CN115397398A - 环状酯肽的局部药物制剂 - Google Patents
环状酯肽的局部药物制剂 Download PDFInfo
- Publication number
- CN115397398A CN115397398A CN202180019115.3A CN202180019115A CN115397398A CN 115397398 A CN115397398 A CN 115397398A CN 202180019115 A CN202180019115 A CN 202180019115A CN 115397398 A CN115397398 A CN 115397398A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- composition
- solubilizing agent
- amount
- diethylene glycol
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 50
- 230000000699 topical effect Effects 0.000 title description 12
- 108010002156 Depsipeptides Proteins 0.000 title description 3
- 239000002904 solvent Substances 0.000 claims abstract description 47
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000011200 topical administration Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 147
- 238000009472 formulation Methods 0.000 claims description 69
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 36
- -1 polysiloxanes Polymers 0.000 claims description 26
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 23
- 239000011159 matrix material Substances 0.000 claims description 22
- 230000002209 hydrophobic effect Effects 0.000 claims description 19
- 239000002674 ointment Substances 0.000 claims description 19
- 235000019271 petrolatum Nutrition 0.000 claims description 19
- 239000003623 enhancer Substances 0.000 claims description 17
- 239000004264 Petrolatum Substances 0.000 claims description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229940066842 petrolatum Drugs 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000002480 mineral oil Substances 0.000 claims description 14
- 235000010446 mineral oil Nutrition 0.000 claims description 14
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 12
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 12
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000005642 Oleic acid Substances 0.000 claims description 12
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 12
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 12
- 239000004200 microcrystalline wax Substances 0.000 claims description 12
- 235000019808 microcrystalline wax Nutrition 0.000 claims description 12
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 12
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 239000006260 foam Substances 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 9
- 201000008937 atopic dermatitis Diseases 0.000 claims description 9
- 239000006071 cream Substances 0.000 claims description 9
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 9
- 229930195729 fatty acid Natural products 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000006210 lotion Substances 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 150000004665 fatty acids Chemical class 0.000 claims description 8
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 239000003925 fat Substances 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 239000012188 paraffin wax Substances 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
- 239000008158 vegetable oil Substances 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 3
- 239000001993 wax Substances 0.000 claims description 3
- 235000019809 paraffin wax Nutrition 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 239000000499 gel Substances 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 14
- 230000035515 penetration Effects 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 239000012049 topical pharmaceutical composition Substances 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000013020 final formulation Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000003883 ointment base Substances 0.000 description 7
- 208000011580 syndromic disease Diseases 0.000 description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000004088 foaming agent Substances 0.000 description 5
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 229960004063 propylene glycol Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960000541 cetyl alcohol Drugs 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
- 210000004207 dermis Anatomy 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 244000309715 mini pig Species 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- QZEXRDYEZBKQHM-FYLONYLUSA-N (2s)-n-[(2s,5s,8s,11r,12s,15s,18s,21r)-2,8-bis[(2s)-butan-2-yl]-21-hydroxy-5-[(4-hydroxyphenyl)methyl]-4,11-dimethyl-15-(2-methylpropyl)-3,6,9,13,16,22-hexaoxo-10-oxa-1,4,7,14,17-pentazabicyclo[16.3.1]docosan-12-yl]-2-(2-methylpropanoylamino)pentanediamid Chemical compound C([C@H]1C(=O)N[C@H](C(O[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]2CC[C@@H](O)N(C2=O)[C@@H]([C@@H](C)CC)C(=O)N1C)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 QZEXRDYEZBKQHM-FYLONYLUSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 244000166124 Eucalyptus globulus Species 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000029422 Hypernatremia Diseases 0.000 description 2
- 208000002260 Keloid Diseases 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229930191564 Monensin Natural products 0.000 description 2
- GAOZTHIDHYLHMS-UHFFFAOYSA-N Monensin A Natural products O1C(CC)(C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CCC1C(O1)(C)CCC21CC(O)C(C)C(C(C)C(OC)C(C)C(O)=O)O2 GAOZTHIDHYLHMS-UHFFFAOYSA-N 0.000 description 2
- 208000011219 Netherton syndrome Diseases 0.000 description 2
- 201000009053 Neurodermatitis Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010037575 Pustular psoriasis Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- APZYKUZPJCQGPP-UHFFFAOYSA-N Tetrahydropiperine Chemical compound C=1C=C2OCOC2=CC=1CCCCC(=O)N1CCCCC1 APZYKUZPJCQGPP-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 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
- 150000001768 cations Chemical class 0.000 description 2
- 239000007765 cera alba Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- LOIYMIARKYCTBW-UPHRSURJSA-N cis-urocanic acid Chemical compound OC(=O)\C=C/C1=CNC=N1 LOIYMIARKYCTBW-UPHRSURJSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000010642 eucalyptus oil Substances 0.000 description 2
- 229940044949 eucalyptus oil Drugs 0.000 description 2
- 150000002191 fatty alcohols Chemical class 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
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 229940075529 glyceryl stearate Drugs 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 230000001969 hypertrophic effect Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 210000001117 keloid Anatomy 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960005358 monensin Drugs 0.000 description 2
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical compound C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000008255 pharmaceutical foam Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 208000017940 prurigo nodularis Diseases 0.000 description 2
- 201000004700 rosacea Diseases 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 230000037380 skin damage Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 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
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- SMWFVJSDGOWFBM-UHFFFAOYSA-N 18-hydroxyoctadecyl hydrogen sulfate Chemical compound OCCCCCCCCCCCCCCCCCCOS(O)(=O)=O SMWFVJSDGOWFBM-UHFFFAOYSA-N 0.000 description 1
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 244000257727 Allium fistulosum Species 0.000 description 1
- 235000008553 Allium fistulosum Nutrition 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OCTANWXFBPBMPD-UHFFFAOYSA-N CCCCCCCCCCCC[N] Chemical compound CCCCCCCCCCCC[N] OCTANWXFBPBMPD-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000032544 Cicatrix Diseases 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
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102100028314 Filaggrin Human genes 0.000 description 1
- 101710088660 Filaggrin Proteins 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 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
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020843 Hyperthermia Diseases 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
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 1
- 102100034868 Kallikrein-5 Human genes 0.000 description 1
- 101710176223 Kallikrein-5 Proteins 0.000 description 1
- 102100034867 Kallikrein-7 Human genes 0.000 description 1
- 101710176222 Kallikrein-7 Proteins 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 101150049485 SPINK5 gene Proteins 0.000 description 1
- 229940119135 Serine peptidase inhibitor Drugs 0.000 description 1
- 208000006981 Skin Abnormalities Diseases 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 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 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940031955 anhydrous lanolin Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 208000025341 autosomal recessive disease Diseases 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 210000004082 barrier epithelial cell Anatomy 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 235000021324 borage oil Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940073669 ceteareth 20 Drugs 0.000 description 1
- 229940056318 ceteth-20 Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000004890 epithelial barrier function Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000294 eucalyptus globulus labille leaf/twig oil Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229960003639 laurocapram Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- 125000001421 myristyl 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])[H] 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 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 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940100460 peg-100 stearate Drugs 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940068917 polyethylene glycols Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001823 pruritic effect Effects 0.000 description 1
- 238000007388 punch biopsy Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003611 tocopherol derivatives Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/15—Depsipeptides; Derivatives thereof
-
- 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
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本文公开了适用于局部施用的式(I)的化合物(LM030)的药物组合物。所述化合物可以为溶解形式,与增溶剂以及一种或多种药用赋形剂一起配制。
Description
相关申请的交叉引用
本申请依照35U.S.C.§119(e)要求于2020年3月6日递交的美国临时申请序列号62/986,526的权益,将其内容以其整体通过引用结合于此。
背景
式(I)的环状酯肽(cyclic depsipeptide,也称作环状缩酚肽)
在国际专利申请WO2009024527中进行了描述。它已被提议用于治疗和预防某些皮肤病症如特应性皮炎(atopic dermatitis)、银屑病(psoriasis)、脓疱型银屑病(pustularpsoriasis)、玫瑰痤疮(rosacea)、瘢痕疙瘩(keloid)、肥厚性瘢痕(hypertrophic scar)、痤疮(acne)、内塞顿综合征(Netherton’s syndrome)和其他瘙痒性皮肤病如结节性痒疹(prurigo nodularis)、未指明的老年人瘙痒(unspecified itch of the elderly)以及其他具有上皮屏障功能障碍的疾病如老化的皮肤。然而,其治疗应用受到了在使用药用赋形剂将该化合物配制成具有可接受稳定性和通过皮肤充分吸收的用于局部施用的制剂方面的困难限制。
式(I)的化合物(也称为LM030)可用于治疗内塞顿综合征。内塞顿综合征由Comel在1949年(Comel M,Dermatology 1949;98:133-136)和内塞顿在1958年(Netherton EW,Arch Dermatol.1958;78:483-487)首次描述。它是一种严重的常染色体隐性遗传病(autosomal recessive disease),其特征在于先天性红皮病(congenitalerythroderma)、“竹状毛(bamboo hair)”和免疫系统异常(Bitoun E等人,Journal ofInvestigative Dermatology 2002;118(2):352-361)。新生儿的内塞顿综合征可能会危及生命,因为缺乏皮肤保护,这导致严重脱水、高钠血症(hypernatremia)、低体温症(hypothermia)、明显体重减轻(gross weight loss)和败血症(sepsis)。由于慢性红皮病(chronic erythroderma)、持续性皮肤感染(persistent cutaneous infection)、营养不良(malnutrition)和代谢紊乱(metabolic disorder),儿童无法茁壮成长是很常见的(Jones SK等人,Br.J.Dermatol.1986;114:741-743;Judge MR等人,Br.J.Dermatol.1994;131:615-621)。老年患者皮肤异常的严重程度可能随着时间的推移而波动。大多数内塞顿综合征患者还患有与免疫系统相关的疾病如食物过敏和哮喘。
内塞顿综合征是由编码丝氨酸肽酶抑制剂、淋巴-上皮Kazal-型相关抑制剂(LEKTI)的SPINK5基因中的突变引起的(Chavanas等人2000;Nat,Genet.25:141-142)。LEKTI的缺失导致表皮蛋白酶的失调和严重的皮肤屏障损伤。据报道,受LEKTI抑制的Kallikrien相关肽酶在内塞顿综合征病理学中起主要作用((Kasparek P等人,PLOSGenetics 2017,13(1);Caubet C等人,Journal of Investigative Dermatology 2004;122:1235-1244)。
特应性皮炎也称为过敏性湿疹(atopic eczema)并且是一种炎性皮肤病。它引起皮肤发炎和刺激,使其极度发痒。抓挠可引起发红、肿胀和开裂。虽然该病况可在任何年龄发生,但它典型地从儿童时期开始,并且可随着时间的推移而改变严重程度。
需要改进的LM030局部制剂来治疗内塞顿综合征、特应性皮炎以及其他皮肤疾病和病症。
概述
本发明提供了一种式(I)的化合物(LM030)以及一种或多种药用赋形剂的药物组合物,其在适用于局部施用的制剂中,其中LM030为与增溶剂一起的溶解形式(增溶形式,solubilized form)。
现已发现,可以将处于与增溶剂一起的溶解形式的LM030掺入到如本文所述的局部药物制剂中,其中所得的局部制剂保持良好的稳定性,同时还在低全身暴露和比先前的制剂低得多的变化性的情况下在皮肤中实现LM030的高生物利用度。在一种优选的局部制剂中,可将溶解的LM030和增溶剂掺入到基质(典型地是疏水性基质)中。
在一些实施方案中,增溶剂选自由以下各项组成的组:二甘醇单乙醚、中链甘油三酯、脂肪酸、丙二醇及其组合。在一些优选的实施方案中,增溶剂是单独的或与脂肪酸比如油酸组合的二甘醇单乙醚。在一些实施方案中,增溶剂是PEG-脂肪酸衍生物。在一些实施方案中,增溶剂是中链甘油三酯或者中链甘油三酯的混合物。
在一些实施方案中,疏水性基质包含一种或多种选自由以下各项组成的组中的赋形剂:石蜡、植物油、动物脂肪、合成甘油酯、蜡、全氟化碳、半全氟化碳、液体聚硅氧烷及其组合。在一些实施方案中,疏水性基质包含一种或多种选自由以下各项组成的组中的赋形剂:矿脂、矿物油和肉豆蔻酸异丙酯及其组合。
本发明的制剂还可以包含表面活性剂和/或稠度增强剂。在一个优选的实施方案中,制剂包含微晶蜡作为稠度增强剂。本发明的制剂适用于局部施用并且可以制备为凝胶剂、霜剂、软膏剂、洗剂、喷雾剂或泡沫剂。
在一些实施方案中,活性剂以组合物的约0.1至约5%w/w的量存在于制剂中。在一些实施方案中,增溶剂以占组合物的约2.5%至约25%(w/w)的量存在于制剂中。当二甘醇单乙醚是增溶剂时,其量优选为组合物的约2.5%(w/w)至约10%(w/w)。
在一个优选的实施方案中,所述制剂是软膏剂,并且包含作为增溶剂的二甘醇单乙醚、作为稠度增强剂的微晶蜡以及矿脂、矿物油和肉豆蔻酸异丙酯的疏水性基质。本发明的制剂可用于治疗内塞顿病、特应性皮炎以及其他皮肤疾病和病症。
还提供了治疗内塞顿病的方法,其包括向有需要的患者局部施用本文所述的药物组合物。局部药物组合物将包含有效量的LM030,优选以约0.1%至约5%(w/w)的量,更优选以约0.2至约1%(w/w)的量,并且最优选以约1%(w/w)的量。组合物可以每天一次或优选每天两次或者根据需要每天超过两次地施用在身体的受侵袭区域上。组合物可以长期地使用或根据需要使用。
详述
式I的化合物(在本文中也称为LM030)在合适局部制剂的制备方面呈现出重大挑战。合适的局部制剂需要足以将治疗量的活性剂递送至皮肤中的受侵袭层的渗透性和穿透性,同时优选地最小化全身暴露以最小化全身性副作用。同时,对于实际使用,制剂必须表现出足够的储存稳定性,以支持用于商业化目的可接受保质期。
LM030在水和水性缓冲液中仅显示出中等溶解度并且在亲脂性赋形剂中显示出低溶解度。在极性有机溶剂中其表现出良好的溶解性,但稳定性差。此外,当该化合物没有溶解时,例如当以混悬制剂提供时,它显示出差的吸收(导致在皮肤的目标层中的药物水平低于治疗)和非常高的变化性(导致不可预测的治疗效果)。在美国专利号8,680,054中描述了配制用于局部施用的LM030方面的困难。特别地,LM030的溶解度和稳定性特性在开发具有足够储存稳定性的局部制剂方面产生了挑战,该局部制剂还能够提供有效量的可用于皮肤渗透的活性剂[参见第4栏,第16-23行]。
本发明的制剂显示出良好的储存稳定性,其与通过美国专利号8,680,054中描述的混悬制剂所观察到的稳定性相当,同时还在低的全身暴露和低得多的变化性的情况下实现了LM030在皮肤中的高吸收。
如在本说明书中使用的,以下词语、短语和符号通常意图具有如下所阐述的含义,除非在使用它们的上下文中另有说明。
如在本发明的制剂中使用的,对式I化合物或LM030或“活性剂”的提及包括为无定形和结晶形式如多晶型物的化合物,以及其类似物、溶剂化物、前药、配合物和药用盐。还包括各种尺寸或研磨形式的化合物,如微粉化颗粒。
“药用盐”是指可接受用于局部药物制剂的式I的化合物的无毒酸或碱土金属盐。代表性盐包括:乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、已酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐(pamoate)、果胶酸盐、过硫酸盐、3-苯基-丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。此外,碱性含氮基团可以用诸如试剂比如烷基进行季铵化。卤化物如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸盐,如二甲基、二乙基、二丁基和二戊基硫酸盐,长链卤化物如癸基月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物,芳烷基卤化物如苄基和苯乙基溴化物等。碱性加成盐可以在化合物的最终分离和纯化期间原位制备,或通过单独使羧酸部分与合适的碱比如药用金属阳离子的氢氧化物、碳酸盐或碳酸氢盐反应或者与氨、或者有机伯胺、仲胺或叔胺反应来制备。药用盐包括基于碱金属和碱土金属的阳离子,如钠、锂、钾、钙、镁、铝盐等,以及无毒的铵、季铵和胺阳离子,包括铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。可用于形成碱加成盐的其他代表性有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、吡啶、甲基吡啶、三乙醇胺等,以及碱性氨基酸如精氨酸、赖氨酸和鸟氨酸。
如本文所使用的,“局部施用”和适用于“局部施用”的组合物具有本领域已知的含义。参见,例如,European Pharmacopoeia(欧洲药典),6.3,01/2009,0132。适用于局部施用的药物组合物典型地包括适用于局部应用的液体和半固体形式。这样的形式包括液体溶液剂和混悬剂、酊剂、凝胶剂、贴剂、泡沫剂、软膏剂、洗剂、棒剂或喷雾剂。
如本文所使用的,疾病或病症的“治疗(treat)”、“治疗(treatment)”或“治疗(treating)”是指改善该疾病或病症,如通过减缓或阻止疾病或病症的进展,或者通过减轻其至少一种症状。“治疗(treat)”、“治疗(treatment)”或“治疗(treating)”还可以指预防或延缓该疾病或病症的发作或发展。
本文中对“约”一个值或参数的提及包括(并描述)涉及该值或参数本身的实施方案。在某些实施方案中,术语“约”包括指示量±10%。在其他实施方案中,术语“约”包括指示量±5%。在某些其他实施方案中,术语“约”包括指示量±1%。此外,除非上下文另有明确规定,单数形式“一种”和“该”包括复数指代。
在适用于局部施用的最终制剂中,本发明的药物组合物包含与增溶剂一起的溶解形式的活性剂以及一种或多种药用赋形剂。溶解的活性剂和增溶剂将在基质内,优选在疏水性基质内。
式I的化合物可以通过WO2009024527中描述的方法获得。本发明组合物中的活性剂的量可以在一定范围内变化,其中有效量依赖于待治疗的病况。典型地,活性剂的量将为约0.1%至约5%(w/w),优选约0.2%至约2.0%(w/w),并且最优选约0.5%至约1.0%(w/w)。
如本文所述的,含有在基质内的与增溶剂一起的溶解形式的LM030的制剂出人意料地显示出相对于任何其他溶解制剂显著改善的稳定性以及与现有技术制剂的混悬制剂相比相当的稳定性。此外,与现有技术制剂相比,本发明的制剂显示出活性剂在皮肤的期望层中的显著更高的生物利用度,以及低的全身暴露与低得多的变化性。本发明的制剂还可以与对局部施用具有相似制剂挑战的其他肽一起使用,包括激肽释放酶5或激肽释放酶7的其他肽抑制剂。这样的肽可以具有约4至约30个氨基酸,这包括例如丝聚蛋白。
增溶剂在本领域是已知的并且可以由技术人员选择以与最终制剂相容。参见DeVilliers,Melgardt(2009)Pharmaceutical Solvents and Solubilizing Agents(药物溶剂和增溶剂)。在:Judith E.Thompson(编辑),A Practical Guide to Contemporary Pharmacy Practice (当代药学实践实用指南),Ed.3,Chapter 15,Lippincott,Williams和Wilkins。
优选的增溶剂是有助于溶解活性剂同时不损害稳定性并且与局部递送系统相容的药用赋形剂。此外,它是非刺激性的并且适合长期应用,使得其可以在受损皮肤如在特应性皮炎(AD)和内塞顿综合征(NS)中出现的皮肤上使用。合适的增溶剂包括二醇如甘油、丙二醇和聚乙二醇;二醇醚如二甘醇单乙醚(以出售)(也称为二(乙二醇)乙醚、(2-(2-乙氧基乙氧基)乙醇、乙基二甘醇、diEGEE));中链甘油三酯(MCT)(例如,长度为6-12个碳)和MCT的混合物如椰子油和Miglyol 812(参见Buss,N.,等人.,J Appl Toxicol.(2018)(38(10):1293-1301);以及脂肪酸如油酸和亚油酸。在一些实施方案中,增溶剂是PEG-脂肪酸衍生物(Casiraghi A.,Selmin F.,Minghetti P.,Cilurzo F.,Montanari L.(2015)Nonionic Surfactants:Polyethylene Glycol(PEG)Ethers and Fatty AcidEsters as Penetration Enhancers(非离子表画活性剂:聚乙二醇(PEG)醚和脂肪酸酯作为渗透增强剂).在:Dragicevic N.,Maibach H.(编辑)Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement(渗透增强中的经皮渗透增 强剂化学方法),Springer,Berlin,Heidelberg中),如癸酸和辛酸的中链脂肪酸甘油三酯的一种PEG衍生物。参见Negi,J.S.,(2019)Nanolipid Materials for DrugDelivery Systems(用于药物输送系统的纳米脂质材料),在:Mohapatra,S.S.,Ranjan,S.,Dasgupta,N.,Mishra R.K.和Thomas,S.(编辑),Characterization and Biology of Nanomaterials for Drua Delivery(用于药物递送的纳米材料的表征和生物学),2019中。此外,增溶剂可以是由Gattefosse,S.A.供应的LabrafacTM亲脂性WL 1349(https://www.cphi-online.com/labrafactm-lipophile-w1-1349-prod486142.html)。
制剂中的增溶剂的量将典型地为组合物的约1.0%(w/w)至50%(w/w),并且优选为组合物的2.5%至15%(w/w),并且最优选为组合物的5%至10%(w/w)。在一些实施方案中,增溶剂是二甘醇单乙醚,并且以组合物的约2.5%至约10%(w/w),优选地以组合物的约5%至约10%(w/w)的量存在。在其他实施方案中,增溶剂是疏水性和亲水性溶剂的混合物,如不同比率的二甘醇单乙醚和油酸的混合物,或者包括聚乙二醇或PEG与不同比率的二甘醇单乙醚和/或油酸的组合的混合物。例如,二甘醇单乙醚和油酸可以各自以组合物的约2.5%(w/w)的量存在。
在一些实施方案中,疏水性基质为溶解的活性剂提供基质。对疏水性基质赋形剂进行选择以掺入有效量的溶解的LM030,同时不会损害最终制剂的稳定性,并且将提供组合物的所需粘度以方便最终用户应用。用于疏水性基质的药用赋形剂是本领域已知的,并且包括石蜡、植物油、动物脂肪、合成甘油酯、蜡、全氟化碳、半全氟化碳和/或液体聚硅氧烷以及它们的混合物。合适的材料还包括固态和液态烃,它们可以是直链或支链的。优选的疏水性材料包括矿物油、矿脂和微晶蜡。在一些实施方案中,组合物包含矿物油、矿脂和微晶蜡的混合物。
疏水性基质组分可构成最终组合物的约50%至约95%(w/w)。在一些实施方案中,疏水性基质包含至多约65%(w/w)的矿物油。在一些实施方案中,组合物包含约20%至约40%(w/w)的矿物油。组合物可含有高达约95%(w/w)的矿脂。在其中最终制剂为软膏剂的实施方案中,组合物可含有约60%至约80%(w/w)的矿脂,并且最优选含有约65%至约70%(w/w)的矿脂。组合物可含有至多约25%(w/w)的微晶蜡,并且优选约0%至约10%(w/w)的微晶蜡。在一些实施方案中,疏水性基质含有矿脂和矿物油的比例为约1∶1至约10:1、优选约2∶1至约4∶1的混合物。
在一些实施方案中,本发明的组合物还包含稠度增强剂。稠度增强剂在本领域是已知的。合适的稠度增强剂包括饱和脂肪酸和饱和脂肪酸酯。在一个优选的实施方案中,掺入肉豆蔻酸异丙酯作为稠度增强剂。
可用于制备局部药物制剂的额外赋形剂可额外地掺入到本发明的制剂中。用于局部药物制剂的赋形剂在本领域是已知的,并且可以基于最终制剂的所需性质进行选择。参见,例如,Handbook of Pharmaceutical Excipients(药用赋形剂手册),Rowe,R.C.和Shesksy,P.J.,等人.,(2012)。组分如表面活性剂、硬化剂或增稠剂、润肤剂、渗透增强剂、防腐剂、抗微生物剂等。例如,最终制剂将适合于以优选的剂型,例如洗剂、霜剂、软膏剂、喷雾剂或泡沫剂进行递送,并且将被优化以最小化皮肤刺激。
表面活性剂可有利地用于增加经皮吸收、渗透增强或释放速率。这样的表面活性剂的实例包括但不限于可作为CETOMACROGOL.RTM.1000获得的ceteareth-20、单硬脂酸甘油酯、二硬脂酸甘油酯、硬脂酸甘油酯、聚氧乙烯硬脂酸酯、硬脂酸甘油酯和PEG-100硬脂酸酯的混合物(作为ArLACEL 1 65)、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、CETETH-20.RTM.、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇倍半油酸酯及其混合物。所采用的表面活性剂的量通常为约0.5%(w/w)至约10%(w/w)。
渗透增强剂可以掺入本发明中并且将进行选择以保持活性剂的稳定性。可用于本发明制剂的渗透增强剂包括例如琉璃苣油、桉树油(eucalyptus oil)(例如,蓝桉油(eucalyptus globulus oil)、细叶桉油(Eucalyptus tereticortis oil)、四氢胡椒碱(THP)、脂肪醇(例如,肉豆蔻醇、鲸蜡醇、硬脂醇)、脂肪酸(例如油酸)、脂肪酸酯(例如肉豆蔻酸异丙酯、棕榈酸异丙酯)、多元醇(例如丙二醇、聚乙二醇、甘油)、聚乙二醇单月桂酸酯、卵磷脂、泊洛沙姆、亲脂性WL 1349、甘油三酯)等。其他合适的渗透增强剂包括但不限于二甘醇、正癸基甲基亚砜、二甲亚砜、二甲基乙酰胺、月桂氮酮(laurocapram)、二甲基甲酰胺、蔗糖单油酸酯、酰胺和其他含氮化合物(例如,脲、2-吡咯烷酮、1-甲基-2-吡咯烷酮、乙醇胺、二乙醇胺和三乙醇胺)、萜烯、烷酮、有机酸(例如柠檬酸和琥珀酸)和N-甲基-2-吡咯烷或其组合。
制剂还可以含有减轻氧化的添加剂以最小化或消除皮肤刺激或皮肤损伤的可能性。合适的减轻刺激的添加剂包括,例如:a-生育酚;单胺氧化酶抑制剂,特别是苯基醇如2-苯基-1-乙醇;甘油;抗坏血酸和抗坏血酸盐;离子载体如莫能菌素(monensin);两亲性胺;氯化铵;N-乙酰半胱氨酸;顺式-尿刊酸(cis-urocanic acid);辣椒素;和氯喹。如果存在的话,减轻刺激的添加剂可以以有效减轻刺激或皮肤损伤的浓度掺入到本发明的制剂中,典型地为约0.05%至约1.0%(w/w)。
如本领域已知的,可以包括抗氧化剂。合适的抗氧化剂包括苯酚衍生物(例如丁基化羟基甲苯(BHT)、丁基化羟基苯甲醚(BHA))、抗坏血酸衍生物(抗坏血酸、抗坏血酸棕榈酸酯)、生育酚衍生物(例如维生素E、维生素E TPGS)、亚硫酸氢盐衍生物(亚硫酸氢Na、偏亚硫酸氢Na)、硫脲及其组合。抗氧化剂的量将典型地为约0.005%至约0.5%(w/w)。
防腐剂在本领域是已知的并且可以被包括以增加组合物的保质期。合适的防腐剂包括酚类、对羟基苯甲酸酯类、尼泊金类、双胍类、汞盐和咪唑烷基脲(imidurea)。防腐剂可以约0.01%至约3%(w/w)的量存在。
在一些实施方案中,本公开内容的药物制剂不包括大量的LM030悬浮液。在一个实施方案中,少于药物制剂的约15%、10%、5%、2%、1%、0.5%或0.1%的LM030处于悬浮状态。
本发明的药物制剂可以掺入到任何合适的局部剂型(包括例如软膏剂、霜剂、洗剂、凝胶剂、泡沫剂和喷雾剂)中。
如本领域公知的,软膏剂是半固体制剂,其典型地基于矿脂或石油衍生物。与其他载体或媒介物一样,软膏剂基质(ointment base)典型地是惰性的、稳定的、无刺激性的和无致敏性的。软膏剂基质可以分为四类:油质基质;可乳化基质;乳液基质;和水溶性基质。油质软膏剂基质包括例如植物油、获自动物的脂肪和获自石油的半固体烃。可乳化软膏剂基质(也称为吸收性软膏剂基质)含有很少水或不含水,并且包括例如硫酸羟基硬脂精、无水羊毛脂和亲水性矿脂。乳液软膏剂基质是油包水(w/o)型乳液或水包油(o/w)型乳液,并且包括例如鲸蜡醇、单硬脂酸甘油酯、羊毛脂、硬脂酸和不同分子量的聚乙二醇或它们的组合。合适烃基质的其他实例包括但不限于硬石蜡、软石蜡或液体石蜡、甘油、蜂蜡、金属皂、粘液(mucilage)、天然来源的油(如杏仁油、玉米油、花生油、蓖麻油或橄榄油)、羊毛脂肪或其衍生物、脂肪酸(如硬脂酸或油酸)或它们的组合。
如本领域公知的,霜剂是粘性液体或半固体水包油型乳液。霜剂基质可以是可水洗的,并且含有油相、乳化剂和水相。油相(也称为“内部”相)可以包括矿脂和脂肪醇如鲸蜡醇或硬脂醇。水相的体积通常(尽管不是必需地)超过油相的体积,并且通常含有保湿剂。霜剂制剂中的乳化剂通常是非离子、阴离子、阳离子或两性表面活性剂或者它们的组合。
凝胶制剂典型地是半固体、悬浮型体系。单相凝胶典型地含有基本均匀分布在整个载体液体中的有机大分子,该载体液体典型地是水性的,但也可以含有油。示例性的“有机大分子”(即胶凝剂)是交联的丙烯酸聚合物如“卡波姆”系列聚合物(例如,可作为商购获得的羧聚烷烯(carboxypolyalkylene)。还可以例举的是亲水性聚合物如聚环氧乙烷、聚氧乙烯-聚氧丙烯共聚物、聚乙烯醇和聚乙烯吡咯烷酮;纤维素聚合物如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯和甲基纤维素;树胶如角叉菜胶、黄蓍胶和黄原胶;海藻酸钠;和明胶。合适的凝胶形成剂的其他实例包括羧聚乙烯衍生物(carboxypoly-methylene derivative)如Carbopol和果胶。
洗剂典型地是在没有摩擦的情况下施加至皮肤表面的制剂,并且典型地是液体或半固体制剂。洗剂通常是固体的悬浮液,并且可以包含水包油型的液体油性乳液。乳液可以用于治疗较大的身体区域,因为易于施加更流动的组合物。因此,洗剂将典型地含有可用于定位和保持活性剂与皮肤接触的化合物(例如甲基纤维素)、羧甲基纤维素钠等。它们还可以包括保湿剂如甘油,或油比如蓖麻油或花生油。
药物泡沫制剂在本领域是已知的。泡沫剂优选地包括至少一种泡沫剂如蛋白质或表面活性剂。表面活性剂例如通过抑制气泡聚结来稳定泡沫剂。参见,Zhao,Y.;Brown,M.B.;Jones,S.J.,Pharmaceutical foams:are they the answer to the dilemma oftopical nanoparticles?(药物泡沫沫剂:它们是解决局部纳米颗粒困境的答案吗?)Nanomedicine(2010)。诸如泡沫剂稳定性、易于铺展和在施加至皮肤后的适当易碎性之类的品质是可以被优化的特征。这些特性可以通过进行泡沫形成和泡沫塌陷性实验来测量。例如,泡沫形成(相对于时间的泡沫高度)可预测产生可喷雾/可铺展泡沫剂。
许多泡沫剂是通过将与溶解的气体推进剂组合的泡沫剂基质进行分配而产生,该推进剂在从容器释放后膨胀而产生泡沫剂的气泡(例如,在WO 2010/125470中公开的那些)。
在某些优选的实施方案中,本发明的局部制剂是软膏剂。在这些优选的实施方案中,LM030以组合物的约0.1至约5%(w/w),优选以约0.5至约1%(w/w)的量存在于制剂中。优选地,增溶剂以组合物的约1.0%至约25%(w/w)的量存在于制剂中。当二甘醇单乙醚为增溶剂时,其优选为组合物的约2.5%(w/w)至约15%(w/w),最优选为约5%至约10%(w/w)。在一个优选的实施方案中,本发明的组合物是软膏剂,LM030以组合物的约1%(w/w)的量存在,为与二甘醇单乙醚(是增溶剂)一起的溶解形式,二甘醇单乙醚以组合物的约5%至约10%(w/w)的量存在;疏水性基质包括矿脂、矿物油和微晶蜡的组合;并且肉豆蔻酸异丙酯作为稠度增强剂以约5%(w/w)的量掺入。
在本发明的另一个实施方案中,将本文所述的LM030的药物组合物局部地施用至有需要的患者以治疗内塞顿病。该局部药物组合物将包含有效量的LM030,优选为约0.1%至约5%(w/w)的量,最优选以约0.5%至约1%(w/w)的量。组合物可以每天一次或优选地每天两次或根据需要每天超过两次地施加在身体的受侵袭区域上。组合物可以长期使用或根据需要使用。
制备本发明的制剂的方法涉及利用增溶剂溶解活性剂LM030,以及将所得的溶液与构成最终制剂所期望的量的赋形剂混合。在一些实施方案中,在与额外的赋形剂组合之前,活性剂将单独用增溶剂溶解。在其他实施方案中,活性剂将在单个步骤中用增溶剂和其他额外赋形剂溶解。可以包括其他赋形剂(包括稠度增强剂以及其他赋形剂)以获得最终制剂所期望的稠度。制备凝胶剂、洗剂、软膏剂、霜剂或泡沫剂最终剂型的方法在本领域是已知的。
在一个实施方案中,剂型是软膏剂。在此实施方案中,在有或没有稠度增强剂的情况下,将疏水性基质材料加热至约70℃至80℃并搅拌以获得熔体,然后在搅拌下冷却至约45℃至55℃。在搅拌的同时加入含有LM030和增溶剂的溶液,然后均化。然后将组合物冷却至约30℃至40℃,并装入最终容器(例如管)中。优选地,活性剂用二甘醇单乙醚(Transcutol HP)溶解,并且亲水性基质包含矿物油、白矿脂、白蜂蜡(微晶蜡)和肉豆蔻酸异丙酯的混合物。
在另一个实施方案中,剂型是凝胶剂。在此实施方案中,LM030通过在室温下与增溶剂和其他赋形剂如抗氧化剂和防腐剂混合直至透明而溶解。在单独的容器中,将基质材料在室温下充分混合,然后加入胶凝赋形剂并在室温下混合直至形成透明凝胶。将溶解的LM030混合物加入到凝胶混合物中并在室温下混合直至获得透明凝胶。
本发明通过以下实施例进一步说明。
实施例
实施例1
在美国专利号8,680,054中描述的现有技术软膏混悬制剂通过其中描述的方法制备,其具有下表1中描述的组成。
表1:制剂A
LM030 1%w/w原始软膏混悬制剂的定量和定性组成
NF:国家处方集(National formulary),Ph Eur:欧洲药典,USP:美国药典
此外,通过合并以下实施例2-5中描述的赋形剂来制备含有用增溶剂溶解的LM030的软膏制剂。
实施例2
表2:制剂B
含有10%Transcutol HP的LM030 1%w/w制剂的定量和定性组成
NF:国家处方集,Ph Eur:欧洲药典,USP:美国药典
通过在室温下将LM030与Transcutol HP合并并且以500-700rpm混合,以获得透明溶液来制备制剂B。分开地,在容器中将白矿脂、矿物油、微晶蜡和肉豆蔻酸异丙酯合并并且在100至200rpm的混合下加热到70℃至80℃以获得熔体。在以100至300rpm的搅拌下将该熔体冷却到45℃至55℃,并在搅拌下加入含有LM030的溶液。将合并物以5500rpm均化3分钟。在以100至300rpm的搅拌下将组合物冷却到30℃至40℃,并将所得的组合物装入到30g铝管中。
实施例3
制剂C通过与制剂B相同的方法制备,其中组成如表3中所示。
表3:制剂C
含有2.5%Transcutol HP和2.5%油酸的LM030 1%w/w制剂的定量和定性组成
实施例4
制剂D通过与制剂B相同的方法制备,其中组成如表4中所示。
表4:制剂D
含有2.5%Transcutol的LM030 1%w/w制剂的定量和定性组成
实施例5
制剂E通过与制剂B相同的方法制备,其中组成如表5中所示。
表5:制剂E
含有5%Transcutol的LM030 1%w/w制剂的定量和定性组成
实施例6
根据以下方法来制备含有1%LM030的局部凝胶制剂,其中组成如表6中所示。将丙二醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯添加到容器中并在室温下使用200-400rpm的混合器速度混合在一起,直到获得透明溶液。然后加入羟丙基纤维素并在室温和300-600rpm的混合器速度下混合,直到获得透明凝胶(A部分)。在另一个容器中,将LM030与以下赋形剂混合:二甘醇单乙醚(Transcutol HP)、肉豆蔻酸异丙酯、柠檬酸一水合物和磷酸氢二钠水合物。将它们在室温和500-700rpm的混合速度下混合,直到透明(B部分)。然后将B部分加入到A部分中并以500-700rpm的混合速度在室温下混合60分钟,直到获得透明凝胶。
表6:制剂F
含有10%Transcutol的LM030 1%w/w凝胶制剂的定量和定性组成
实施例7:稳定性测试
下表显示了在相同的温度和时间条件下,LM030在配制为混悬制剂和配制为溶解形式时的稳定性。
表7:
基于以上呈现的数据,LM030在水溶液的存在下显示出较差的稳定性,但是当溶解在某些增溶剂中时显示出可接受的稳定性。然而,显示出良好稳定性的大多数溶剂也显示出有限的溶解度,由此提供的暴露对于产生所需的治疗效果是不充分的。
在室温和40℃下储存一周或两周后,测试实施例1和2中描述的软膏剂制剂A(含有在混悬制剂中的LM030)和制剂B(含有溶解在Transcutol HP中的LM030)的稳定性。结果如表8中所示。
表8
与现有技术制剂A相比,制剂B在标准和加速条件下都显示出相当的稳定性。LM030溶解在制剂B中,而它在制剂A中为混悬液形式。
此外,将制剂C与实施例1的现有技术制剂A进行比较,并在室温和在40℃下储存一周或两周后测试稳定性。结果如表9中所示。
表9
制剂C在两种条件下都显示出与制剂A相当的稳定性。
实施例8:药代动力学研究
使用年轻的雌性哥廷根小型猪(Gottingen minipig)进行药代动力学研究。将测试制剂施加到每组的三只动物,BID持续两天,其中施用15%的表面积。样品从血浆以及真皮和表皮获得。为了分离表皮和真皮,在胶带剥离后,获得穿孔活检。然后,兽医在解剖显微镜的帮助下使用手术刀将两个层分开。然后将这两个层放置在试管中并冷冻直至分析。
表10:PK结果
在第二个PK研究中,比较来自实施例1的软膏剂制剂A和B以及来自实施例6(制剂F)的凝胶制剂,如上所述在小型猪中比较测试制剂,其中每天两次施用,持续七天。结果显示在表11中。在食物消耗、体重增加、临床观察和Draize评分(红斑、水肿)方面没有发现不良结果,也没有发现组之间的显著差异。
表11:PK结果
*每组1-2只动物,具有0.5-5ng/ml水平。LLOQ 0.5ng/ml血浆,5ng/g组织
#任何时间点的峰值水平
^上午施用后大约7.5h
与原始混悬制剂相比,含有5%Trancutol、10%Transcutol和2.5%Transcutol/2.5%油酸作为增溶剂的测试制剂在真皮和表皮中均显示出改善的LM030吸收,同时还保持低的全身性暴露并且不良事件没有显著增加。
实施例9:稳定性数据
制备含以下组成的本发明制剂。
材料 | 等级* | %LM-030 1%软膏剂 |
白矿脂 | USP | 67.00 |
矿物油 | USP | 20.00 |
白蜂蜡 | NF | 2.00 |
肉豆蔻酸异丙酯 | NF | 5.00 |
Transcutol HP | NF | 5.00 |
LM-030 | IH | 1.00 |
100% |
在以下三种条件下在三个月、六个月和九个月处测试稳定性:5℃、25℃/60%RH和30℃/65%RH。该制剂在所有条件下均显示出良好的稳定性,如表12、13和14中所示。
本公开内容的范围不受所描述的具体实施方案的限制,这些具体实施方案意图作为本公开内容的个别方面的单一举例说明,并且功能等效的任何组合物或方法都在本公开内容的范围内。对本领域技术人员显而易见的是,在不背离本公开内容的精神或范围的情况下,可以对本公开内容的方法和组合物进行各种修改和变化。因此,本公开内容意图覆盖本公开内容的修改和变化,只要它们落入所附权利要求及其等效物的范围内。
本说明书中提及的所有出版物和专利申请均以引用方式并入本文,其程度与每个单个出版物或专利申请被具体地且单个地指明以引用方式并入的程度相同。
Claims (34)
2.根据权利要求1所述的药物组合物,其中所述增溶剂选自由以下各项组成的组:二甘醇单乙醚、中链甘油三酯、脂肪酸、丙二醇及其组合。
3.根据权利要求2所述的药物组合物,其中所述增溶剂包括二甘醇单乙醚。
4.根据权利要求2所述的药物组合物,其中所述增溶剂包括二甘醇单乙醚和脂肪酸的混合物。
5.根据权利要求1所述的药物组合物,所述药物组合物还包含表面活性剂。
6.根据权利要求1所述的药物组合物,所述药物组合物还包含稠度增强剂。
7.根据权利要求2所述的药物组合物,其中所述增溶剂包括油酸。
8.根据权利要求2所述的药物组合物,其中所述增溶剂是中链甘油三酯或者中链甘油三酯的混合物。
11.根据权利要求1所述的药物组合物,其中所述组合物是凝胶剂。
12.根据权利要求1所述的药物组合物,其中所述组合物是软膏剂。
13.根据权利要求1所述的药物组合物,其中所述组合物是霜剂。
14.根据权利要求1所述的药物组合物,其中所述组合物是洗剂。
15.根据权利要求1所述的药物组合物,其中所述组合物是喷雾剂。
16.根据权利要求1所述的药物组合物,其中所述组合物是泡沫剂。
17.根据权利要求1所述的药物组合物,其中所述溶解的式1的化合物在疏水性基质内,所述疏水性基质包含一种或多种选自由以下各项组成的组中的赋形剂:石蜡、植物油、动物脂肪、合成甘油酯、蜡、全氟化碳、半全氟化碳和液体聚硅氧烷。
18.根据权利要求17所述的药物组合物,所述药物组合物还包含作为稠度增强剂的肉豆蔻酸异丙酯。
19.根据权利要求17所述的药物组合物,其中所述疏水性基质包含一种或多种选自由以下各项组成的组中的赋形剂:矿脂、石蜡、矿物油和微晶蜡。
20.根据权利要求1所述的药物组合物,其中所述式I的化合物以所述组合物的约0.1至约5%w/w的量存在。
21.根据权利要求20所述的药物组合物,其中所述增溶剂以所述组合物的约5%至约25%(w/w)的量存在。
22.根据权利要求21所述的药物组合物,其中所述增溶剂包括二甘醇单乙醚,所述二甘醇单乙醚的量为所述组合物的约10%(w/w)。
23.根据权利要求21所述的药物组合物,其中所述增溶剂包括二甘醇单乙醚,所述二甘醇单乙醚的量为所述组合物的约5%(w/w)。
24.根据权利要求21所述的药物组合物,其中所述增溶剂包括二甘醇单乙醚和油酸的混合物。
25.根据权利要求24所述的药物组合物,其中所述二甘醇单乙醚的量为所述组合物的约2.5%(w/w)并且所述油酸的量为所述组合物的约2.5%(w/w)。
27.根据权利要求26所述的药物组合物,所述药物组合物还包含作为稠度增强剂的肉豆蔻酸异丙酯。
28.根据权利要求26所述的药物组合物,其中所述式I的化合物以所述组合物的约0.1%至约5%(w/w)的量存在。
29.根据权利要求28所述的药物组合物,其中所述二甘醇单乙醚以所述组合物的约5%至约25%(w/w)的量存在。
30.根据权利要求27所述的药物组合物,其中所述肉豆蔻酸异丙酯以所述组合物的约2.5%至约20%(w/w)的量存在。
31.根据权利要求30所述的药物组合物,其中所述疏水性基质包含矿脂、矿物油和微晶蜡的组合。
32.根据权利要求31所述的药物组合物,其中所述组合物是软膏剂。
33.一种用于治疗内塞顿病的方法,所述方法包括施用根据权利要求1-32中任一项所述的药物组合物。
34.一种用于治疗特应性皮炎的方法,所述方法包括施用根据权利要求1-32中任一项所述的药物组合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062986526P | 2020-03-06 | 2020-03-06 | |
US62/986,526 | 2020-03-06 | ||
PCT/US2021/021138 WO2021178834A1 (en) | 2020-03-06 | 2021-03-05 | Topical pharmaceutical formulations of a cyclic depsipeptide |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115397398A true CN115397398A (zh) | 2022-11-25 |
Family
ID=77613860
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180019115.3A Pending CN115397398A (zh) | 2020-03-06 | 2021-03-05 | 环状酯肽的局部药物制剂 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230000945A1 (zh) |
EP (1) | EP4114358A4 (zh) |
JP (1) | JP2023516754A (zh) |
CN (1) | CN115397398A (zh) |
CA (1) | CA3174475A1 (zh) |
WO (1) | WO2021178834A1 (zh) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8895537B2 (en) * | 2010-10-29 | 2014-11-25 | Infirst Healthcare Ltd. | Compositions and methods for treating cardiovascular diseases |
US8680054B2 (en) * | 2011-04-20 | 2014-03-25 | Novartis Ag | Suspension type topical formulations comprising cyclic depsipeptide |
-
2021
- 2021-03-05 WO PCT/US2021/021138 patent/WO2021178834A1/en unknown
- 2021-03-05 JP JP2022553585A patent/JP2023516754A/ja active Pending
- 2021-03-05 EP EP21765119.9A patent/EP4114358A4/en active Pending
- 2021-03-05 CA CA3174475A patent/CA3174475A1/en active Pending
- 2021-03-05 CN CN202180019115.3A patent/CN115397398A/zh active Pending
-
2022
- 2022-09-06 US US17/929,980 patent/US20230000945A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
CA3174475A1 (en) | 2021-09-10 |
JP2023516754A (ja) | 2023-04-20 |
US20230000945A1 (en) | 2023-01-05 |
EP4114358A4 (en) | 2024-03-27 |
WO2021178834A1 (en) | 2021-09-10 |
EP4114358A1 (en) | 2023-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2972843T3 (es) | Composiciones farmacéuticas de roflumilast en mezclas acuosas de disolventes farmacéuticamente aceptables miscibles en agua | |
CA3102689C (en) | Method and formulation for improving roflumilast skin penetration lag time | |
TW201940174A (zh) | 包含托法替尼的局部配方 | |
JP6385938B2 (ja) | 外用ステロイド組成物および方法 | |
US20220273627A1 (en) | Topical composition comprising tacrolimus | |
US20220211730A1 (en) | Treatment of skin conditions using high krafft temperature anionic surfactants | |
KR20210045987A (ko) | 국소적 유지성 조성물 | |
KR20050042475A (ko) | 국소 무수 및 에탄올-없는 아스코마이신 조성물 | |
JP7268132B2 (ja) | 局所用組成物 | |
US20230338383A1 (en) | Laureth-4 containing topical formulations | |
CN115397398A (zh) | 环状酯肽的局部药物制剂 | |
JP7512365B2 (ja) | 油性外用液 | |
KR102681877B1 (ko) | 수-혼화성, 약학적으로 허용가능한 용매의 수성 혼합물 내 로플루밀라스트의 약학 조성물 | |
US20220040138A1 (en) | Teriflunomide topical pharmaceutical compositions | |
WO2023102559A1 (en) | Topical formulations of ruxolitinib with an organic amine ph adjusting agent for treatment of skin diseases | |
AU2022399851A1 (en) | Topical formulations of ruxolitinib with an organic amine ph adjusting agent for treatment of skin diseases | |
CN117157080A (zh) | 用于治疗皮肤病的含维生素d类似物的jak抑制剂 | |
JP2007502799A (ja) | ラベンダスチンの医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |