIED PHARMACY, vol. 21, no. 1, 29 February 2004 (2004-02-29), CN , pages 23 - 25, XP009520567, ISSN: 1007-7693, DOI: 10.13748/j.cnki.issn1007-7693.2004.01.010 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115252449A (en) * | 2022-08-17 | 2022-11-01 | 上海臻臣化妆品有限公司 | Azelaic acid aqueous solution, preparation method thereof and cosmetic composition |
| CN116370325A (en) * | 2023-03-23 | 2023-07-04 | 上海科黛生物科技有限公司 | Transparent azelaic acid gel and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112220741A (en) | 2021-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022105225A1 (en) | Azelaic acid gel, preparation method therefor and application thereof | |
| KR102141081B1 (en) | Composition for skin cell anti-inflammation or skin whitening | |
| US20080233145A1 (en) | Pharmaceutical Compositions Comprising Old Man's Beard (Usnea Barbata) and St. John's Wort (Hypericum Perforatum) and Their Use | |
| US20160144038A1 (en) | Water-soluble supramolecular complexes | |
| JPH07277939A (en) | Skin external preparation | |
| JP2007262012A (en) | Hyaluronic acid production promoter, skin external preparation containing the hyaluronic acid production promoter, cosmetic, quasi drug, chapped skin ameliorating agent, and wrinkle ameliorating agent | |
| KR20200028547A (en) | Transparent liposome composition containing centella asiatica extract | |
| JP2000256131A (en) | Tyrosinase production inhibitor and skin lotion containing the same | |
| CA2926874C (en) | Icotinib-containing topical skin pharmaceutical compositions and uses thereof | |
| JPH08176005A (en) | Living body-aging preventive and composition for skin | |
| CN113332161A (en) | Ammonium glycyrrhetate hydrogel as well as preparation method and application thereof | |
| JP2001342112A (en) | Skin care preparation | |
| JP3754646B2 (en) | Topical skin preparation | |
| WO2015078397A1 (en) | Chinese herbal medicine for repairing ultraviolet damage and promoting energy metabolism, and uses thereof in cosmetics | |
| JP2006151831A (en) | Antioxidant, dna damage inhibitor or skin care preparation | |
| JP2001114636A (en) | Hyaluronic acid production and catalase production promoting agent, fibroblast activating agent and skin lotion | |
| TWI597068B (en) | Composition for improving skin defensive power | |
| JP2001261548A (en) | Skin care preparation | |
| JP5450918B2 (en) | Topical skin preparation | |
| JP3895636B2 (en) | Anti-aging agent and external preparation for skin using the same | |
| JP5746807B2 (en) | Cosmetic composition for skin | |
| JP2006117607A (en) | Skin care preparation | |
| JP3746260B2 (en) | Topical skin preparation | |
| JP2007077101A (en) | External preparation for skin | |
| US20220088060A1 (en) | Nail compositions having antifungal properties |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21893379 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21893379 Country of ref document: EP Kind code of ref document: A1 |