CN101534863A - 用于向皮肤或粘膜施用的组合物 - Google Patents
用于向皮肤或粘膜施用的组合物 Download PDFInfo
- Publication number
- CN101534863A CN101534863A CNA2007800418843A CN200780041884A CN101534863A CN 101534863 A CN101534863 A CN 101534863A CN A2007800418843 A CNA2007800418843 A CN A2007800418843A CN 200780041884 A CN200780041884 A CN 200780041884A CN 101534863 A CN101534863 A CN 101534863A
- Authority
- CN
- China
- Prior art keywords
- alginic acid
- molecular weight
- skin
- compositions
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 193
- 235000010443 alginic acid Nutrition 0.000 claims abstract description 199
- 229920000615 alginic acid Polymers 0.000 claims abstract description 199
- 239000000783 alginic acid Substances 0.000 claims abstract description 196
- 229960001126 alginic acid Drugs 0.000 claims abstract description 196
- 150000004781 alginic acids Chemical class 0.000 claims abstract description 195
- 150000003839 salts Chemical class 0.000 claims abstract description 92
- 210000004877 mucosa Anatomy 0.000 claims abstract description 40
- 230000003013 cytotoxicity Effects 0.000 claims abstract description 33
- 231100000135 cytotoxicity Toxicity 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims description 41
- 238000002360 preparation method Methods 0.000 claims description 35
- 239000003889 eye drop Substances 0.000 claims description 22
- 231100000433 cytotoxic Toxicity 0.000 claims description 18
- 230000001472 cytotoxic effect Effects 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 11
- 210000000214 mouth Anatomy 0.000 claims description 11
- 210000000664 rectum Anatomy 0.000 claims description 10
- 210000003491 skin Anatomy 0.000 abstract description 97
- 210000004027 cell Anatomy 0.000 abstract description 18
- 210000004927 skin cell Anatomy 0.000 abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 description 80
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 238000005227 gel permeation chromatography Methods 0.000 description 19
- -1 alginic acid salt Chemical class 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000010828 elution Methods 0.000 description 11
- 238000000569 multi-angle light scattering Methods 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000012937 correction Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 229920000945 Amylopectin Polymers 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 210000000695 crystalline len Anatomy 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
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- 239000000126 substance Substances 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000001117 sulphuric acid Substances 0.000 description 5
- 235000011149 sulphuric acid Nutrition 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- AEMOLEFTQBMNLQ-VANFPWTGSA-N D-mannopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-VANFPWTGSA-N 0.000 description 4
- 241001260563 Lessonia nigrescens Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000000645 desinfectant Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000010354 integration Effects 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- 229930182837 (R)-adrenaline Natural products 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AEMOLEFTQBMNLQ-BZINKQHNSA-N D-Guluronic Acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-BZINKQHNSA-N 0.000 description 3
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 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 3
- 241001491705 Macrocystis pyrifera Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229940072056 alginate Drugs 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960005139 epinephrine Drugs 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229960002449 glycine Drugs 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000000622 irritating effect Effects 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229940083542 sodium Drugs 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 208000034628 Celiac artery compression syndrome Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 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 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 241000147041 Guaiacum officinale Species 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
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- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002675 Polyoxyl Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 229960003731 amlexanox Drugs 0.000 description 2
- SGRYPYWGNKJSDL-UHFFFAOYSA-N amlexanox Chemical compound NC1=C(C(O)=O)C=C2C(=O)C3=CC(C(C)C)=CC=C3OC2=N1 SGRYPYWGNKJSDL-UHFFFAOYSA-N 0.000 description 2
- 238000002266 amputation Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001437 anti-cataract Effects 0.000 description 2
- 230000001384 anti-glaucoma Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
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- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229940088529 claritin Drugs 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 2
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
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- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
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- 239000012467 final product Substances 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 229940091561 guaiac Drugs 0.000 description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
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- 231100000021 irritant Toxicity 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
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- 210000002200 mouth mucosa Anatomy 0.000 description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
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- 235000011056 potassium acetate Nutrition 0.000 description 2
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- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 2
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
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- 239000010935 stainless steel Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960000654 sulfafurazole Drugs 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
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Abstract
本发明公开了一种用于向皮肤或粘膜施用的组合物,其特征在于,包含藻酸和/或其盐,所述组合物对皮肤细胞或粘膜细胞的细胞毒性降低,并且具有更高的安全性。所述用于向皮肤或粘膜施用的组合物包含基本上不含有分子量等于或小于3,500的低分子量级分的藻酸和/或其盐。
Description
技术领域
本发明涉及一种用于向皮肤或粘膜施用的组合物,其特征在于,包含藻酸和/或其盐,并且对皮肤或粘膜细胞的细胞毒性有所降低。此外,本发明还涉及一种用于降低藻酸和/或其盐的细胞毒性的方法。
背景技术
藻酸具有在与二价或更高价的阳离子(如Ca2+)进行部分交联后变为凝胶(更粘稠)的作用,已知藻酸可以作为用于粘膜(如眼粘膜、鼻粘膜和口腔粘膜)的成分而施用(参见专利文献1)。还发现,当将含有藻酸的制剂施用于皮肤或粘膜时,存在于皮肤或粘膜上的少量Ca2+与藻酸相接触,使得所述制剂在皮肤或粘膜上凝胶化(更粘稠),并因此可用于提高制剂在施用部位的滞留和维持活性成分所产生的作用。
因为皮肤和粘膜(尤其是粘膜)对刺激和毒性非常敏感,因此给它们施用的成分需要具有低刺激性和低毒性。就刺激性而言,已报道藻酸不仅具有低刺激性,还具有降低其它化合物刺激性的作用(参见专利文献2)。就细胞毒性而言,已报道藻酸的钙盐具有细胞毒性(参见专利文献3)。然而,迄今为止,还没有充分地检查过其它藻酸盐以及藻酸本身的细胞毒性。
近来,对安全性的关注增加;因此,提供细胞毒性尽可能低的用于向皮肤或粘膜施用的组合物是所期望的。
专利文献1:日本专利申请公开No.2002-332248
专利文献2:日本专利申请公开No.2006-517200
专利文献3:日本专利申请公开No.2001-212223
发明内容
本发明所要解决的问题
本发明的目的是提供一种用于向皮肤或粘膜施用的组合物,其特征在于,包含藻酸和/或其盐,降低对皮肤或粘膜的细胞毒性并且增加安全性。此外,本发明的目的还在于提供一种用于降低藻酸和/或其盐的细胞毒性的方法。
解决问题的技术方案
作为用于解决上述问题的广泛研究的结果,本发明人发现了以下几点:
(i)因为常规的藻酸和/或其盐是从海带(tangle weed)等中纯化并可为活体所接受的,所以存在分子量为约380至1,000,000多种的藻酸。包含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐占总量的约7至20%(通过GPC方法的峰面积比)。
(ii)分子量等于或小于3,500的低分子量级分对粘膜细胞具有细胞毒作用;然而,分子量大于3,500的级分则对粘膜细胞不具有细胞毒作用。
(iii)通过选择基本上不含有分子量等于或小于3,500的低分子量级分的藻酸和/或其盐并将它们混合成用于向皮肤或粘膜施用的组合物,可显著降低用于向皮肤或粘膜施用的组合物的细胞毒性;因此可增加其安全性。
本发明通过做出基于上述发现的进一步改进而得以完成。
具体地,本发明涉及用于向皮肤和粘膜施用的以下组合物:
项目1-1:一种用于向皮肤或粘膜施用的组合物,其特征在于,包含藻酸和/或其盐,所述藻酸和/或其盐基本上不含有分子量等于或小于3,500的低分子量级分。
项目1-2:根据项目1-1的所述用于向皮肤或粘膜施用的组合物,其中所述藻酸和/或其盐所包含的分子量为大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
项目1-3:根据项目1-1的所述用于向皮肤或粘膜施用的组合物,其中所述藻酸和/或其盐的含量为所述组合物总量的0.001~20wt.%。
项目1-4:根据项目1-1的所述用于向皮肤或粘膜施用的组合物,其为液体制剂。
项目1-5:根据项目1-1的所述用于向皮肤或粘膜施用的组合物,其为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目1-6:根据项目1-1的用于向皮肤或粘膜施用的组合物,其为滴眼剂或洗眼剂。
此外,本发明涉及用于降低藻酸和/或其盐的细胞毒性的以下方法:
项目2-1:一种用于降低藻酸和/或其盐的细胞毒性的方法,其包括从所述藻酸和/或其盐中基本上除去分子量等于或小于3,500的低分子量级分的步骤。
项目2-2:根据项目2-1的所述用于降低的方法,其中所述除去步骤是从藻酸和/或其盐中除去低分子量级分,从而使得分子量大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
本发明还涉及以下用途:
项目3-1:基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐在制备用于向皮肤或粘膜施用的组合物中的用途。
项目3-2:根据项目3-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物的细胞毒性降低。
项目3-3:根据项目3-1的所述用途,其中所述藻酸和/或其盐所包含的分子量大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
项目3-4:根据项目3-1的所述用途,其中所述藻酸和/或其盐的含量为基于所述用于向皮肤或粘膜施用的组合物总量的0.001~20wt.%。
项目3-5:根据项目3-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为液体制剂。
项目3-6:根据项目3-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目3-7:根据项目3-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为滴眼剂或洗眼剂。
本发明还涉及以下用途:
项目4-1:基本上不含有分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免用于向皮肤或粘膜施用的组合物引起细胞毒性的用途。
项目4-2:根据项目4-1的所述用途,其中所述藻酸和/或其盐所包含的分子量大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
项目4-3:根据项目4-1的所述用途,其是在制备细胞毒性降低的用于向皮肤或粘膜施用的组合物中的用途。
项目4-4:根据项目4-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为液体制剂。
项目4-5:根据项目4-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目4-6:根据项目4-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为滴眼剂或洗眼剂。
本发明还涉及以下用途:
项目5-1:基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免用于向皮肤或粘膜施用的组合物引起对皮肤或粘膜的细胞毒性并提高其中所含活性成分在皮肤或粘膜上的滞留的用途。
项目5-2:根据项目5-1的所述用途,其中所述藻酸和/或其盐所包含的分子量大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
项目5-3:根据项目5-1的所述用途,其是在制备细胞毒性降低的用于向皮肤或粘膜施用的组合物中的用途。
项目5-4:根据项目5-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为液体制剂。
项目5-5:根据项目5-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目5-6:根据项目5-1的所述用途,其中所述用于向皮肤或粘膜施用的组合物为滴眼剂或洗眼剂。
本发明还涉及藻酸和/或其盐的以下用途:
项目6-1:藻酸和/或其盐,所述藻酸和/或其盐基本上不含分子量等于或小于3,500的低分子量级分,用于避免引起对皮肤或粘膜的细胞毒性。
项目6-2:根据项目6-1的所述藻酸和/或其盐,其包含基于分子量大于等于380的级分总量的2.5%或更少的分子量大于等于380至小于等于3,500的级分。
项目6-3:根据项目6-1的所述藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为液体制剂。
项目6-4:根据项目6-1的藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目6-5:根据项目6-1的所述藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为滴眼剂或洗眼剂。
本发明还涉及藻酸和/或其盐的以下用途:
项目7-1:藻酸和/或其盐,所述藻酸和/或其盐基本上不含分子量等于或小于3,500的低分子量级分,用于避免用于向皮肤或粘膜施用的组合物引起对皮肤或粘膜的细胞毒性和增加其中所含活性成分在皮肤或粘膜上滞留。
项目7-2:根据项目7-1的所述藻酸和/或其盐,其包含基于分子量大于等于380的级分总量的2.5%或更少的分子量大于等于380至小于等于3,500的级分。
项目7-3:根据项目7-1的所述藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为液体制剂。
项目7-4:根据项目7-1的所述藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
项目7-5:根据项目7-1的所述藻酸和/或其盐,其中所述用于向皮肤或粘膜施用的组合物为滴眼剂或洗眼剂。
发明效果
在本发明的用于向皮肤或粘膜施用的组合物中,藻酸和/或其盐的细胞毒性显著降低;因此,可将其安全地用于对毒性敏感的粘膜。
通常使用的藻酸和/或其盐在溶液中容易沉淀;因此,它们难以配制。本发明所用的藻酸和/或其盐可抑制沉淀的形成。因此,本发明用于向皮肤或粘膜施用的组合物还具有与常规使用的藻酸和/或其盐相比易于配制的优点。
此外,本发明用于向皮肤或粘膜施用的组合物通过所包含的藻酸和/或其盐在与体液(如汗液和泪液)相接触时对皮肤或粘膜的作用而具有粘度增加和凝胶强度提高的极好效果。因此,本发明用于向皮肤或粘膜施用的组合物可用于避免对皮肤或粘膜的细胞毒性、提高用于向皮肤或粘膜施用的组合物中所包含活性成分的滞留以及维持所述活性成分的作用。
本发明用于降低藻酸和/或其盐的细胞毒性的方法提供了降低对粘膜细胞或皮肤细胞的细胞毒性的藻酸和/或其盐;因此,所述方法可用于提供混合形成细胞毒性降低和安全性增加的用于向皮肤或粘膜施用之组合物的基础成分。
具体实施方式
I.用于向皮肤或粘膜施用的组合物
所述藻酸是由甘露糖醛酸(以下可简称为“M”)和古洛糖醛酸(以下可简称为“G”)构成的多糖,为嵌段共聚物,其中甘露糖醛酸的均聚物部分(MM部分)、古洛糖醛酸的均聚物部分(GG部分)以及无规排列的甘露糖醛酸和古洛糖醛酸的部分(MG部分)是无规键合的。
在本发明的用于向皮肤或粘膜施用的组合物中,使用基本上不含分子量等于或小于3,500的低分子量级分的藻酸或其盐。“基本上不含分子量等于或小于3,500的低分子量级分的藻酸”意指其中除去分子量等于或小于3,500的低分子量级分的藻酸,除了其中不可能被完全除去的分子量等于或小于3,500的低分子量级分以外,所述藻酸不包含低分子量级分。更具体地,作为“基本上不含分子量等于或小于3,500的低分子量级分的藻酸”的一个实例,以下描述了当进行GPC方法时,分子量大于或等于380至等于或小于3,500的级分(与分子量大于或等于380至等于或小于3,500的分子量相对应的总峰面积)占分子量大于或等于380的级分的总量(与分子量大于或等于380的级分相对应的总峰面积)的比例(下文简称为“分子量等于或小于3,500的比例)为2.5%或更小的藻酸。
基于降低对皮肤或粘膜细胞的毒性的出发点,本发明用于向皮肤或粘膜施用的组合物中所使用的藻酸中分子量等于或小于3,500的比例优选为0至小于2.0%,更优选为0至小于1.5%,最优选为0至小于1.0%。换言之,本发明中所使用的藻酸中分子量大于3,500的级分(高分子量级分)占分子量大于或等于380的级分总量的97.5%以上,优选为98.0至100%,更优选为98.5至100%,最优选为99.0至100%。
在本发明中,可通过凝胶渗透色谱方法(GPC方法)测定藻酸的分子量和分子量等于或小于3,500的比例。具体条件示于参比实施例中。
对于本发明中使用的藻酸和/或其盐而言,甘露糖醛酸与古洛糖醛酸的组成比(M/G比;摩尔比)并非特别限定的。例如,广泛使用M/G比为0.4至4.0的藻酸。M/G比越小,组合物就越容易开始胶凝。因此,从改善药理活性成分在施用部位的滞留的观点来看,M/G比为2.5或更小,优选2.0或更小,更优选1.6或更小,最优选1.0或更小是所期望的。在本发明中,所述M/G比是通过将藻酸分为几个组成部分(block unit)、将其分级并分别进行定量而计算的值;根据A.Haug et al.,Carbohyd.Res.32(1974),第217-225页中所述的方法具体测定所述比值。
在本发明中所用的藻酸和/或其盐中,MM部分、GG部分和MG部分的比例并没有特别限定,其可根据所述用于向皮肤或粘膜施用的组合物的用途或形式而进行适当选择。
本发明中所用的藻酸的盐没有具体限定,只要其形式是基本上不含分子量等于或小于3,500的低分子量级分的藻酸的盐并且是药理或生理上可接受的即可。所述藻酸盐的具体实例包括钠盐、钾盐、三乙醇胺盐、铵盐等。所述藻酸盐可单独使用或者以其两种或更多种类型的任意组合而使用。
在本发明的用于向皮肤或粘膜施用的组合物中,可使用单一类型的藻酸及其盐,或者可使用其两种或更多种类型的任意组合,只要其基本上不含分子量等于或小于3,500的低分子量级分即可。特别地,将藻酸、藻酸钠和藻酸钾优选用在本发明中,因为它们是可溶于水的。从有效实现本发明效果、易于制备等观点来看,藻酸是特别优选的。
可通过对可得到的藻酸和/或其盐、或根据常规方法等由海带纯化的藻酸和/或其盐进行凝胶过滤除去分子量等于或小于3,500的级分而制得上述分子量范围的藻酸和/或其盐。或者,可通过将可得到的藻酸和/或其盐、或根据常规方法由海带纯化的藻酸和/或其盐加入到比水极性低的溶液中并收集所产生的沉淀而制备上述分子量范围的藻酸和/或其盐。比水极性低的溶液的具体实例包括低级醇(如甲醇和乙醇),有机溶剂(如丙酮),以及它们和水的液体混合物。
当本发明中所用藻酸和/或其盐是由海带纯化而来的时,用作原料的海带的实例包括来自智利的褐海藻(Lessonia nigrescens)、来自智利的Lessonia flavicans、来自西海岸的巨藻(Macrocystis pyrifera)、来自南非的Ecklonia maxima、来自塔斯马尼亚的海洋巨藻(Durvillaea potatorum)、来自北欧的褐藻(Ascophyllum nodosum)、来自北欧的北方海带(Laminaria hyperborea)、来自北欧的掌状海带(Laminaria digitata)等。
在本发明的用于向皮肤或粘膜施用的组合物中,所述藻酸级分的混合比不是特别限定的,可以根据所施用粘膜的类型、用于向皮肤或粘膜施用的组合物的形式等进行适当选择。具体地,所述藻酸级分(换算为藻酸的重量)的混合比通常为基于用于向皮肤或粘膜施用的所述组合物的总量的0.001~20wt.%,优选0.005~10wt.%。具体地,针对所述用于向皮肤或粘膜施用的组合物的每种用途的所述藻酸级分(换算为藻酸的重量)的混合比如下:
当所述组合物是眼用组合物时,其通常为0.001~1wt.%,优选0.005~1wt.%,更优选0.01~0.5wt.%,最优选0.01~0.2wt.%;
当所述组合物是鼻用组合物时,其通常为0.001~10wt.%,优选0.01~5wt.%,更优选0.05~1wt.%;
当所述组合物是口腔用组合物时,其通常为0.001~20wt.%,优选0.01~10wt.%,更优选0.01~5wt.%;
当所述组合物是直肠用组合物、阴道用组合物或尿道用组合物时,其通常为0.001~10wt.%,优选0.005~5wt.%,更优选0.01~2wt.%;
当所述组合物是皮肤用组合物时,其通常为0.001~20wt.%,优选0.01~10wt.%,更优选0.01~5wt.%。
本发明的用于向皮肤或粘膜施用的组合物除了上述的藻酸和/或其盐以外,还可包含活性成分(药理活性成分、生理活性成分等)。这些成分的实施例包括但不限于解充血剂、调节眼肌的药物、抗炎药物或收敛剂、抗过敏药物、维生素、氨基酸、抗菌药物或消毒剂、糖类、聚合物或其衍生物、纤维素或其衍生物、局部麻醉剂、抗青光眼药物和抗白内障药物。本发明中所用药理活性成分和生理活性成分包括以下成分:
解充血药:例如α-肾上腺素能药物如肾上腺素、盐酸肾上腺素、盐酸麻黄碱、盐酸羟甲唑啉、盐酸四氢唑啉、盐酸萘唑啉、盐酸苯福林、盐酸甲基麻黄碱、重酒石酸肾上腺素、硝酸萘唑啉等,所有这些化合物均可为d-形式、l-形式或dl-形式;
调节眼肌的药物:例如具有与乙酰胆碱类似的活性中心的胆碱酯酶抑制剂,如甲硫酸新斯的明、托品酰胺、土木香素、硫酸阿托品等;
抗炎药物或收敛剂:例如硫酸锌、乳酸锌、尿囊素、ε-氨基己酸、吲哚美辛、氯化溶菌酶、硝酸银、普拉洛芬、薁磺酸钠、甘草酸二钾、甘草酸二铵、双氯芬酸钠、溴芬那酸钠、盐酸小檗碱、硫酸小檗碱等;
抗过敏药物:例如左卡巴斯汀、氨来呫诺(amlexanox)、异丁司特、他扎司特、曲尼司特、异西喷地、二苯特罗、曲普立啶、曲吡那敏、松齐拉敏、美海屈林、芬乙嗪、奥沙米特、甲磺司特、色甘酸钠、吡嘧司特钾等;
维生素:例如视黄醇乙酸酯、视黄醇棕榈酸酯、盐酸吡哆醇、黄素腺嘌呤二核苷酸钠、磷酸吡哆醇、氰钴铵、泛醇、泛酸钙、泛酸钠、抗坏血酸、醋酸生育酚、烟酸生育酚酯、琥珀酸生育酚酯、生育酚琥珀酸钙、泛醌衍生物等;
氨基酸:例如氨基乙磺酸(牛磺酸)、谷氨酸、肌酸酐、天冬氨酸钠、天冬氨酸钾、天冬氨酸镁和天冬氨酸镁钾、谷氨酸、谷氨酸钠、谷氨酸镁、ε-氨基己酸、甘氨酸、丙氨酸、精氨酸、赖氨酸、γ-氨基丁酸、γ-氨基戊酸、硫酸软骨素钠等,所有这些化合物均可为d-形式、l-形式或dl-形式;
抗菌药物或消毒剂:例如烷基多氨基乙基甘氨酸(alkylpolyaminoethylglycine)、氯霉素、磺胺甲基异噁唑、磺胺异噁唑、磺胺甲基异噁唑钠、磺胺异噁唑二乙醇胺、磺胺异噁唑单乙醇胺、碘胺甲基异噁唑钠(sulfisomezole sodium)、磺胺二甲异嘧啶钠、氧氟沙星、诺氟沙星、左氧氟沙星、盐酸洛美沙星、阿昔洛韦等;
糖类:例如单糖、二糖,尤其是葡萄糖、麦芽糖、海藻糖、蔗糖、环糊精、木糖醇、山梨醇、甘露醇等;
聚合物或其衍生物:例如阿拉伯胶、刺梧桐胶、黄原胶、角豆胶、瓜耳胶、愈创木胶(guaiac)、温百籽、达马脂、黄蓍胶、安息香胶、刺槐豆胶、酪蛋白、琼脂、糊精、葡聚糖、角叉菜胶、明胶、胶原、果胶、淀粉、聚半乳糖醛酸、几丁质及其衍生物、壳聚糖及其衍生物、弹性蛋白、肝素、类肝素、硫酸肝素、硫酸类肝素、透明质酸、硫酸软骨素、神经酰胺、聚乙烯醇(完全或部分皂化的)、聚乙烯吡咯烷酮、聚乙烯甲基丙烯酸酯、聚丙烯酸、羧乙烯聚合物(carboxyvinylpolymer)、聚乙烯亚胺、核糖核酸、脱氧核糖核酸、聚乙二醇(macrogol)及其可药用盐等;
纤维素或其衍生物:例如乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、羧乙基纤维素、硝酸纤维素等;
局部麻醉剂:例如盐酸普鲁卡因、盐酸利多卡因等;
抗青光眼药物:例如异丙基乌诺前列酮、肾上腺素、盐酸阿可乐定、盐酸卡替洛尔、盐酸地匹福林、盐酸杜塞酰胺、盐酸毛果芸香碱、盐酸布那唑嗪、盐酸布拉洛尔、盐酸倍他洛尔、盐酸苯呋洛尔、卡巴胆碱、盐酸左布诺洛尔、肾上腺素二戊酸盐、溴地斯的明、尼普洛尔(nipradiolol)、马来酸噻吗洛尔、拉坦前列腺素等;
抗白内障药物:例如谷胱甘肽、吡诺克辛和5,12-二氢四氮戊省二磺酸钠(sodium 5,12-dihydro azapentacene disulfonate)。
每种成分的混合比在皮肤施用制剂、粘膜施用制剂等领域中是已知的。因此,本发明用于向皮肤或粘膜施用的组合物中上述成分的混合比将根据所述用于向皮肤或粘膜施用的组合物的剂型、药理活性成分或生理活性成分的种类等而进行适当选择。例如,所述药理活性成分或生理活性成分的混合比可选自基于所述用于向皮肤或粘膜施用的组合物总量的约0.0001至30wt.%,优选约0.001至10wt%。
本发明用于向皮肤或粘膜施用的组合物可包含一种成分或添加剂、或者相组合的超过一种的成分或添加剂,其可根据所述组合物的用途或形式依据常规方法选自多种成分和添加剂,只要本发明的效果不受到影响即可。这些成分或添加剂的实例包括通常用于制备半固体或液体制剂的载体(含水溶剂、水性基质或油性基质等),以及各种添加剂如表面活性剂、防腐剂、消毒剂或抗菌药物、pH调节剂、张力调节剂(tonicityagent)、螯合剂、缓冲剂和稳定剂。
本发明用于向皮肤或粘膜施用的组合物中的典型成分的实例包括但不限于:
载体:含水溶剂比如水和含水乙醇;
表面活性剂:例如非离子表面活性剂如聚氧乙烯(以下称为POE)-聚氧丙烯(以下称为POP)嵌段共聚物(例如泊洛沙姆407)、乙二胺的POE-POP嵌段共聚物加合物(例如泊洛沙胺)、POE失水山梨醇单油酸酯、POE氢化蓖麻油(例如POE(60)氢化蓖麻油)和硬脂酸聚烃氧酯(polyoxyl stearate);甘氨酸型两性表面活性剂如烷基二氨基乙基甘氨酸;阳离子表面活性剂如烷基季铵盐(例如苯扎氯铵、苄索氯铵)等,括号内的数字代表所加的摩尔数;
防腐剂、消毒剂或抗菌药物:例如烷基二氨基乙基甘氨酸盐酸盐、苯甲酸钠、乙醇、苯扎氯铵、苄索氯铵、葡糖酸氯己定、氯丁醇、山梨酸、山梨酸钾、脱氢乙酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、硫酸羟喹啉、苯乙醇、苄醇、双胍(例如聚六亚甲基双胍)、(Rhodia)等;
pH调节剂:例如盐酸、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、三乙醇胺、单乙醇胺、二异丙醇胺、硫酸、聚磷酸、丙酸、草酸、葡糖酸、富马酸、乳酸、酒石酸、苹果酸、琥珀酸、葡糖酸内酯、乙酸铵等;
张力调节剂:例如亚硫酸氢钠、亚硫酸钠、氯化钾、氯化钙、氯化钠、氯化镁、乙酸钾、乙酸钠、碳酸氢钠、碳酸钠、硫代硫酸钠、硫酸镁、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾、甘油、丙二醇等;
螯合剂:例如抗坏血酸、依地酸四钠、依地酸钠、柠檬酸等;
缓冲剂:例如柠檬酸盐缓冲剂、乙酸盐缓冲剂、碳酸盐缓冲剂、硼酸盐缓冲剂、磷酸盐缓冲剂等。更具体地是柠檬酸、柠檬酸钠、乙酸、乙酸钾、乙酸钠、碳酸氢钠、碳酸钠、硼酸、硼砂、磷酸、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾等;
稳定剂:例如二丁基羟基甲苯、氨基丁三醇、甲醛次硫酸氢钠(雕白粉)、生育酚、焦亚硫酸钠、单乙醇胺、单硬脂酸铝、单硬脂酸甘油酯等。
本发明用于向皮肤或粘膜施用的组合物的剂型没有特别限定。可列举出包括液体、混悬剂、软膏、乳膏、凝胶、洗剂、粘附剂(adhesivepreparation)、喷雾剂以及气雾剂的多种剂型。这些剂型中优选使用液体。
可根据制剂等依照常规方法利用合适的基质或添加剂制备本发明用于向皮肤或粘膜施用的组合物。
本发明用于向皮肤或粘膜施用的组合物的施用部位可以是皮肤或粘膜,优选粘膜。作为施用部位的粘膜的类型没有特别限定,本发明的组合物可以施用给构成活体的多种粘膜。具体地,当本发明的组合物作为用于粘膜施用的组合物使用时,其可用作用于眼粘膜(比如角膜和结膜)施用的眼用组合物;用作用于鼻腔、耳腔等施用的耳鼻用组合物;用作用于口的牙槽弓、舌、唇,口腔粘膜等施用的口腔用组合物;用于直肠施用的直肠用组合物;用于阴道施用的阴道用组合物;用于尿道施用的尿道用组合物等。
上述眼用组合物的实例包括滴眼剂(包括眼科药物、眼科溶液)、洗眼剂(包括洗眼剂(eye lotion)、洗眼液(collyrium))、眼膏、隐形眼镜用的溶液、以及隐形眼镜护理产品(清洗溶液、储备溶液、消毒溶液、多用途溶液等)。上述滴眼剂和洗眼剂包括可在适当位置接触时滴入的滴眼剂和洗眼剂。本文中使用的术语隐形眼镜包括所有类型的隐形眼镜,包括硬隐形眼镜(包括可透过氧的硬隐形眼镜)、软隐形眼镜等。上述耳鼻用组合物的实例包括滴鼻剂(包括洗鼻剂(collunarium)和鼻内溶液(nasal solution))、洗鼻剂(包括洗鼻药物和洗鼻溶液)以及滴耳剂(包括耳鼻用药物和耳鼻用溶液)。上述口腔用组合物的实例尤其包括口咽药物(oropharyngeal drug)、漱口剂(mouth wash)等。上述直肠用组合物的实例包括痔疮剂(hemorrhoidal agent)、栓剂等。上述阴道用组合物的实例包括阴道栓剂和阴道乳膏。尿道用组合物的实例包括润肠剂(demulcent)和表面麻醉剂。
在上述施用方法中,本发明用于向皮肤或粘膜施用的组合物优选作为眼用组合物、更优选作为滴眼剂或洗眼剂来使用。在构成活体的粘膜中,已知眼粘膜是容易受到细胞毒性的有害作用影响的粘膜之一;然而,本发明用于向皮肤或粘膜施用的组合物也可用于对细胞毒性的有害作用敏感的眼粘膜,所述组合物具有高安全性而不引起对眼粘膜的细胞毒性。优选洗眼剂,因为其大量用于清洗眼粘膜。
II.用于降低藻酸和/或其盐的细胞毒性的方法
如上所述,可通过从藻酸和/或其盐中基本上除去分子量等于或小于3,500的低分子量级分而提供对粘膜或皮肤细胞不产生细胞毒性的藻酸和/或其盐。因此,本发明还从不同的方面提供了一种用于降低藻酸和/或其盐的细胞毒性的方法,所述方法包括从藻酸和/或其盐中基本上除去分子量等于或小于3,500的低分子量级分的步骤。在所述降低方法中,用于从藻酸和/或其盐中基本上除去分子量等于或小于3,500的低分子量级分的方法描述于上述“I.用于向皮肤或粘膜施用的组合物”部分中。
III.基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐
的用途
如上所述,所述基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐可用于制备用于向皮肤或粘膜施用的组合物,尤其是用于向皮肤或粘膜施用的具有降低的细胞毒性的组合物。因此,本发明还提供了基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐在制备用于向皮肤或粘膜施用的组合物中的用途。
此外,所述藻酸和/或其盐可用于避免引起用于向皮肤或粘膜施用的组合物的细胞毒性,所述组合物包含含有分子量等于或小于3,500的低分子量级分的藻酸和/或其盐。因此,本发明还提供了基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免引起细胞毒性的用途。本发明还提供了基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免引起对皮肤或粘膜的细胞毒性、增加用于向皮肤或粘膜施用的组合物中所包含活性成分的滞留的用途。
IV.基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐
的用途
如上所述,基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐可通过包含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐而用于避免引起对皮肤或粘膜的细胞毒性。因此,本发明还提供了基本上不含分子量等于或小于3,500的低分子量级分的用于避免引起对皮肤或粘膜的细胞毒性的藻酸和/或其盐。
此外,所述藻酸和/或其盐可用于避免引起对皮肤或粘膜的细胞毒性,增加用于向皮肤或粘膜施用的组合物中所含活性成分在皮肤或粘膜上的滞留。因此,本发明还提供了基本上不含分子量等于或小于3,500的低分子量级分的用于避免引起对皮肤或粘膜的细胞毒性、增加用于向皮肤或粘膜施用的组合物中所含活性成分在皮肤或粘膜上的滞留的藻酸和/或其盐。
实施例
以下实施例和测试实施例更详细地举例说明本发明,但不应解释为限制其范围。
参比实施例
测定藻酸分子量的方法
根据以下方法测定藻酸的分子量和分子量等于或小于3,500的比例。首先,将八种已知分子量的支链淀粉标准品用作分子量标志物,以通过将GPC方法的保留时间对支链淀粉的分子量作图来绘制校正曲线。然后,将藻酸(校正藻酸样品)进行GPC方法,根据前述绘制的校正曲线得到藻酸(所述校正藻酸样品)的估计重均分子量。此外,在使用多角度激光散射检测器(MALS)作为检测器以得到重均分子量的情况下,将藻酸(校正藻酸样品)进行GPC方法,由此校正前述利用支链淀粉得到的关系方程。然后,通过利用此校正关系方程,测定所述藻酸的分子量和分子量等于或小于3,500的比例。详细内容如下。
(1)GPC测定条件
采用以下测定条件进行联用液相色谱法的凝胶渗透色谱方法(GPC方法)。
(1-1)检测器:差示折光检测器或多角度激光散射检测器(MALS)
(1-1-1)多角度激光散射检测器(MALS):使用DAWN-EOS型多角度激光散射检测器。
(1-1-2)波长设定为690nm(半导体激光器)。
(1-1-3)第二维里系数(A2)×浓度(c)设定为0mol/g。
(1-1-4)折光指数增量(dn/dc)设定为0.114mL/g。
(1-1-5)温度设定为23±2℃。
(1-2)柱:将三根不锈钢柱相连使用,每根柱分别填充有用于聚环氧乙烷或聚乙二醇的水溶液的分子量为10,000,000、400,000和5,000的排阻限度的亲水性乙烯基聚合物(粒径分别为13μm、10μm和7μm)。每根不锈钢柱的内径为7.8mm,长度为30cm。
(1-3)柱温设定为35℃。
(1-4)流动相:使用通过以下方法得到的溶液:将11.5g磷酸二氢铵和17.5g氯化钠溶解在蒸馏水中至总体积为1000mL,并用磷酸将pH调节至4.0。
(1-5)流动相的流速设定为0.75mL/分钟。在本研究中,基线的稳定很重要;因此,温度控制和仪器平衡必须充分进行,以获得稳定的基线。在参比路径打开的情况下流动相运行超过一夜后,再在参比路径关闭的情况下运行流动相超过一夜。在分析中,室温不应改变;仪器内部(比如柱、管和检测器)的温度也必须保持恒定。
(2)利用分子量标志物得到校正曲线
将可获得的作为分子量标志物的支链淀粉标准品(八种以上已知分子量为5,900~788,000的支链淀粉)和葡萄糖分别溶解在上述GPC测定条件所述的流动相中至0.1w/v%的浓度,并将其每100μL进行下述的GPC方法以获得其洗脱时间。通过将在y轴上的每种支链淀粉标准品的分子量M的对数(log10M)对其在x轴上的洗脱时间作图而得到支链淀粉标准品的校正曲线,确定所述校正曲线的线性方程(以下方程1)。
方程1:y=ax+b
y:log10M
x:洗脱时间
(3)校正曲线的线性方程的校正
(3-1)校正藻酸样品的制备
将100g干海带(Lessonia nigrescens)切断、用水清洗,并在3L 0.2wt.%的硫酸中浸泡2小时。取出提取物,并将残留物在1L次氯酸钠(有效氯:10.5wt.%)水溶液中浸泡10分钟,然后收集残留物,随后加入3L纯化水并静置10小时。向此溶液中加入同样体积的以硫酸酸化的甲醇-水溶液(2wt.%硫酸、90wt.%甲醇、余量为水),并将所得沉淀通过过滤回收并干燥。将此3g干燥沉淀分批加入到250mL水中并搅拌10分钟。在确认已均匀分散在水中后,加入0.825g碳酸钠,并将混合物再搅拌20分钟以溶解沉淀。在确认沉淀已完全溶解后,加入水至总重量为300g以得到藻酸的粗溶液。向200g此藻酸粗溶液中分批加入1,800mL丙酮,然后搅拌30分钟,然后通过滤纸(φ110mm)过滤溶液。收集滤纸上得到的残留物,然后在室温下将其干燥,蒸馏掉丙酮以得到校正藻酸样品。
(3-2)利用支链淀粉标准品测定校正藻酸样品的假定重均分子量
将以上制备的校正藻酸样品称重并在上述GPC测定条件中所述的流动相中溶解成0.1w/v%的浓度以制备样品溶液。将该样品溶液进行GPC方法以进行分析。在对此校正藻酸样品进行分析之后的数据处理中,将藻酸的峰分为每0.1分钟洗脱时间的i部分,并通过自动积分方法计算每一部分的面积(An)。此外,将每个部分的洗脱时间代入方程1以计算其M值,所述M值被视为是每一部分藻酸的假定分子量(Mn假定)。此外,将每一部分的面积值(An)除以该部分藻酸的假定分子量(Mn假定)以计算该部分藻酸分子的假定数目(Nn假定)。将由此计算的假定分子量(Mn假定)和假定分子数(Nn假定)代入以下方程2中以计算校正藻酸样品的假定重均分子量(Mw假定)。
方程2
(3-3)校正藻酸样品的真实重均分子量的测定
将校正藻酸样品称重并在上述GPC测定条件中所述的流动相中溶解成0.5w/v%的浓度以制备样品溶液。将100μL该样品溶液进行GPC方法,对该方法而言将多角度激光散射检测器(MALS)相连接作为检测器,并通过GPC-MALS方法测定真实重均分子量(Mw真实)。通过Berry作图分析对所检测到的单个峰进行重均分子量的计算,并读出斜率的值。
(3-4)线性方程的校正
通过校正藻酸的假定分子量(Mn假定)使得利用方程2计算的藻酸假定重均分子量(Mw假定)等于在上述(3-3)GPC-MALS方法中所计算的真实重均分子量(Mw真实),测定每一部分藻酸的真实分子量(Mn真实)。具体而言,计算b′,使得Mw真实等于通过将以下值代入上述方程2中的Mn假定和Nn假定后所计算得到的值。
利用以下方程3(其中包含以上得到的a和b′)来得到藻酸的真实校正曲线。
方程3:y=ax+b′
y:log10Malg
x:洗脱时间
Malg:藻酸的分子量
(4)分子量和分子量等于或小于3,500的峰面积的计算
对于要测定的藻酸和/或其盐来说,将通过GPC方法得到的色谱图中每一个峰的洗脱时间应用到上述方程3中所表示的校正曲线上,从而计算每一个峰的分子量。
在本发明中,利用Agilent 1100系列Agilent ChemStation(AgilentTechnologies)采用以下设定条件通过自动积分方法或通过类似方法来计算通过GPC方法得到的色谱图中的峰面积。
·初始设定
斜率灵敏度 5
峰宽 10
峰面积截除 100
峰高截除 10
肩斜
·程序
0.1秒钟:积分关闭
相应于分子量1,100,000的藻酸的洗脱时间:Baseline at Valleys开
相应于分子量1,000,000的藻酸的洗脱时间:积分开
相应于分子量3,500的藻酸的洗脱时间:分流峰开
相应于分子量3,000的藻酸的洗脱时间:斜率灵敏度2.5。
分子量等于或小于3,500的藻酸的峰面积计算为分子量等于或大于380至等于或小于3,500的藻酸的峰面积。
测试实施例1
1.藻酸的制备
其中未除去低分子量级分的藻酸的制备
向5g来自智利的干海带(Lessonia nigrescens)片中加入100mL水;使混合物在室温下静置60分钟,然后在90~100℃的水浴中加热30分钟,同时偶尔用玻璃棒进行搅拌。然后,将混合物在4℃冷却约3小时,利用滤纸(ADVANTEC,No.2,φ110mm)过滤,然后收集滤液。向50mL此溶液中加入450mL丙酮,然后搅拌并以同样方式通过滤纸过滤,然后收集沉淀。干燥沉淀而得到藻酸(对比实施例1)。
其中除去了低分子量级分的藻酸的制备和低分子量级分藻酸的制备
将100g来自智利的干海带(Lessonia nigrescens)切断、用水清洗,并在3L 0.2wt.%的硫酸中浸泡2小时。取出提取物,并将残留物在1L次氯酸钠(有效氯:10.5wt.%)水溶液中浸泡10分钟,然后收集残留物,随后加入3L纯化水并静置10小时。向此溶液中加入同样体积的以硫酸酸化的甲醇-水溶液(2wt.%硫酸、90wt.%甲醇、余量为水),并将所得沉淀通过过滤回收并干燥。将此3g干燥沉淀分批加入到250mL水中并搅拌10分钟。在确认已均匀分散在水中后,加入0.825g碳酸钠,并将混合物再搅拌20分钟以溶解沉淀。在确认沉淀已完全溶解后,加入水至总重量为300g以得到藻酸的粗溶液。向200g由此获得的藻酸粗溶液中分批加入1,800mL丙酮,然后搅拌30分钟,然后通过滤纸(ADVANTEC,No.2,φ110mm)过滤溶液。收集滤纸上得到的残留物,然后在室温下将其干燥,蒸馏掉丙酮以得到未溶解在丙酮中的藻酸级分(即其中除去低分子量级分的藻酸,实施例1)。相反,收集过滤后得到的滤液并在减压下(100~150mmHg,25℃)蒸馏掉丙酮和水,以得到溶解在丙酮中的藻酸级分(即低分子量级分藻酸;对比实施例2)。
2.所制备藻酸的分子量分布的测定
通过利用液相色谱法(Agilent 1100系统(Agilent Technologies)),控制器/数据处理装置:G2170AJ ChemStation,泵:G1311A,注射器:G1329A,检测器:差示折光检测器G1362A(预设温度:35℃),恒温箱:G1316A)并根据在以上参比实施例中所述的条件和方法,测定上述实施例1和对比实施例1和2中所得到的藻酸中分子量等于或小于3,500的比例。
根据上述参比实施例中所述的方法,通过以下步骤测定分子量等于或小于3,500的比例:制备校正藻酸样品,测定所述校正藻酸样品的重均分子量,利用支链淀粉标准品(Shodex P-82,Showa Denko)绘制校正曲线,针对实施例1以及对比实施例1和2的藻酸计算通过GPC方法所检测到的每个峰的分子量和所述峰的面积。
每种藻酸(实施例1以及对比实施例1和2)中分子量等于或小于3,500的比例的结果如下。
表1
实施例1 | 对比实施例1 | 对比实施例2 | |
分子量小于等于3,500的比例 | 2.3% | 7.7% | 12.4% |
3.所制备藻酸的细胞毒性的评价
进行了对上述制备的藻酸(实施例1以及对比实施例1和2)的细胞毒性的测试。首先,通过将每种藻酸在细胞培养基培养基199(GIBCO)(添加有10%(v/v)胎牛血清(Daiichi Kagaku Yakuhin))中溶解成0.2或2.0%(w/v)的浓度而制备藻酸溶液。然后,将兔角膜上皮细胞系SIRC(ATCC编号:CCL-60)以2.0×105个细胞/孔铺板于48孔微孔板(Corning)中,并加入以上制备的藻酸溶液以得到最终浓度为0.1或1.0%(w/v)的藻酸,然后将细胞在37℃、5% CO2和90%相对湿度的条件下培养。向作为对照的不含所制备藻酸溶液的板孔中加入同样体积的细胞培养基。在开始培养48小时后,收集上清液,加入用于活细胞检测的10%(v/v)细胞计数试剂盒-8(Dojin Kagaku)的试剂,然后将其在37℃、5% CO2和90%相对湿度的条件下培养1小时。1小时后,利用分光光度计(Thermo Electron)测量通过与活细胞反应而进行染色的染料的吸光度(450nm)。利用所观察的吸光度的值,以下面的方程计算细胞活力,并评价每种藻酸的细胞毒性。
方程5
细胞活力(%)=100×(其中加入了每种藻酸溶液的组的吸光度-含有用于活细胞检测的试剂之培养基的吸光度)/(对照组的吸光度-含有用于活细胞检测的试剂之培养基的吸光度)
结果示于图1中。通过加入对比实施例2的1.0%(w/v)的藻酸溶液,产生了高细胞毒性,具体细胞活力为约5%。此外,显微镜观察也证实了加入了对比实施例2的藻酸的细胞丧失了其粘附能力并漂浮。相反,经验证实施例1的藻酸的毒性与对比实施例1和2的藻酸相比明显降低。这些结果揭示了藻酸的细胞毒性来源于成分中所含的低分子量级分。此外,还证实了可通过向用于向皮肤和粘膜施用的组合物中选择性地加入基本上不含有低分子量级分的藻酸来降低对粘膜细胞的细胞毒性。
测试实施例2 藻酸刺激性的评价
利用实施例1的藻酸制备以下制剂实施例1的滴眼剂。在通过0.22μm孔径的滤膜过滤后,将所述滴眼剂无菌填充进塑料容器中。
制剂实施例1
将此滴眼剂施用于5名健康成人(3名男性,2名女性),并根据以下标准评价刺激感。
评价方法
+:有刺激感
±:有轻微刺激感
-:没有刺激感
所得结果显示在表2中。结果证实了制剂实施例1的滴眼剂提供了良好的使用感觉;在滴眼后即刻、或甚至滴眼后5分钟或10分钟都没有受试者抱怨有刺激感。
表2
评价以与制剂实施例1相同的方式(除了使用对比实施例1的藻酸代替实施例1的藻酸以外)制备的滴眼剂(对比制剂实施例1)在滴眼后的刺激性。结果表明,将对比制剂实施例1的滴眼剂滴眼后,一些受试者立即报告了刺激感。
从以上结果可以确认,包含分子量等于或小于3,500的低分子量级分的藻酸对粘膜细胞具有细胞毒性,并且可在滴眼时引起刺激感。相比较而言,其中分子量等于或小于3,500的低分子量级分已被基本上除去的藻酸表明显著降低对粘膜细胞的细胞毒性,并且在滴眼时不引起刺激感;因此,其在安全性和使用感觉上具有优越性。
测试实施例3 藻酸刺激性的评价
制备其中实施例1的藻酸的浓度为0.01g/100mL的滴眼剂(制剂实施例2)和其中实施例1的藻酸的浓度为0.2g/100mL的滴眼剂(制剂实施例3)。对于制剂实施例2和3的滴眼剂而言,除了藻酸和其浓度以外,所含成分与制剂实施例1的成分相同。
以与上述测试实施例2相同的方式评价滴眼后制剂实施例2和3的滴眼剂的刺激感。结果是在滴眼后即刻、甚至在滴眼后5分钟或10分钟都没有受试者抱怨制剂实施例2或3的滴眼剂的刺激性。
制剂实施例
使用实施例1的藻酸来制备表3至5中所示的制剂(制剂实施例4到11)。
表3
表4
表5
附图简要说明
图1是表示藻酸(实施例1和对比实施例1-2)的细胞毒性测试结果的图。
Claims (12)
1.一种用于向皮肤或粘膜施用的组合物,其特征在于,包含藻酸和/或其盐,所述藻酸和/或其盐基本上不含有分子量等于或小于3,500的低分子量级分。
2.根据权利要求1的用于向皮肤或粘膜施用的组合物,其中所述藻酸和/或其盐所包含的分子量大于等于380至小于等于3,500的级分占分子量大于等于380的级分总量的2.5%或更少。
3.根据权利要求1的用于向皮肤或粘膜施用的组合物,其中所述藻酸和/或其盐的含量为所述组合物总量的0.001~20wt.%。
4.根据权利要求1的用于向皮肤或粘膜施用的组合物,其为液体制剂。
5.根据权利要求1的用于向皮肤或粘膜施用的组合物,其为眼用组合物、耳鼻用组合物、口腔用组合物、直肠用组合物、阴道用组合物或尿道用组合物。
6.根据权利要求1的用于向皮肤或粘膜施用的组合物,其为滴眼剂或洗眼剂。
7.一种用于降低藻酸和/或其盐的细胞毒性的方法,其包括从所述藻酸和/或其盐中基本上除去分子量等于或小于3,500的低分子量级分的步骤。
8.基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐在制备用于向皮肤或粘膜施用的组合物中的用途。
9.基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免用于向皮肤或粘膜施用的组合物引起细胞毒性的用途。
10.基本上不含分子量等于或小于3,500的低分子量级分的藻酸和/或其盐用于避免引起对皮肤或粘膜的细胞毒性并提高用于向皮肤或粘膜施用的组合物中所含活性成分在皮肤或粘膜上的滞留的用途。
11.藻酸和/或其盐,所述藻酸和/或其盐基本上不含分子量等于或小于3,500的低分子量级分,用于避免引起对皮肤或粘膜的细胞毒性。
12.藻酸和/或其盐,所述藻酸和/或其盐基本上不含分子量等于或小于3,500的低分子量级分,用于避免引起对皮肤或粘膜的细胞毒性和提高用于向皮肤或粘膜施用的组合物中所含活性成分在皮肤或粘膜上的滞留。
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JP2000038342A (ja) * | 1998-05-18 | 2000-02-08 | Kyowa Yakuhin Kogyo Kk | 褥瘡・損傷皮膚修復用製剤 |
US6309380B1 (en) * | 1999-01-27 | 2001-10-30 | Marian L. Larson | Drug delivery via conformal film |
JP4017783B2 (ja) * | 1999-03-25 | 2007-12-05 | 焼津水産化学工業株式会社 | 昆布エキスの製造方法 |
JP4294252B2 (ja) * | 2001-03-08 | 2009-07-08 | ロート製薬株式会社 | Gリッチなアルギン酸含有組成物 |
JP3974431B2 (ja) * | 2001-03-08 | 2007-09-12 | ロート製薬株式会社 | アルギン酸含有組成物 |
-
2007
- 2007-11-09 WO PCT/JP2007/071830 patent/WO2008056786A1/ja active Application Filing
- 2007-11-09 CN CNA2007800418843A patent/CN101534863A/zh active Pending
- 2007-11-09 JP JP2008543147A patent/JPWO2008056786A1/ja active Pending
- 2007-11-09 US US12/513,593 patent/US20100069323A1/en not_active Abandoned
- 2007-11-09 RU RU2009122167/15A patent/RU2009122167A/ru not_active Application Discontinuation
- 2007-11-09 GB GB0909307A patent/GB2456476A/en not_active Withdrawn
- 2007-11-09 BR BRPI0718707-6A patent/BRPI0718707A2/pt not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102085395A (zh) * | 2009-12-02 | 2011-06-08 | 日本乐敦制药株式会社 | 硅酮水凝胶隐形眼镜用眼科组合物 |
Also Published As
Publication number | Publication date |
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GB0909307D0 (en) | 2009-07-15 |
JPWO2008056786A1 (ja) | 2010-02-25 |
US20100069323A1 (en) | 2010-03-18 |
RU2009122167A (ru) | 2010-12-20 |
WO2008056786A1 (fr) | 2008-05-15 |
GB2456476A (en) | 2009-07-22 |
GB2456476A8 (en) | 2009-10-14 |
BRPI0718707A2 (pt) | 2014-01-07 |
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