CN110325180A - 含有美金刚的经皮吸收型液体制剂 - Google Patents
含有美金刚的经皮吸收型液体制剂 Download PDFInfo
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- CN110325180A CN110325180A CN201880011753.9A CN201880011753A CN110325180A CN 110325180 A CN110325180 A CN 110325180A CN 201880011753 A CN201880011753 A CN 201880011753A CN 110325180 A CN110325180 A CN 110325180A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960004640 memantine Drugs 0.000 title claims abstract description 35
- 239000007788 liquid Substances 0.000 title claims abstract description 30
- 206010040880 Skin irritation Diseases 0.000 claims abstract description 16
- 231100000475 skin irritation Toxicity 0.000 claims abstract description 16
- 230000036556 skin irritation Effects 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003655 absorption accelerator Substances 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract description 50
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract description 43
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 230000035699 permeability Effects 0.000 abstract description 10
- 230000007774 longterm Effects 0.000 abstract description 2
- 239000012530 fluid Substances 0.000 description 15
- 235000011187 glycerol Nutrition 0.000 description 15
- 239000000203 mixture Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 4
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- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 4
- 150000008105 phosphatidylcholines Chemical class 0.000 description 4
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010015150 Erythema Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
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- 238000001764 infiltration Methods 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
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- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000208202 Linaceae Species 0.000 description 2
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- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001246 colloidal dispersion Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 2
- 229940043276 diisopropanolamine Drugs 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- RQKFOGXUTRDQPB-UHFFFAOYSA-N hydron;2,3,5,6-tetramethylpyrazine;chloride Chemical compound Cl.CC1=NC(C)=C(C)N=C1C RQKFOGXUTRDQPB-UHFFFAOYSA-N 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000001095 phosphatidyl group Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 239000004577 thatch Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical class CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- AXPZIVKEZRHGAS-UHFFFAOYSA-N 3-benzyl-5-[(2-nitrophenoxy)methyl]oxolan-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1OCC1OC(=O)C(CC=2C=CC=CC=2)C1 AXPZIVKEZRHGAS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- RODZIAKMFCIGPL-UHFFFAOYSA-N P.I.I Chemical compound P.I.I RODZIAKMFCIGPL-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- YNIRKEZIDLCCMC-UHFFFAOYSA-K trisodium;phosphate;hydrate Chemical compound [OH-].[Na+].[Na+].[Na+].OP([O-])([O-])=O YNIRKEZIDLCCMC-UHFFFAOYSA-K 0.000 description 1
- 229960004418 trolamine Drugs 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
- A61K9/0012—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- 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
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
本发明的目的是提供一种含有美金刚的外用制剂，其皮肤刺激性降低，而且具有优异的经皮渗透性、适合长期连续投药。本发明的外用制剂是，含有美金刚或其盐，并且含有以下组分的经皮吸收型液体制剂：0.05～1.5w％的磷脂酰胆碱、35～55w％的丙二醇、18‑30w％的甘油、22‑32w％的水。水的含量小于22w％，皮肤刺激性可能会变强；大于32w％，皮肤渗透性可能会低下。甘油的含量小于18w％，皮肤刺激可能会变强；大于30w％，皮肤渗透性可能会低下。
Description
技术领域
本发明涉及一种含有美金刚作为活性成分的经皮吸收型液体制剂，更具体而言，涉及一种降低皮肤刺激性的外用制剂组合物。
背景技术
美金刚具有N-甲基-D-天冬氨酸(NMDA)受体抑制作用，被用作阿尔茨海默型认知障碍症的治疗药物。目前，盐酸美金刚的经口给药剂型可以使用薄膜包衣片及口腔崩解片。但认知障碍症状发病时，口服治疗药物会变得困难。因此，已有提出通过贴剂方式经皮给药美金刚的方案。然而，美金刚的经皮给药因显示强烈的皮肤刺激性，不适合长期持续给药。
作为解决上述美金刚皮肤刺激问题的手段，已有提出降低美金刚的经皮渗透速度至一定值以下的方法(专利文献1)、以含磷脂酰胆碱的组合物来降低皮肤刺激性的方法(专利文献2)等。
现有技术文献：
专利文献：
专利文献1:JP-A-2009-13171
专利文献2:WO 2016/186157
发明内容
发明要解决的问题：
本发明的目的是，提供一种降低皮肤刺激性且具有优异皮肤渗透性、适合长期连续给药的、含有美金刚的外用制剂。
解决问题的技术方案：
本发明人努力研究的结果，发现在美金刚的经皮吸收型液体制剂中将磷脂酰胆碱、丙二醇、甘油以及水按一定比例配制成组合物，上述问题可得以解决，从而完成了本发明。
本发明可例举如下(1)-(8)：
[1]一种经皮吸收型液体制剂，含有美金刚或其盐，并且含有：
[2]上述[1]所述的经皮吸收型液体制剂，还含有链烷醇胺和/或高级醇。
[3]上述[2]所述的经皮吸收型液体制剂，所述链烷醇胺是三乙醇胺。
[4]上述[2]或[3]所述的经皮吸收型液体制剂，所述高级醇是油醇。
[5]一种经皮吸收促进剂，用于有效成分为美金刚或其盐的经皮吸收液体制剂，皮肤刺激性降低，并且含有：
[6]上述[5]所述的经皮吸收促进剂，还含有链烷醇胺和/或高级醇。
[7]上述[6]所述的经皮吸收促进剂，所述链烷醇胺是三乙醇胺。
[8]上述[6]或[7]所述的经皮吸收促进剂，所述高级醇是油醇。
附图说明
图1是依赖于磷脂酰胆碱浓度变化的美金刚经皮渗透量的变化示意图。
具体实施方式
本发明的经皮吸收型液体制剂(以下称为“本发明液体制剂”)，含有美金刚(1-氨基-3，5-二甲基金刚烷)或其盐(以下也合称“美金刚”)作为有效成分。美金刚的成盐，可例示如下：盐酸盐、氢溴酸、硝酸盐、硫酸盐、磷酸盐等无机盐；丙酸盐、乳酸盐、酒石酸盐、草酸盐、富马酸盐、马来酸盐、柠檬酸盐、丙二酸盐等有机酸盐。其中，一般选用盐酸美金刚。美金刚或其盐的含量，例如可以是占本发明液体制剂总重量的0.1～25wt％、1～15wt％或4～12wt％。
美金刚或其盐溶解或呈胶体分布在磷脂酰胆碱、丙二醇、甘油及水所组成的水性溶媒中。
磷脂酰胆碱是化学式(I)所示化合物的总称，通常，以含有R1和R2的不同种类及组合的混合物形式提供。
[化学式1]
(式中，R1及R2表示相同或不同的、C12-22烃基。)
本发明中，R1、R2中至少有一个是不饱和烃基，可使用不饱和磷脂酰胆碱。虽然R1和R2也可以是含有棕榈基(16：0)、硬脂基(18：0)等的饱和烃基，但本发明可使用的不饱和磷脂酰胆碱中，这些饱和烃基的含有率为小于80％，优选小于70％，更优选小于60％，特别优选小于50％。不饱和烃基可例示如下：棕榈酰基(16∶1)，油基(18∶1)，亚油基(18∶2)，亚麻基(18∶3)。本发明中不饱和磷脂酰胆碱所含的不饱和烃基，具有18个碳原子，例如油基、亚油基、亚麻基等，该不饱和烃基的含有率在20％以上为优选，更优选为30％以上，特别优选为40％以上。使用不饱和磷脂酰胆碱，可制备出具有优异皮肤渗透性的稳定溶剂或胶体分散液。
本发明中的不饱和磷脂酰胆碱，可以优选使用天然提取自大豆卵磷脂、蛋黄卵磷脂等、且含量为95％以上的高纯度磷脂酰胆碱。不优选使用经化学和/或生物改性的磷脂酰胆碱，例如使用经加氢处理得到的氢化磷脂酰胆碱、酶分解等得到的溶血磷脂酰胆碱等，可能无法获得稳定的胶体分散液。但是，即使是经化学或生物改性的磷脂酰胆碱，如天然来源的卵磷脂的部分氢化产物等，也具有高不饱和度和高纯度的磷脂酰胆碱(例如，碘值为20以上，以及溶血卵磷脂含量小于10％)，可以用作本发明的“不饱和磷脂酰胆碱”。
磷脂酰胆碱的含量，通常在占本发明液体制剂总重量的0.01～2wt％范围内选择。美金刚的经皮渗透量密切依赖于磷脂酰胆碱的浓度。磷脂酰胆碱的含量优选0.05～1.5wt％，更优选0.075～1.0wt％。特别是在0.09～0.11wt％范围内，美金刚的经皮渗透性显著提高。
水(例如纯净水)的含量范围是，占本发明液体制剂总重量的约22wt％～约32wt％。水含量如果小于约22wt％，皮肤刺激性可能会变强，而大于约32wt％，经皮渗透性会降低。
甘油的含量范围是，占本发明液体制剂总重量的约18wt％～约30wt％。甘油的含量如果小于18wt％，皮肤刺激性可能会变强，而大于约30wt％，经皮渗透性可能会降低。
水与甘油的重量比可以是，例如，水∶甘油＝0.9∶1～1.5∶1，优选为水∶甘油＝1∶0.9～1.4∶1。
丙二醇的含量范围可以是本发明液体制剂总重量的约35wt％～约55wt％，优选为约40wt％～约50wt％。丙二醇的含量如果小于约35wt％，经皮渗透性可能会变差，如果大于55wt％，皮肤刺激性可能会变强。
水与丙二醇的重量比可以是，例如，水：丙二醇＝1∶1.2～1∶2.1，水∶丙二醇＝1∶1.5～1∶2.0。
甘油与丙二醇的重量比可以是，例如，甘油∶丙二醇＝1∶1.4～1∶2.6，甘油∶丙二醇＝1∶1.6～1∶2.4。
本发明液体制剂，还优选含有链烷醇胺。含有链烷醇胺，使美金刚的皮肤渗透性进一步提高。链烷醇胺可使用具有2至12个碳原子的伯、仲或叔链烷醇胺。其中，仲、叔链烷醇胺为优选，叔链烷醇胺为特别优选。具体可例示如，二乙醇胺、三乙醇胺、二异丙醇胺和三异丙醇胺。三乙醇胺是特别优选的，因为其具有优异的皮肤渗透促进效果。链烷醇胺的含量，可在占本发明液体制剂总重量的约0.001w/w％～约0.1w/w％的范围内进行选择。
本发明液体制剂，可进一步含有油醇、异硬脂醇等高级醇。含有高级醇，使美金刚的皮肤渗透性可以进一步得到提高。特别是，可缩短美金刚的经皮吸收迟延时间，用于皮肤后可快速达到最大皮肤渗透速度。高级醇的含量可选自以下范围：占本发明液体制剂总重量的约0.01wt％～约2.0wt％，优选为约0.01～约1.0wt％或约0.04～约0.06wt％。
本发明液体制剂，还可根据需要含有用于外用制剂或化妆品原料的各种添加剂。这些添加剂包括香料、抗氧化剂、防腐剂、着色剂、缓冲剂、PH调节剂、紫外线吸收剂、抗菌剂等。抗氧化剂，例如有：生育酚乙酸酯、乙二胺四乙酸二钠，异抗坏血酸，1,3-丁二醇，焦亚硫酸钠等。防腐剂，例如有山梨酸、牛磺酸等。PH调节剂，例如有：柠檬酸、醋酸、酒石酸等有机酸；磷酸、盐酸等无机酸；磷酸氢钠、磷酸氢二钾等磷酸盐。
将本发明液体制剂施用于皮肤的方法没有特别限制，如涂布或喷雾法、或将液体制剂负载于合适的载体敷贴在皮肤上给药的方法等。其中，敷贴负载有本发明液体制剂的载体(无纺布、发泡基质等)的方法为优选，因为它具有调整剂量容易、可处理性良好的特点。
实施例
以下，通过实施例对本发明进行更详细说明，但本发明并不受这些实施例的任何限制。
[皮肤渗透性试验]
制备如表1所示成分(wt％)的液体制剂A～G。对所得液体制剂用弗兰茨扩散池(Franz cell)法来进行体外皮肤渗透性试验。用作试验的皮肤是5周龄(雄性)无毛大鼠腹部切下的皮肤。表中的JP(日本药典)甘油所含水分约为15wt％(下同)。在试验开始后6小时的皮肤累积渗透量(μg/cm2)如表1所示。
[皮肤刺激性试验]
将所得液体制剂含浸于无纺布，贴敷于哺乳类皮肤表面24小时，评价皮肤刺激性。结果如表1所示。刺激性评价通过目测确认，按以下标准进行。
++：观察到明显的红斑。
+：观察到红斑。
--：未见皮肤刺激。
[表1]
液体制剂D及液体制剂G，显示出优异的皮肤渗透性，且没有皮肤刺激。液体制剂B及液体制剂C，虽无皮肤刺激，但美金刚的皮肤渗透不充分。这可以认为是因为水含量较多、丙二醇含量较少所致。液体制剂E，美金刚的皮肤渗透性优异，但观察到有皮肤刺激。这可以认为是因为丙二醇含量较高、甘油含量较低所致。液体制剂A的皮肤渗透性较低、且观察到皮肤刺激。这可以认为是因为甘油含量多、水含量较少所致。液体制剂F因含有丙二醇和磷脂酰胆碱而显示优异的皮肤渗透性，但也观察到明显的皮肤刺激(红斑)。这可以认为是因为不含甘油所致。
[用猪皮进行体外经皮渗透试验/兔皮单次刺激性试验]
制备如表2所示成分(wt％)的实施例1和2、以及比较例1的液体制剂。对所得液体制剂，用猪皮进行体外经皮渗透试验、以及兔皮单次给药皮肤刺激性试验。各采样点的皮肤累积渗透量(μg/cm2)如表2所示。
单次皮肤刺激性试验中，将浸有液体制剂的无纺布(2.5cm×2.5cm)敷贴在兔皮背部24小时，移除后的皮肤刺激性按Draize法进行评价。单次刺激指数(P.I.I.)如表2所示。
[表2]
实施例的本发明液体制剂，可得到充分的美金刚皮肤渗透性，但几乎没有表现出皮肤刺激。
按表3所示成分(wt％)制备磷脂酰胆碱浓度各异的六种液体制剂(实3-1～实3-3以及比3-1～3-3)，用弗兰茨扩散池(Franz cell)法来测定美金刚的皮肤渗透量。
用作试验的皮肤是5周龄(雄性)无毛大鼠腹部切下的皮肤。在试验开始后6小时的皮肤累积渗透量(μg/cm2)如表3及图1所示。
[表3]
美金刚的皮肤渗透在磷脂酰胆碱浓度为0.1wt％的实施例3-2中最大，这显示出其对磷脂酰胆碱浓度的较大依赖性。
[实施例4～6]
按常规方法制备表4所示成分(wt％)的实施例4～6的液体制剂。
[表4]
| 实施例4 | 实施例5 | 实施例6 | |
| 盐酸美金刚 | 5.0 | 7.5 | 10.0 |
| 磷脂酰胆碱 | 0.1 | 0.1 | 0.1 |
| 丙二醇 | 46.149 | 43.644 | 45.139 |
| 浓甘油 | 24.0 | 24.0 | 19.0 |
| 纯净水 | 24.0 | 24.0 | 25.0 |
| 三乙醇胺 | 0.01 | 0.015 | 0.020 |
| 油醇 | 0.05 | 0.05 | 0.05 |
| 磷酸氢钠水合物 | 0.501 | 0.501 | 0.501 |
| 磷酸氢二钾 | 0.190 | 0.190 | 0.190 |
| 总量 | 100.0 | 100.0 | 100.0 |
实施例4～6的本发明液体制剂，可得到充分的美金刚皮肤渗透性，但几乎没有表现出皮肤刺激。
Claims (3)
1.一种经皮吸收型液体制剂，其特征在于，含有美金刚或其盐，并且含有：
2.根据权利要求1所述的经皮吸收型液体制剂，其特征在于，还含有链烷醇胺和/或高级醇。
3.一种经皮吸收促进剂，其特征在于，用于有效成分为美金刚或其盐的经皮吸收液体制剂，皮肤刺激性降低，并且含有：
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| JPH10194994A (ja) * | 1997-01-16 | 1998-07-28 | Pola Chem Ind Inc | 吸収促進組成物 |
| WO2007070679A2 (en) * | 2005-12-14 | 2007-06-21 | Zars, Inc. | Compositions and methods for dermally treating pain |
| WO2011024354A1 (ja) * | 2009-08-25 | 2011-03-03 | 株式会社メドレックス | ホスファチジルコリンの経皮投与組成物とその製造方法 |
| WO2015072564A1 (ja) * | 2013-11-17 | 2015-05-21 | 株式会社メドレックス | 経皮吸収型コロイド液剤 |
| US20160256552A1 (en) * | 2013-11-17 | 2016-09-08 | Medrx Co., Ltd | Transdermal colloidal solution agent |
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| JP5403948B2 (ja) | 2007-06-07 | 2014-01-29 | 久光製薬株式会社 | メマンチン含有経皮吸収製剤 |
| US20180147138A1 (en) | 2015-05-19 | 2018-05-31 | Medrx Co., Ltd | Transdermal liquid preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10194994A (ja) * | 1997-01-16 | 1998-07-28 | Pola Chem Ind Inc | 吸収促進組成物 |
| WO2007070679A2 (en) * | 2005-12-14 | 2007-06-21 | Zars, Inc. | Compositions and methods for dermally treating pain |
| WO2011024354A1 (ja) * | 2009-08-25 | 2011-03-03 | 株式会社メドレックス | ホスファチジルコリンの経皮投与組成物とその製造方法 |
| WO2015072564A1 (ja) * | 2013-11-17 | 2015-05-21 | 株式会社メドレックス | 経皮吸収型コロイド液剤 |
| US20160256552A1 (en) * | 2013-11-17 | 2016-09-08 | Medrx Co., Ltd | Transdermal colloidal solution agent |
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| JPWO2018190313A1 (ja) | 2020-03-05 |
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