CN1711997A - 5-keto-amine pentanoic acid salt externally-applied preparation and production thereof - Google Patents
5-keto-amine pentanoic acid salt externally-applied preparation and production thereof Download PDFInfo
- Publication number
- CN1711997A CN1711997A CN 200410025169 CN200410025169A CN1711997A CN 1711997 A CN1711997 A CN 1711997A CN 200410025169 CN200410025169 CN 200410025169 CN 200410025169 A CN200410025169 A CN 200410025169A CN 1711997 A CN1711997 A CN 1711997A
- Authority
- CN
- China
- Prior art keywords
- sodium
- excipient
- aminolevulinate
- preparation
- potassium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 38
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims description 28
- 239000000843 powder Substances 0.000 claims description 17
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 8
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 8
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 230000002421 anti-septic effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021538 borax Inorganic materials 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- 239000004328 sodium tetraborate Substances 0.000 claims description 4
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- OJIYIVCMRYCWSE-UHFFFAOYSA-M Domiphen bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CCOC1=CC=CC=C1 OJIYIVCMRYCWSE-UHFFFAOYSA-M 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 235000010419 agar Nutrition 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- XPYXIISTHPGMMP-UHFFFAOYSA-N azane;hexadecane Chemical compound N.CCCCCCCCCCCCCCCC XPYXIISTHPGMMP-UHFFFAOYSA-N 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 2
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 229960001859 domiphen bromide Drugs 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 2
- 239000011812 mixed powder Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229920001277 pectin Polymers 0.000 claims description 2
- 239000001814 pectin Substances 0.000 claims description 2
- 235000010987 pectin Nutrition 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000004302 potassium sorbate Substances 0.000 claims description 2
- 235000010241 potassium sorbate Nutrition 0.000 claims description 2
- 229940069338 potassium sorbate Drugs 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 229960003415 propylparaben Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229960004249 sodium acetate Drugs 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 229960004025 sodium salicylate Drugs 0.000 claims description 2
- 229940074404 sodium succinate Drugs 0.000 claims description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- -1 tragakanta Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims 1
- 238000004659 sterilization and disinfection Methods 0.000 claims 1
- BWHGMFYTDQEALD-UHFFFAOYSA-N 5-amino-2-oxopentanoic acid Chemical compound [NH3+]CCCC(=O)C([O-])=O BWHGMFYTDQEALD-UHFFFAOYSA-N 0.000 abstract 2
- 230000007794 irritation Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- BLOIUFYKQCCAGP-UHFFFAOYSA-N 5-aminopentanoic acid;hydron;chloride Chemical compound Cl.NCCCCC(O)=O BLOIUFYKQCCAGP-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
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- 239000012153 distilled water Substances 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000019802 Sexually transmitted disease Diseases 0.000 description 2
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- 230000003287 optical effect Effects 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- 208000017983 photosensitivity disease Diseases 0.000 description 2
- 210000005000 reproductive tract Anatomy 0.000 description 2
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- 239000007779 soft material Substances 0.000 description 2
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- 230000000638 stimulation Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- ZCFFYALKHPIRKJ-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical compound N1C(C=C2C(=C(C)C(=CC=3C(C)=C(CCC(O)=O)C(N=3)=C3)N2)C=C)=C(C)C(C=C)=C1C=C1C(C)=C(CCC(O)=O)C3=N1 ZCFFYALKHPIRKJ-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920000832 Cutin Polymers 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
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- 229910052742 iron Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009287 sand filtration Methods 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
An exterior-applied medicine of 5-aminoketovalerate is prepared from the powdered excipient containing 5-aminoketovalerate and water as solvent. Its preparing process is also disclosed. Its advantage is no irritation.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of optical dynamic therapy medicine 5-aminolevulinate external preparation and preparation method thereof with photosensitive activity.
Background technology
Photodynamics is meant that intracellular photosensitizer is under the irradiation of specific light, the effect that makes this cell necrose and wither away, and the participation of this process need aerobic, so be referred to as photosensitization-Oxidation, chemically claiming this photosensitization that act as, reaching in biology and medically be referred to as photodynamics.With the method that photodynamics is cured the disease, be called photodynamic therapy (Photodynamiotherapy, PDT).
The 5-aminolevulinate, claim δ-aminolevulinate (δ-aminolevulinicacid again, ALA) be precursor in haemachrome self circulation, be normal endogenous material in the body, be synthetic necessary a kind of indirect material-hemoporphyrin (ProtoporphyrinIX, raw material PpIX) of ferrohemoglobin.Under the normal condition, the ALA in the living cells is a trace, and itself does not have heliosensitivity.After exogenous ALA enters human body, can absorb by grown fireballing cell selective, and also the long period is detained in it to be converted into PpIX in cell.Intracellular PpIX then has very strong heliosensitivity, behind the red light irradiation of specific wavelength, promptly produce active oxygen such as singlet oxygen (
1O
2) and other free radical etc. and kill this cell (cell, wart somatic cell that carcinoma cell, HPV and HSV infect), i.e. photodynamic reaction, but the normal adjacent tissue cell then is not affected.The ALA external or oral after carry out optical dynamic therapy, can be used for the treatment of various malignant tumor such as skin carcinoma, condyloma acuminatum, infectious disease etc.
When the 5-aminolevulinate is applied to diseased region, often be made into solution.A kind of 5-aminolevulinic acid salt pref that has gone on the market, adopt the administrator administration, the powder of 5--aminolevulinate contains two ends in administrator with dissolving respectively with solution, the ampoule that will contain powder and solution in use squeezes broken, jolting makes the dissolving of 5-aminolevulinate, and solution is applied to diseased region after oozing out by the filter membrane extruding at tip.The solvent of dissolving usefulness comprises ethanol, propylene glycol etc., is used for skin cancer treatment, has the softening skin cutin, sorbefacient effect.
The 5-aminolevulinate is the treatment that is used for sexually transmitted disease (STD) such as condyloma acuminatum in another purposes medically, and such disease is sent out in positions such as reproductive tract well.Above-mentioned preparation is owing to contain zest solvents such as ethanol, propylene glycol, as is used for the treatment of disease such as condyloma acuminatum, and mucosal sites such as patient's reproductive tract are had stronger stimulation.Suitable preparation should have less zest under the situation that guarantees medicine stability.Therefore press for the 5-aminolevulinate external preparation that exploitation is applicable to mucosa delivery.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of 5-aminolevulinate external preparation and preparation method thereof, to overcome the above-mentioned defective that prior art exists, satisfy people's needs.
5-aminolevulinate external preparation of the present invention is a kind of compositions, and the excipient and the dissolution solvent of the 5-aminolevulinate for the treatment of effective dose by containing of solid powdery are formed.
The weight percent content of 5-aminolevulinate is 50～100% in the preferred excipient, is preferably 75～95%;
Containing the excipient of the 5-aminolevulinate for the treatment of effective dose and the w/v of dissolution solvent is: 5～35%, and mg/ml is preferably 10～30%, mg/ml, concrete concentration can be regulated as required;
Said salt comprises a kind of in hydrochlorate, sulfate or the succinate;
Said excipient comprise permeation promoter and/or viscosifier and or stabilizing agent and/or antiseptic and/or lubricant and/or pH regulator agent;
Described permeation promoter is a water soluble adjuvant, is selected from following at least a: glucose, lactose, mannitol, sucrose, sodium benzoate, sodium salicylate, sodium chloride, Polyethylene Glycol or polyvinylpyrrolidone;
Described viscosifier are natural or synthetic colloidal substance, can produce certain viscosity, be selected from following at least a: methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, sodium carboxymethyl cellulose, alginate, polyvinylpyrrolidone class, polyvinyl alcohol, carbopol, tragakanta, arabic gum, xanthan gum, agar, pectin, gelatin, collagen, chitosan.
Described stabilizing agent mainly refers to metal ion a flat iron plate for making cakes mixture, especially is selected from ethylenediaminetetraacetic acid or disodiumedetate.
Described antiseptic is selected from following at least a: methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, chlorobutanol, thimerosal, phenylmercuric nitrate, benzyl alcohol, benzalkonium chloride, cetylpyridinium chloride, bromination hexadecane ammonium, domiphen bromide.
Described lubricant is added in the pressed powder, plays the fluidizer effect, is not added on dissolving with in the solvent, is selected from following at least a: polyethylene glycols, sodium lauryl sulphate, fumaric acid.
Described pH regulator agent is selected from following at least a: sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, sodium citrate, sodium succinate, sodium acetate, Borax.
5-aminolevulinate external preparation of the present invention, used dissolving solvent are water or the aqueous solution that contains above-mentioned excipient.
5-aminolevulinate external preparation of the present invention, pressed powder partly are fine powder or granule.Particulate flowability is better than fine powder, is beneficial to packing.
The preparation method of 5-aminolevulinate external preparation of the present invention comprises the steps:
5-aminolevulinate and various excipient are all pulverized, and crossed 60～100 mesh sieves;
Medicine that sieves and excipient are by the equivalent method mixing that progressively increases;
Mixed-powder adopts dry method well known in the art or wet granulation, obtains fine powder or granule.
Before using fine powder or granule are mixed with dissolution solvent, coat the affected part.
By above-mentioned disclosed technical scheme as seen, preparation of the present invention is a solvent with water, and patient's mucosal sites is not had stimulation, is a kind of more satisfactory 5-aminolevulinate external preparation.
The specific embodiment
Embodiment 1
5-aminovaleric acid hydrochloride external preparation (granulation)
By following set of dispense ratio preparation 5-aminovaleric acid hydrochloride external preparation.
Prescription:
The pressed powder part
5-aminovaleric acid hydrochloride hydrochlorate 10.00g
Polyvinylpyrrolidone 0.5g (viscosifier)
Polyethylene Glycol 0.1g (permeation promoter)
The dissolving solvent
Ethyl hydroxybenzoate 0.15g (antiseptic)
Disodiumedetate 0.75g (stabilizing agent)
Borax 5.00g (pH regulator agent)
Hypromellose 1.50g (viscosifier)
Add water to 150ml
Prepare pressed powder and dissolving solvent by following preparation method.
The pressed powder part
5-aminovaleric acid hydrochloride hydrochlorate is pulverized, and cross 80 mesh sieves, add polyvinylpyrrolidonepowder powder, mix homogeneously, the polyvinylpyrrolidone ethanol solution of adding 5%, the system soft material was crossed 20 mesh sieve system wet granulars, in 30 ℃ of dryings 1 hour, must do granule, after measuring medicament contg, packing, gland.
The dissolving solvent
Ethyl hydroxybenzoate adds in the 100ml water, is heated to 60 ℃, makes it dissolving, puts cold, add disodiumedetate, Borax, hypromellose, stir and make dissolving, the sand filtration rod is just filtered, and crosses 0.45 μ m microporous filter membrane fine straining, be filled in the glass bottle filtrate branch, and pressure sterilizing must dissolve and use solvent.
Embodiment 2
5-aminovaleric acid hydrochloride external preparation (granulation, dissolving is a water with solvent)
By following set of dispense ratio preparation 5-aminovaleric acid hydrochloride external preparation.
Prescription:
The pressed powder part
5-aminovaleric acid hydrochloride hydrochlorate 47.2g
Ethyl hydroxybenzoate 0.12g
Disodiumedetate 1.00g
Polyvinylpyrrolidone 4.00g
Polyethylene Glycol 0.5g
Dissolving is a distilled water with solvent.
By the method preparation that is similar to embodiment 1.5-aminovaleric acid hydrochloride hydrochlorate and ethyl hydroxybenzoate, disodiumedetate, polyvinylpyrrolidone are pulverized, and mistake 80 mesh sieves, mix homogeneously, the Polyethylene Glycol ethanol solution of adding 10%, the system soft material is crossed 20 mesh sieve system wet granulars, in 30 ℃ of dryings 1 hour, must do granule, packing, gland.
Embodiment 3
5-aminovaleric acid hydrochloride external preparation (spray drying method)
By following set of dispense ratio preparation 5-aminovaleric acid hydrochloride external preparation.Dissolving with solvent is
Distilled water
Prescription:
The pressed powder part
5-aminovaleric acid hydrochloride hydrochlorate 47.2g
Ethyl hydroxybenzoate 0.12g
Disodiumedetate 1.00g
Polyvinylpyrrolidone 4.00g
Polyethylene Glycol 1.0g
Dissolving is a distilled water with solvent.
With ethyl hydroxybenzoate, disodiumedetate, polyvinylpyrrolidone with 5% dissolve with ethanol solution, with BUCHI 191 type spray dryers spraying system fine powder, condition is: inlet temperature is 140 ℃, outlet temperature is 85～95 ℃, charging rate is 0.5～2ml/min, and nozzle diameter is 0.7mm.5-aminovaleric acid hydrochloride hydrochlorate is pulverized, and crossed 80 mesh sieves,, add Polyethylene Glycol micropowder (200 order), mixing, packing, gland with spraying fine powder mix homogeneously.
The present invention describes by above description and embodiment, more than is described as nonrestrictively, does not limit claim scope of the present invention.
Claims (9)
1. a 5-aminolevulinate external preparation is characterized in that, the excipient and the dissolution solvent of the 5-aminolevulinate for the treatment of effective dose by containing of solid powdery are formed; Used dissolution solvent is water or the aqueous solution that contains described excipient.
2. preparation according to claim 1 is characterized in that, the weight percent content of 5-aminolevulinate is 50～100% in the excipient.
3. preparation according to claim 2 is characterized in that, the weight percent content of 5-aminolevulinate is 75～95% in the excipient.
4. preparation according to claim 1 is characterized in that, contains the excipient of the 5-aminolevulinate for the treatment of effective dose and the w/v of dissolution solvent to be: 5～35%, and mg/ml.
5. preparation according to claim 4 is characterized in that, contains the excipient of the 5-aminolevulinate for the treatment of effective dose and the w/v of dissolution solvent to be: 10～30%, and mg/ml.
6. preparation according to claim 1 is characterized in that, said excipient comprises permeation promoter and/or viscosifier and or stabilizing agent and/or antiseptic and/or lubricant and/or pH regulator agent.
7. preparation according to claim 6, it is characterized in that, described permeation promoter is a water soluble adjuvant, is selected from following at least a: glucose, lactose, mannitol, sucrose, sodium benzoate, sodium salicylate, sodium chloride, Polyethylene Glycol or polyvinylpyrrolidone;
Described viscosifier are natural or synthetic colloidal substance, can produce certain viscosity, be selected from following at least a: methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, sodium carboxymethyl cellulose, alginate, polyvinylpyrrolidone, polyvinyl alcohol, carbopol, tragakanta, arabic gum, xanthan gum, agar, pectin, gelatin, collagen, chitosan;
Described stabilizing agent is selected from ethylenediaminetetraacetic acid or disodiumedetate;
Described antiseptic is selected from following at least a: methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, chlorobutanol, thimerosal, phenylmercuric nitrate, benzyl alcohol, benzalkonium chloride, cetylpyridinium chloride, bromination hexadecane ammonium, domiphen bromide;
Described lubricant is selected from following at least a: Polyethylene Glycol, sodium lauryl sulphate, fumaric acid.
Described pH regulator agent is selected from following at least a: sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, sodium citrate, sodium succinate, sodium acetate, Borax.
8. according to each described preparation of claim 1～7, it is characterized in that said salt comprises a kind of in hydrochlorate, sulfate or the succinate.
9. according to the preparation method of each described preparation of claim 1～8, it is characterized in that, comprise the steps:
5-aminolevulinate and various excipient are all pulverized, and crossed 60～100 mesh sieves;
Medicine that sieves and excipient mixing;
Mixed-powder adopts dry method well known in the art or wet granulation, obtains fine powder or granule;
The water that will contain excipient, pressure sterilizing is made the dissolving solvent;
Or, make the dissolving solvent with the sterilization of hydro-thermal pressure.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100251699A CN100484520C (en) | 2004-06-15 | 2004-06-15 | 5-aminoketone valerate externally-applied preparation and production thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100251699A CN100484520C (en) | 2004-06-15 | 2004-06-15 | 5-aminoketone valerate externally-applied preparation and production thereof |
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| CN1711997A true CN1711997A (en) | 2005-12-28 |
| CN100484520C CN100484520C (en) | 2009-05-06 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101874795A (en) * | 2009-04-28 | 2010-11-03 | 上海复旦张江生物医药股份有限公司 | Application of 5-aminolevulinic acid in preparing medicaments for treating HPV (Human Papilloma Virus) infection |
| CN102670577A (en) * | 2012-05-18 | 2012-09-19 | 上海复旦张江生物医药股份有限公司 | Photo-sensitizer composition, and using method and application thereof |
| CN101745102B (en) * | 2008-12-16 | 2013-08-07 | 上海复旦张江生物医药股份有限公司 | Composition of 5-aminolevulinic acid and derivative thereof as well as application thereof |
-
2004
- 2004-06-15 CN CNB2004100251699A patent/CN100484520C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101745102B (en) * | 2008-12-16 | 2013-08-07 | 上海复旦张江生物医药股份有限公司 | Composition of 5-aminolevulinic acid and derivative thereof as well as application thereof |
| CN101874795A (en) * | 2009-04-28 | 2010-11-03 | 上海复旦张江生物医药股份有限公司 | Application of 5-aminolevulinic acid in preparing medicaments for treating HPV (Human Papilloma Virus) infection |
| CN102670577A (en) * | 2012-05-18 | 2012-09-19 | 上海复旦张江生物医药股份有限公司 | Photo-sensitizer composition, and using method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN100484520C (en) | 2009-05-06 |
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