WO2016044750A1 - Topical formulations of growth factors - Google Patents
Topical formulations of growth factors Download PDFInfo
- Publication number
- WO2016044750A1 WO2016044750A1 PCT/US2015/050986 US2015050986W WO2016044750A1 WO 2016044750 A1 WO2016044750 A1 WO 2016044750A1 US 2015050986 W US2015050986 W US 2015050986W WO 2016044750 A1 WO2016044750 A1 WO 2016044750A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hgh
- composition
- patch
- administered
- hours
- Prior art date
Links
- 239000003102 growth factor Substances 0.000 title description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 120
- 238000000034 method Methods 0.000 claims abstract description 32
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 108
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 38
- 229960003639 laurocapram Drugs 0.000 claims description 34
- 210000002966 serum Anatomy 0.000 claims description 25
- 229960004063 propylene glycol Drugs 0.000 claims description 24
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 22
- 229920001993 poloxamer 188 Polymers 0.000 claims description 22
- 229940044519 poloxamer 188 Drugs 0.000 claims description 22
- 238000009825 accumulation Methods 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 230000001737 promoting effect Effects 0.000 claims description 3
- 238000011200 topical administration Methods 0.000 claims description 3
- 238000003860 storage Methods 0.000 claims description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 10
- 150000002605 large molecules Chemical class 0.000 abstract description 9
- 229920002521 macromolecule Polymers 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000035475 disorder Diseases 0.000 abstract description 3
- 208000024891 symptom Diseases 0.000 abstract description 3
- 230000006872 improvement Effects 0.000 abstract description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 72
- 102000002265 Human Growth Hormone Human genes 0.000 description 71
- 239000000854 Human Growth Hormone Substances 0.000 description 71
- 238000009472 formulation Methods 0.000 description 67
- 229920001577 copolymer Polymers 0.000 description 50
- 239000003623 enhancer Substances 0.000 description 44
- 239000003814 drug Substances 0.000 description 38
- 210000003491 skin Anatomy 0.000 description 26
- 229940124597 therapeutic agent Drugs 0.000 description 15
- 230000000699 topical effect Effects 0.000 description 15
- 230000035515 penetration Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 12
- 230000004907 flux Effects 0.000 description 11
- 239000000499 gel Substances 0.000 description 11
- 230000003232 mucoadhesive effect Effects 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- -1 but not limited to Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000003961 penetration enhancing agent Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 230000037317 transdermal delivery Effects 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 8
- 239000011148 porous material Substances 0.000 description 8
- 210000000434 stratum corneum Anatomy 0.000 description 8
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 7
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000004088 simulation Methods 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical class OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 210000004877 mucosa Anatomy 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- 206010056438 Growth hormone deficiency Diseases 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 229940106189 ceramide Drugs 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 229920001983 poloxamer Polymers 0.000 description 4
- 229920001987 poloxamine Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 241000282412 Homo Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000004888 barrier function Effects 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
- 230000036757 core body temperature Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 102100036717 Growth hormone variant Human genes 0.000 description 2
- 101710191157 Growth hormone variant Proteins 0.000 description 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- APZYKUZPJCQGPP-UHFFFAOYSA-N Tetrahydropiperine Chemical compound C=1C=C2OCOC2=CC=1CCCCC(=O)N1CCCCC1 APZYKUZPJCQGPP-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 2
- 150000001783 ceramides Chemical class 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 150000002314 glycerols Chemical class 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 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 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000009738 saturating Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-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
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 229920002491 Diethylaminoethyl-dextran Polymers 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 108050007673 Somatotropin Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 235000021324 borage oil Nutrition 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000001339 epidermal cell Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012737 fresh medium Substances 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
- 229940063135 genotropin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000867 larynx Anatomy 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
- 150000004668 long chain fatty acids Chemical group 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 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
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229960004532 somatropin Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 238000013334 tissue model Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229940100640 transdermal system Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- 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
- 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
- A61K9/70—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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
Definitions
- transdermal patch segment of the pharmaceutical industry currently commands a relatively small share of the rapidly growing global drug delivery market ($21.5 billion in 2010, projected growth to $31.5 billion by 2015).
- Approved patches are currently available for drugs with properties that lend themselves to passive permeation across the skin when applied topically such as estrogen, nicotine, nitroglycerin, scopolamine, fentanyl and clonidine.
- patch-based penetration enhancement formulations have been limited to delivering small chemical drugs below a molecular weight size of 500 daltons (the so-called “rule of 500”) due to the physical constraints of effectively transporting large water-soluble compounds across the thick, keratin-rich, armor- like outer layer of skin (stratum corneum).
- the underlying cellular layers that comprise the viable epidermis also present a rate-limiting barrier to transdermal drug delivery after successful penetration of the stratum corneum.
- the barrier to drug diffusion across the epidermis is probably the presence of tight junctions. Removal of the full epidermis increased skin permeability by 1-2 orders of magnitude depending on the molecule delivered.
- compositions Provided herein are compositions, methods of treatment using such compositions, and methods of making such compositions wherein the compositions comprise a large molecule.
- the compositions, and devices and kits comprising such compositions provide new and useful improvements as alternatives for addressing diseases, disorders and symptoms thereof in a subject.
- composition comprising propylene glycol (PG), poloxamer 188 (P188), laurocapram (LP) and human growth hormone (hGH).
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- hGH human growth hormone
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- PG propylene glycol
- P188 poloxamer 188
- LP laurocapram
- the hGH is lyophilized hGH
- the hGH is present in a range of 0.1-10 mg/50 ⁇ _;
- IGF-1 insulin-like growth factor 1
- the IGF-1 is present in a range of 0.1-10 mg/50 ⁇ _;
- composition herein that is devoid of azone.
- Another aspect is a method of promoting growth in a subject comprising administration of any composition herein to the subject. In other aspects, the method is that wherein:
- the administration is topically;
- the hGH is administered at a range of 0.1-10 mg/50 ⁇ _/0 ⁇ 2 ;
- hGH is via a patch attached to the subject for up to 168 hours;
- hGH is via a patch attached to the subject for up to 24 hours
- hGH is via a patch attached to the subject for up to 168, 144, 120, 96, 72, 48, or 24 hours;
- the permeation of hGH through EpiDermFTTM is at least 1 ng/cm /hr 24 hours after initial administration;
- the permeation of hGH through EpiDermFTTM is at least 1 ng/cm /hr 48 hours after initial administration;
- the permeation of hGH through EpiDermFTTM is at least 1 ng/cm /hr 72 hours after initial administration;
- the permeation of hGH through EpiDermFTTM is at least 1 ng/cm /hr 168, 144, 120, 96, 72, 48, or 24 hours after initial administration;
- composition of claim 1 is in solid form
- composition of claim 1 is in gel form
- the hGH is administered continuously and consistently over at least 7 days;
- the hGH is administered continuously and consistently over at least 3 days;
- the hGH is administered continuously and consistently over at least 24 hours;
- the hGH is administered continuously and consistently over at least 168, 144, 120, 96, 72, 48, or 24 hours; the hGH is administered such that serum hGH accumulation of at least 5-200 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
- the hGH is administered such that serum hGH accumulation of at least 10-150 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
- the hGH is administered such that serum hGH accumulation of at least 5-100 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
- the hGH is administered such that serum hGH accumulation of at least 10-125 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
- the hGH is administered at a dosage of 0.5-100 mg/wk;
- the hGH is administered at a dosage of 1-50 mg/wk;
- the hGH is administered at a dosage of 0.5-15 mg/wk.
- kits comprising a composition of herein and a device for topical administration of the composition herein.
- the kit is that wherein:
- the device is a patch
- composition herein is in solid form
- composition herein is in gel form
- the patch further comprises an adhesive material
- the patch is 1 x 1 (cm x cm) to 10 x 10 (cm x cm);
- the patch is 1 x 1, 2 x 2, 3 x 3, 4 x 4, 5 x 5, 6 x 6, 7 x 7, 8 x 8, 9 x 9 or 10 x 10 (cm x cm).
- Another aspect is a device comprising a composition herein and a patch. In other aspects, the device is that wherein: the patch comprises a backing;
- the patch comprises an adhesive
- the patch comprises a laminate coated with a composition
- the patch comprises a release liner
- the patch comprises the composition herein in solid form
- the patch comprises the composition herein in gel form
- the patch is 1 x 1 (cm x cm) to 10 x 10 (cm x cm);
- the patch is 1 x 1, 2 x 2, 3 x 3, 4 x 4, 5 x 5, 6 x 6, 7 x 7, 8 x 8, 9 x 9 or 10 x 10 (cm x cm).
- the device e.g., patch
- a surface of the device adjacent to the contact site can be between about 1 and about 100 square centimeters in size, including range of integers (e.g., 1-10, 5-50, 50-100, etc.), or any integer between about 1 and about 100.
- the device can be between about 1 and about 25 cubic centimeters in size.
- the therapeutic-agent-containing formulation can include a thermo- sensitive polymer.
- the thermo- sensitive polymer can include a poloxamer or a poloxamine.
- the poloxamer can be poloxamer 188.
- the device e.g., a patch
- the device can comprise a dermoadhesive agent.
- the dermoadhesive agent in the therapeutic-agent-containing formulation can be selected from the group including of propylene glycol, dipropylene glycol, polyethylene glycol, glycerine, butylene glycol, glycol derivatives with glycerol esters, and non-ionizable glycol ether derivatives.
- FIG. 1 depicts hGH steady state-flux in a topical patch administration.
- FIG. 2 depicts in vitro serum hGH levels of topical patch embodiments.
- FIG. 3 depicts hGH patch dosing of the invention compared to injection.
- FIG. 4 depicts atomic structure of stratum corneum.
- FIG. 5-7 depict tables showing the results of a pharmacokinetic (PK) simulation model to demonstrate that hGH patch embodiments of reasonable patch dimensions, total patch dose, and maximum duration of action can achieve upper end of the range of normal random serum hGH levels within 12 hours after application for each age/gender group: a) FIG. 5 for men (5 ng/mL); b) FIG. 6 for women (10 ng/mL); and c) FIG.7 for children (20 ng/mL).
- PK pharmacokinetic
- FIG. 8 depicts a table showing comparison by age/gender of simulated hGH patch PK values.
- FIG. 9 depicts equations for pharmacokinetic modeling to predict patch size and duration of action.
- perforation shall be understood to refer to a series of holes made into a material that allows easy separation of two sections of the material.
- the holes may be circular or may be elongated.
- the process of creating perforations involves puncturing the material with a tool.
- Perforations can be formed by a hole punch or a cutting edge that includes "nicks," (i.e., indentations) where the two sections of the material are not separated.
- perforations can be made by a cutting wheel or a grinding wheel that includes nicks in the wheel's circumference.
- Ranges provided herein are understood to be shorthand for all of the values within the range.
- a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (as well as fractions thereof unless the context clearly dictates otherwise).
- the co-polymer/enhancer formulations disclosed herein are comprised of individual components generally regarded as safe (GRAS) and are thermo- sensitive, or dermoadhesive, and enhance the penetration of therapeutics across skin or other surfaces.
- the individual components may possess two or more of these three properties (primary, secondary and/or tertiary properties).
- the co-polymer/enhancer formulations can be embodied as a passive transdermal delivery patch that delivers one or more therapeutics continuously for up to 7 days or more.
- therapeutic uses of the co-polymer/enhancer co-polymer/enhancer formulations for non-invasive, needle-free delivery of large peptide drugs including but not limited to hGH, IGF-1, etc.
- the delivery system comprises co-polymers of poloxamer 188 (PI 88) and propylene glycol (PG), the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration- enhancing peptides), and one or more therapeutic agents.
- the delivery formulation disclosed herein can be used for transdermal delivery of large molecule perishable drugs (e.g. peptides or proteins) useful for enhancing or promoting growth in a subject.
- the delivery system comprises co-polymers of poloxamer 188 (PI 88) and propylene glycol, the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration-enhancing peptides), and one or more therapeutic agents.
- PI 88 poloxamer 188
- Azone the penetration-enhancer laurocapram
- other classes of penetration-enhancing compounds including short penetration-enhancing peptides
- the co-polymer/enhancer formulations disclosed herein are thermo-sensitive; that is, solid at room temperature for ease of application, for example, to the skin (30-32° C) or insertion into the vaginal canal to coat the cervical transformation zone (core body temperature of 37° C), and transition (melt) to a gel or liquid phase at these physiological temperatures.
- the ratio of poloxamer 188, propylene glycol, laurocapram, and a specific drug in a formulation may be altered to determine the transition temperature.
- a specific composition may determine a solid-to-gel transition at skin temperature 30-32° C, while a different composition may determine a solid-to-gel transition at core body temperature of 37° C.
- the co- polymer/enhancer formulations in gel or liquid phase adhere to and enhance large and small molecule penetration across the skin or mucosa.
- the co-polymer/enhancer formulations disclosed herein allow for noninvasive, targeted delivery of therapeutics across the skin and mucosal surfaces. Additionally, the present co-polymer/enhancer formulations use safe, inexpensive ingredients, are easy to administer and are suitable for use in a wide range of clinical settings. The co-polymer/enhancer formulations can easily be administered by healthcare workers or by self-administration by the patient, and under conditions of extreme temperature, high humidity, poor lighting, lack of space or lack of adequate supply of electricity or water.
- co-polymer/enhancer formulations for topical delivery of therapeutics.
- the co-polymer/enhancer formulations of this disclosure are thermo-sensitive, mucoadhesive or dermoadhesive, and enhance the penetration of therapeutics across the full thickness of the skin or mucosal surfaces.
- the novel topical delivery formulation comprises a thermo-sensitive polymer, a mucoadhesive or dermoadhesive polymer, a penetration enhancer and, optionally, one or more therapeutic agents (e.g., large molecule therapeutic agent, growth factor).
- the co-polymer/enhancer formulation comprises co-polymer of one or more thermo-sensitive polymers, one or more mucoadhesive or dermoadhesive polymers and one or more penetration-enhancing agents.
- the co-polymer/enhancer formulation comprises co-polymer of poloxamer 188 and propylene glycol, the penetration- enhancer laurocapram and, optionally, one or more therapeutic agents.
- the co-polymer/enhancer formulation comprises one or more polymeric materials including, but not limited to, poloxamer and poloxamine.
- Poloxamers useful according to this disclosure include, but are not limited to, poloxamer 188, 407, 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, and 403.
- Poloxamines useful according to this disclosure include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
- the co-polymer/enhancer formulation can comprise one or more polymeric materials including, but not limited to, polylactic acid and copolymers, polyvinyl acetate, celluloses and derivatives (such as carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyalkyl methyl celluloses and alkyl celluloses), crosslinked dextrans, polyethylene glycol, diethylaminoethyl dextran, poly(cyanoacrylates), copolymers of PEG and PLA, poly(lactic-co-glycolic acid), poly(ortho esters) and hydrogels.
- the polymeric material is pharmaceutically- acceptable, biodegradable, mucoadhesive or dermoadhesive and/or enhances the penetration of therapeutics across the skin and/or mucosal surface.
- the co-polymer/enhancer formulation further comprises one or more mucoadhesive or dermoadhesive agents.
- the mucoadhesive or dermoadhesive agent promotes adhesion of the co-polymer/enhancer formulation to the skin or mucosa membranes.
- the mucoadhesive or dermoadhesive agent also enhances the penetration of therapeutics across the skin and/or mucosal surface.
- Mucoadhesive or dermoadhesive agents useful according to this disclosure include, but are not limited to, polyols such as, propylene glycol, dipropylene glycol, polyethylene glycol, glycerine and butylene glycol; glycol derivatives with glycerol esters, such as, oleic acid esters of propylene glycol; and non-ionizable glycol ether derivatives, such as, ethoxydiglycol.
- polyols such as, propylene glycol, dipropylene glycol, polyethylene glycol, glycerine and butylene glycol
- glycol derivatives with glycerol esters such as, oleic acid esters of propylene glycol
- non-ionizable glycol ether derivatives such as, ethoxydiglycol.
- Mucoadhesive or dermoadhesive agents useful according to this disclosure can also include polymers such as, polyethylene glycol caprylic/capric glycerides; vinyl polymers (e.g., polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polyvinyl pyrrolidone); cellulosic derivatives, such as, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose; polysaccharides, such as, alginic acid and sodium alginate.
- polymers such as, polyethylene glycol caprylic/capric glycerides; vinyl polymers (e.g., polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polyvinyl pyrrolidone); cellulosic derivatives, such as, methyl cellulose
- the topical delivery formulation further comprises one or more penetration enhancers.
- Penetration enhancers useful according to this disclosure include, but are not limited to, laurocapram, diethylene glycol, monoethyl ether, n-decyl methyl sulfoxide, dimethyl sulfoxide, dimethylacetamidedimethylformamide, sucrose monooleate, amides and other nitrogenous compounds (e.g., urea, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine), organic acids (e.g., citric acid and succinic acid), N- methyl-2-pyrrolidine, borage oil, tetrahydropiperine (THP), alcohols (e.g., methanol, ethanol, propanol, octanol, benzyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol), fatty acids (e.g., oleic acid
- the co-polymer/enhancer formulation is solid or semi-solid at room temperature, begins to melt at temperatures slightly below, and completely melts at physiological temperatures.
- room temperature is below 30 °C, below 28 °C, below 25 °C, below 23 °C, below 20 °C, or below 18 °C.
- the co-polymer/enhancer formulation melts, or begins to melt, at a temperature ranging from about 30 °C to 42 °C, 32 °C to 40 °C, 33 °C to 40 °C, 35 °C to 38 °C, or 34 °C to 37 °C. In certain embodiments, the co-polymer/enhancer formulation melts, or begins to melt, at a temperature above 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, or 37 °C.
- the biopolymer formulation melts, or begins to melt, at a temperature below 45 °C, 44 °C, 43 °C, 42 °C, 41 °C, 40 °C, 39 °C, 38 °C, 37 °C, 36 °C, 35 °C, or 34 °C.
- the desired thermal property of the co-polymer/enhancer formulation can be achieved by adjusting the relative ratio (e.g., in terms of weight percentages or molar amounts) of various ingredients including, the thermo-sensitive polymeric material, the mucoadhesive agent, the penetration enhancer and/or the therapeutic agent.
- the co-polymer/enhancer formulation comprises a polymeric material at a weight percentage of about 20% to about 95%, about 25% to about 90%, about 30% to about 85%, about 35% to about 80%, about 40% to about 70%, about 50% to about 90%, about 50% to about 85%, about 60% to about 80%, about 30% to about 40%, about 30% to about 50%, about 70% to about 90%, about 70% to about 85% or about 70% to about 80%.
- the co-polymer/enhancer formulation comprises a mucoadhesive or deraioadhesive agent at a weight percentage of about 5% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 20%, about 5% to about 30%, about 5% to about 20%, about 5% to about 15% or about 15% to about 30%.
- the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration ranging from about 1 to about 12 %, about 2 to about 11%, about 3 to about 10%, about 4 to about 9%, about 5 to about 8%, about 2 to about 9 %, about 3 to about 8%, about 4 to about 7%, about 2 to about 5%, or about 6 to about 7% by weight.
- the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration above 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30% by weight.
- the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration below 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6% or 5% by weight.
- the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 100:0, 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 0: 100.
- the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 70:30 (37 °C or core body temperature) or 50/50 (30-32 °C or skin temperature).
- the co-polymer/enhancer formulation comprises laurocapram at a concentration of about 1 to about 12 %, about 2 to about 11%, about 3 to about 10%, about 4 to about 9%, about 5 to about 8%, about 2 to about 9 %, about 3 to about 8%, about 4 to about 7%, about 2 to about 5%, or about 6 to about 7% by weight.
- the co- polymer/enhancer formulation comprises about 12% laurocapram by weight.
- the co-polymer/enhancer formulation comprises about 2% laurocapram, by weight.
- the co-polymer/enhancer formulation comprises about ⁇ 12%, ⁇ 11%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1%, laurocapram by weight. It is contemplated that the amount of laurocapram can be selected to be a balance between a desired flux rate and negative side effects (e.g., irritation, toxicity).
- the co-polymer/enhancer formulation can be used for topical delivery of a variety of small or large therapeutic agents not previously achieved using penetration enhancers including, but not limited to, large peptides and proteins greater than about 50 amino acids, (e.g., >53 amino acids, >60 amino acids, >70 amino acids), nucleic acids, compounds with unique physicochemical structures and/or properties not considered amenable to passive transdermal or transmucosal delivery.
- penetration enhancers including, but not limited to, large peptides and proteins greater than about 50 amino acids, (e.g., >53 amino acids, >60 amino acids, >70 amino acids), nucleic acids, compounds with unique physicochemical structures and/or properties not considered amenable to passive transdermal or transmucosal delivery.
- hormones can include but not be limited to human or bovine growth hormone (hGH or bGH), or insulin-like growth factor 1 (IGF-1).
- hGH or bGH human or bovine growth hormone
- IGF-1 insulin-like growth factor 1
- the co-polymer/enhancer formulation comprises a therapeutic agent at a concentration ranging from 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 0.1 mM to about 1.5 mM, about 0.5 mM to about 2 mM, or about 0.5 mM to about 1.5 mM, about 0.01 mM to about 30 mM, about 0.01 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.05 mM to about 20 mM, or about 0.05 mM to about 15 mM.
- Amounts of therapeutic agents incorporated into co-polymer/enhancer formulations disclosed herein can also be determined by those skilled in the art (e.g., based upon age, bioavailability of a therapeutic agent, etc.) such that the therapeutic agent is delivered to a subject in amounts that effect a therapeutic benefit to the subject.
- the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation of this disclosure using any standard topical patch design or variations thereof, having in common the direct application (bio-interface) with the skin or mucosal surface.
- the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation comprising poloxamer 188 and propylene glycol, laurocapram and, optionally, one or more therapeutic agents.
- subject describes an organism, including mammals such as primates, to which treatment with the formulations according to the subject disclosure can be provided.
- Mammalian species that can benefit from the disclosed methods of treatment include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters.
- the co-polymer/enhancer formulation of this disclosure is administered to skin or mucosal surfaces including, but not limited to, cervix, vagina, anus, rectum, eye, ear, nose, thorax, vulva, larynx, and head and neck.
- Embodiments of this disclosure allow for topical delivery of therapeutics across the full- thickness skin barrier including the keratinized apical layer of skin (stratum corneum), the epidermal cell layer, and the dermis, and/or mucosa. At least one embodiment allows for topical delivery of therapeutics across non-keratinized surface of skin and/or mucosa. At least one embodiment allows for topical delivery of therapeutics into, or across, multiple layers of cervical squamous epithelial cells. At least one embodiment allows for topical delivery of therapeutics to the basal keratinocytes of skin and/or mucosa.
- At least one embodiment can be used as a non-invasive topical transdermal or transmucosal delivery system (or device) applied to normal skin or mucosal surfaces to obviate the need for subcutaneous injection of therapeutic compounds.
- a patch for topical transdermal delivery of a composition herein can include any suitable material (e.g., transdermal system, backings, liners, membranes and tapes, and the like) well known in the transdermal delivery art. Such materials are commercially available from various sources and known in the art. See for example, those available from 3M Drug Delivery Systems, St. Paul, MN.
- the subject disclosure also provides for therapeutic or pharmaceutical formulations comprising the co-polymer/enhancer formulation in a form that can be combined with a pharmaceutically acceptable carrier.
- the therapeutic or pharmaceutical formulation is solid at room temperature and transitions to a gel or liquid at desired physiological temperatures.
- carrier refers to a diluent, adjuvant, excipient or vehicle with which the compound is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum oil such as mineral oil, vegetable oil such as peanut oil, soybean oil and sesame oil, animal oil or oil of synthetic origin.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
- the therapeutic formulation if desired, can also contain minor amounts of wetting, emulsifying or pH buffering agents. These formulations can take the form of creams, foam, patches, lotions, drops, sprays, gel, oils, aerosol, powders, ointment, solutions, suspensions, emulsion and the like.
- the formulation can be formulated with traditional binders and carriers such as triglycerides.
- Such formulations contain a therapeutically effective amount of the therapeutic formulation, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
- the formulation should suit the mode of administration.
- the subject disclosure also provides for the modification of the ingredient such that it is more stable once administered to a subject, i.e., once administered it has a longer time period of effectiveness as compared to the unmodified form.
- modifications are well known to those of skill in the art, e.g., microencapsulation, etc.
- the amount of the therapeutic or pharmaceutical formulation of this disclosure which is effective in the treatment of a particular disease, condition or disorder will depend on the route of administration and the seriousness of the disease, condition or disorder and should be decided according to the judgment of the practitioner and each patient's circumstances.
- kits containing therapeutic compositions herein are stable in a wide range of temperatures below the desired melting temperature.
- the active therapeutic agents can be reconstituted by mixing pre-measured quantities of each component immediately prior to use.
- the kits can include a covering package material (e.g., plastic, foil, polymer material, etc.) suitable to protect the kit and its contents (e.g., active agent, patch, device) from degradation and contamination.
- hGH somatotropin and growth hormone- 1
- GH- 2 somatotropin and growth hormone-2
- a convenient, non-invasive and affordable transdermal patch formulation capable of achieving passive delivery of large molecule drugs such as hGH and insulin for multiple days.
- a novel platform technology a composition, applied to the transdermal delivery of hGH (22, 128 Da). This solution was lyophilized overnight. The lyophilized powder was reconstituted in an optimized formulation to create a stock solution.
- the formulation consisted of about 49% poloxamer 188, about 39% propylene glycol, and about 12% laurocapram (wt./wt./wt).
- Formulations containing hGH at different concentrations were freshly prepared from the stock solution immediately prior to application as 50 ⁇ ⁇ gel to EpidermPTTM (EFT-300) tissue inserts, which are mitotically and metabolically active human skin equivalents (HSEs) when cultured in maintenance medium at 32°C. Formulations over the dose range of 0.0001- 1.0 mg/0.6 cm hGH were incubated at 32° C for 7-days. Equal volume of medium was sampled and replenished every 12 rs. hGH concentrations were measured using the Quantikine ® ELISA kit (R&D Systems) as per manufacturer' s instructions. Steady-state hGH flux (J ss ) was calculated using Pick' s first law.
- FIG. 1 We observed a clear dose-response (FIG 1).
- FOG 1 We tested the feasibility of developing an effective extended- wear hGH patch capable of providing constant and consistent drug delivery to replace daily or weekly injections for therapy of growth hormone deficiency (GHD) in children and adults. Feasibility was demonstrated by using J Facebook from these in vitro studies along with published pharmacokinetic (PK) data for hGH in humans to perform simulations using two different PK models as described in the figures below.
- PK pharmacokinetic
- FIG 1 Passive transdermal delivery of human growth hormone (hGH, somatropin) continuously over 7-days using an embodiment of a formulation.
- hGH has a molecular weight (MW) of 22,124 Da, which is -3.8X larger than human insulin (5,808 Da).
- the flux of hGH exhibits a dose-response in the range of 0.0005-0.5 mg/0.6 cm over the course of a 7-day study in a highly robust human skin equivalent model (HSE).
- MatTek's EpiDermFTTM (EFT- 300) tissue inserts are barrier-enhanced (i.e.
- stratum corneum 3X the thickness of normal human skin
- full-thickness the thickness of normal human skin
- metabolically and mitotically active HSEs that remain viable for at least 7- days when maintained in serum-containing medium in a tissue culture incubator at 32° C (skin temperature).
- Continuous and consistent transdermal delivery was observed, as indicated by the linear accumulation plots (same amount of delivery each day characteristic of constant steady- state flux rates). Saturation was observed at an administered dose of 0.3 mg/0.6 cm , since the accumulation curves for the 0.3 mg/0.6 cm and 0.5 mg/0.6 cm doses are superimposable, although the true saturating dose may be between 0.2-0.3 mg/0.6 cm .
- FIG 2 Table showing extrapolated serum hGH levels in humans as a determinant of hGH patch dimensions or surface area (cm ) and time (1-7 days). Extrapolated serum hGH levels are from flux observed for a 0.5 mg/0.6 cm saturating dose of an embodiment of an hGH formulation in EpiDermFTTM (EFT-300) accumulation dose-response studies using 2.5 ml of maintenance medium (FIG. 1), extrapolated to 5L adult blood volume.
- EFT-300 epiDermFTTM
- FIG. 1 maintenance medium
- Shadowing (light blue) in upper left quadrant corresponds to patch size and time required to remain in the normal range of random serum levels specific for Men ( ⁇ 5 ng/mL or 226 pmol/L). Shadowing (intermediate blue) in middle diagonal cells corresponds to additional patch size and time required to remain in normal range of random serum levels specific for Women: ⁇ 10 ng/mL (452 pmol/L).
- Shadowing in right lower quadrant corresponds to patch size and time required to remain in normal range of random serum levels specific for Children 0-20 ng/mL (0- 904 pmol/L).
- Shadowing in right lower quadrant corresponds to patch size and time required to remain in normal range of random serum levels specific for Newborns: 5-40 ng/mL (226-1808 pmol/L).
- the extrapolated serum hGH levels are derived from an in vitro tissue model that only assesses transdermal transport as a measure of accumulation of permeant as a function of time to demonstrate constant and consistent delivery (curve should be linear; slope defines dose- response).
- the values reflect a model of 100% drug metabolism/elimination each day since medium is removed and replaced with fresh medium every 24 hours for the duration of the 7-day study; this methodology is a requirement for creating "in sink” conditions for calculating steady- state flux from Fick's 1st Law of Diffusion.
- FIG 3 Table showing extrapolated maximum hGH patch size carrying an equivalent absolute amount of hGH (upper limit) compared to weekly therapy with Genotropin® for GHD by injection.
- FIG 4 Remarkably, the complex structure of skin morphology has not been fully elucidated. It was first proposed by Wertz, Swartzendruber, Madison and Downing (1983) that the fat layer of the stratum corneum extracellular space is composed of saturated long-chain ceramides, free fatty acids and cholesterol in a 1: 1: 1 molar ratio. Norlen (2001) proposed that the fat layer exists as a single and coherent gel phase. It was not until 2012 that Norlen' s team reported the use of very high magnification cryoelectron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation to determine the atomic structure of the stratum corneum lipid matrix in situ, in its near-native state. The structure is composed of stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety; the free fatty acid is associated with the long-chain fatty acid moiety of the ceramide.
- EM cryoele
- FIG 5-7 Tables showing the results of a pharmacokinetic (PK) simulation model to demonstrate that hGH patch embodiments of reasonable patch dimensions, total patch dose, and maximum duration of action can achieve upper end of the range of normal random serum hGH levels within 12 hours after application for each age/gender group: a) FIG. 5 for men (5 ng/mL); b) FIG. 6 for women (10 ng/mL); and c) FIG.7 for children (20 ng/mL). Setting the target levels at the upper end of the normal range is intended to enhance the robustness of the proof-of- concept PK simulations.
- PK pharmacokinetic
- Results are based on hGH steady-state flux observed for embodiments of hGH formulations over the dose range of 0.005-0.5 mg/0.6 cm in EpiDermFTTM (EFT-300) accumulation dose-response studies using 2.5 ml of maintenance medium (FIG 1).
- Pharmacokinetic calculations are based on non-compartmental analysis (NCA) when the elimination process follows first-order kinetics, as most of drugs do when they are used at their therapeutic doses (Foye's Principles of Medicinal Chemistry).
- NCA non-compartmental analysis
- the ideal simulation model of transdermal patch delivery would require use of published PK data from continuous subcutaneous infusion.
- FIG 8 Table showing comparison by age/gender of simulated hGH patch PK values.
- the values corresponding to the columns highlighted in red in FIG 5-7 indicate that patch dimensions are below 8 x 8 cm (upper limit of convenient size) and below 10 x 10 cm (upper limit of usage), and that the duration of action is up to 12-weeks. The latter supports the feasibility of developing an effective extended- wear hGH patch by a wide margin, certainly a 1-2 week patch that is the most practical life-span for extended-wear use.
- FIG 9 Equations for pharmacokinetic modeling to predict patch size and duration of action. Although there is no steady-state level for serum hGH in normal individuals due to its wide fluctuation throughout the day, there is a range for random serum hGH measurements according to age/gender.
- the steady- state constant (C ss ) in equation 3 is utilized to define a hypothetical target serum steady-state level that can be achieved by constant and consistent delivery by an hGH patch in the setting of GHD.
- Passive transdermal delivery of large molecule drugs mediated by embodiments of formulations as disclosed herein is hypothesized to occur by the synergistic effects of its components (thermosensitive polymer, dermoadhesive agent, and a chemical penetration enhancer)— all of which contribute chemical penetration enhancing properties.
- polyxamer 182 suggests the possibility of the formation of "pores" in which the lipophilic polyoxypropylene core interacts with the surrounding structure of the extracellular lipid matrix of the stratum corneum (as determined above), while the hydrophilic moieties of the flanking polyoxyethylene arms are partitioned in the center of the pore.
- the sizes of such putative pores might differ over a range in a stochastic distribution. The size distribution of such putative pores might follow a bell-shaped curve, such that small molecule drugs "pass through” all of the pores, intermediate-sized drugs (e.g.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
Provided herein are compositions, methods of treatment using such compositions, and methods of making such compositions wherein the compositions comprise a large molecule. The compositions, and devices and kits comprising such compositions provide new and useful improvements as alternatives for addressing diseases, disorders and symptoms thereof in a subject.
Description
Topical Formulations of Growth Factors
The transdermal patch segment of the pharmaceutical industry currently commands a relatively small share of the rapidly growing global drug delivery market ($21.5 billion in 2010, projected growth to $31.5 billion by 2015). Approved patches are currently available for drugs with properties that lend themselves to passive permeation across the skin when applied topically such as estrogen, nicotine, nitroglycerin, scopolamine, fentanyl and clonidine.
To date, patch-based penetration enhancement formulations have been limited to delivering small chemical drugs below a molecular weight size of 500 daltons (the so-called "rule of 500") due to the physical constraints of effectively transporting large water-soluble compounds across the thick, keratin-rich, armor- like outer layer of skin (stratum corneum). The underlying cellular layers that comprise the viable epidermis, also present a rate-limiting barrier to transdermal drug delivery after successful penetration of the stratum corneum. The barrier to drug diffusion across the epidermis is probably the presence of tight junctions. Removal of the full epidermis increased skin permeability by 1-2 orders of magnitude depending on the molecule delivered.
Currently, there is a need for improved delivery of large molecular weight molecules across skin and systemically in order to address diseases, disorders, and symptoms thereof in patients in need.
SUMMARY
Provided herein are compositions, methods of treatment using such compositions, and methods of making such compositions wherein the compositions comprise a large molecule. The
compositions, and devices and kits comprising such compositions provide new and useful improvements as alternatives for addressing diseases, disorders and symptoms thereof in a subject.
One aspect is a composition comprising propylene glycol (PG), poloxamer 188 (P188), laurocapram (LP) and human growth hormone (hGH). The composition is that wherein:
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 49:39: 12 (by weight);
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 55:43:2 (by weight);
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 56:44:0 (by weight);
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 50:50: 12 (by weight);
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 50:50:2 (by weight);
the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 50:50:0 (by weight);
the hGH is lyophilized hGH;
the hGH is present in a range of 0.1-10 mg/50 μΙ_;
further comprising insulin-like growth factor 1 (IGF-1);
the IGF-1 is present in a range of 0.1-10 mg/50 μΙ_;
the composition herein that is devoid of azone.
Another aspect is a method of promoting growth in a subject comprising administration of any composition herein to the subject. In other aspects, the method is that wherein:
the administration is topically;
the hGH is administered at a range of 0.1-10 mg/50 μΙ_/0ΠΊ2;
the administration of hGH is via a patch attached to the subject for up to 168 hours;
the administration of hGH is via a patch attached to the subject for up to 24 hours;
the administration of hGH is via a patch attached to the subject for up to 168, 144, 120, 96, 72, 48, or 24 hours;
the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 24 hours after initial administration;
the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 48 hours after initial administration;
the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 72 hours after initial administration;
the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 168, 144, 120, 96, 72, 48, or 24 hours after initial administration;
the composition of claim 1 is in solid form;
the composition of claim 1 is in gel form;
the hGH is administered continuously and consistently over at least 7 days;
the hGH is administered continuously and consistently over at least 3 days;
the hGH is administered continuously and consistently over at least 24 hours;
the hGH is administered continuously and consistently over at least 168, 144, 120, 96, 72, 48, or 24 hours;
the hGH is administered such that serum hGH accumulation of at least 5-200 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
the hGH is administered such that serum hGH accumulation of at least 10-150 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
the hGH is administered such that serum hGH accumulation of at least 5-100 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
the hGH is administered such that serum hGH accumulation of at least 10-125 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);
the hGH is administered at a dosage of 0.5-100 mg/wk;
the hGH is administered at a dosage of 1-50 mg/wk;
the hGH is administered at a dosage of 0.5-15 mg/wk.
Another aspect is a kit comprising a composition of herein and a device for topical administration of the composition herein. In other aspects, the kit is that wherein:
the device is a patch;
the composition herein is in solid form;
the composition herein is in gel form;
the patch further comprises an adhesive material;
it further comprises a cover material to protect the composition herein during shipping and storage;
the patch is 1 x 1 (cm x cm) to 10 x 10 (cm x cm);
the patch is 1 x 1, 2 x 2, 3 x 3, 4 x 4, 5 x 5, 6 x 6, 7 x 7, 8 x 8, 9 x 9 or 10 x 10 (cm x cm). Another aspect is a device comprising a composition herein and a patch. In other aspects, the device is that wherein:
the patch comprises a backing;
the patch comprises an adhesive;
the patch comprises a laminate coated with a composition;
the patch comprises a release liner;
the patch comprises the composition herein in solid form;
the patch comprises the composition herein in gel form;
the patch is 1 x 1 (cm x cm) to 10 x 10 (cm x cm);
the patch is 1 x 1, 2 x 2, 3 x 3, 4 x 4, 5 x 5, 6 x 6, 7 x 7, 8 x 8, 9 x 9 or 10 x 10 (cm x cm). Accumulation of active agent via sustained release patch can be calculated based on the minimum steady-state flux rate at 1 ng/cm /hr. For example, at such rate then in the first 24 hrs, accumulation is: (1 ng/0.6 cm /hr) x 24 hr/2.5 ml = 16 ng/ml. After 168 hrs, accumulation is: (1 ng/0.6 cm2/hr) x 168 hr/2.5 ml = 112 ng/ml.
In an aspect, the device (e.g., patch) provides a steady-state flux (permeation) of active agent at a constant rate. So, if set at a minimum at 1 ng/ cm /hr, one obtains 24 ng/ cm in 24 hours. The rate remains the same every consecutive 24 hours (1 day) for up to 7 days. So, whether 24 or 168 hours after administration, the steady-state flux remains the same.
A surface of the device adjacent to the contact site can be between about 1 and about 100 square centimeters in size, including range of integers (e.g., 1-10, 5-50, 50-100, etc.), or any integer between about 1 and about 100. In some embodiments, the device can be between about 1 and about 25 cubic centimeters in size.
The therapeutic-agent-containing formulation can include a thermo- sensitive polymer. In some embodiments, the thermo- sensitive polymer can include a poloxamer or a poloxamine. The poloxamer can be poloxamer 188.
The device (e.g., a patch) can comprise a dermoadhesive agent. The dermoadhesive agent in the therapeutic-agent-containing formulation can be selected from the group including of propylene glycol, dipropylene glycol, polyethylene glycol, glycerine, butylene glycol, glycol derivatives with glycerol esters, and non-ionizable glycol ether derivatives.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts hGH steady state-flux in a topical patch administration.
FIG. 2 depicts in vitro serum hGH levels of topical patch embodiments.
FIG. 3 depicts hGH patch dosing of the invention compared to injection.
FIG. 4 depicts atomic structure of stratum corneum.
FIG. 5-7 depict tables showing the results of a pharmacokinetic (PK) simulation model to demonstrate that hGH patch embodiments of reasonable patch dimensions, total patch dose, and maximum duration of action can achieve upper end of the range of normal random serum hGH levels within 12 hours after application for each age/gender group: a) FIG. 5 for men (5 ng/mL); b) FIG. 6 for women (10 ng/mL); and c) FIG.7 for children (20 ng/mL).
FIG. 8 depicts a table showing comparison by age/gender of simulated hGH patch PK values.
FIG. 9 depicts equations for pharmacokinetic modeling to predict patch size and duration of action.
DEFINITIONS
This disclosure can be better understood with reference to the following definitions:
As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.
Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. "About" can be understood as within 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
As used herein, the terms "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them under U.S. patent law and can mean "includes," "including," and the like.
Unless specifically stated or obvious from context, the term "or," as used herein, is understood to be inclusive.
The term "perforation" shall be understood to refer to a series of holes made into a material that allows easy separation of two sections of the material. The holes may be circular or may be elongated. The process of creating perforations involves puncturing the material with a tool. Perforations can be formed by a hole punch or a cutting edge that includes "nicks," (i.e., indentations) where the two sections of the material are not separated. Alternately, perforations
can be made by a cutting wheel or a grinding wheel that includes nicks in the wheel's circumference.
Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (as well as fractions thereof unless the context clearly dictates otherwise).
DETAILED DESCRIPTION OF THIS DISCLOSURE
At least one embodiment of this disclosure provides co-polymer/enhancer formulations for passive topical and transdermal delivery of large molecule drugs. Advantageously, in the preferred embodiments, the co-polymer/enhancer formulations disclosed herein are comprised of individual components generally regarded as safe (GRAS) and are thermo- sensitive, or dermoadhesive, and enhance the penetration of therapeutics across skin or other surfaces. The individual components may possess two or more of these three properties (primary, secondary and/or tertiary properties). The co-polymer/enhancer formulations can be embodied as a passive transdermal delivery patch that delivers one or more therapeutics continuously for up to 7 days or more. Also provided are therapeutic uses of the co-polymer/enhancer co-polymer/enhancer formulations for non-invasive, needle-free delivery of large peptide drugs including but not limited to hGH, IGF-1, etc.
In a preferred embodiment, the delivery system comprises co-polymers of poloxamer 188 (PI 88) and propylene glycol (PG), the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration-
enhancing peptides), and one or more therapeutic agents. In a preferred embodiment, the delivery formulation disclosed herein can be used for transdermal delivery of large molecule perishable drugs (e.g. peptides or proteins) useful for enhancing or promoting growth in a subject.
In a preferred embodiment, the delivery system comprises co-polymers of poloxamer 188 (PI 88) and propylene glycol, the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration-enhancing peptides), and one or more therapeutic agents.
The co-polymer/enhancer formulations disclosed herein are thermo-sensitive; that is, solid at room temperature for ease of application, for example, to the skin (30-32° C) or insertion into the vaginal canal to coat the cervical transformation zone (core body temperature of 37° C), and transition (melt) to a gel or liquid phase at these physiological temperatures. The ratio of poloxamer 188, propylene glycol, laurocapram, and a specific drug in a formulation may be altered to determine the transition temperature. For example, a specific composition may determine a solid-to-gel transition at skin temperature 30-32° C, while a different composition may determine a solid-to-gel transition at core body temperature of 37° C. Furthermore, the co- polymer/enhancer formulations in gel or liquid phase adhere to and enhance large and small molecule penetration across the skin or mucosa.
Advantageously, the co-polymer/enhancer formulations disclosed herein allow for noninvasive, targeted delivery of therapeutics across the skin and mucosal surfaces. Additionally, the present co-polymer/enhancer formulations use safe, inexpensive ingredients, are easy to administer and are suitable for use in a wide range of clinical settings. The co-polymer/enhancer formulations can easily be administered by healthcare workers or by self-administration by the
patient, and under conditions of extreme temperature, high humidity, poor lighting, lack of space or lack of adequate supply of electricity or water.
Co-Polymer/Enhancer Formulation for Topical Delivery of Therapeutic Compounds
One aspect of this disclosure provides co-polymer/enhancer formulations for topical delivery of therapeutics. Advantageously, the co-polymer/enhancer formulations of this disclosure are thermo-sensitive, mucoadhesive or dermoadhesive, and enhance the penetration of therapeutics across the full thickness of the skin or mucosal surfaces.
In one embodiment, the novel topical delivery formulation comprises a thermo-sensitive polymer, a mucoadhesive or dermoadhesive polymer, a penetration enhancer and, optionally, one or more therapeutic agents (e.g., large molecule therapeutic agent, growth factor).
In one embodiment, the co-polymer/enhancer formulation comprises co-polymer of one or more thermo-sensitive polymers, one or more mucoadhesive or dermoadhesive polymers and one or more penetration-enhancing agents. In a preferred embodiment, the co-polymer/enhancer formulation comprises co-polymer of poloxamer 188 and propylene glycol, the penetration- enhancer laurocapram and, optionally, one or more therapeutic agents.
In one embodiment, the co-polymer/enhancer formulation comprises one or more polymeric materials including, but not limited to, poloxamer and poloxamine. Poloxamers useful according to this disclosure include, but are not limited to, poloxamer 188, 407, 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, and 403. Poloxamines useful according to this disclosure include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508.
In certain embodiments, the co-polymer/enhancer formulation can comprise one or more polymeric materials including, but not limited to, polylactic acid and copolymers, polyvinyl acetate, celluloses and derivatives (such as carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyalkyl methyl celluloses and alkyl celluloses), crosslinked dextrans, polyethylene glycol, diethylaminoethyl dextran, poly(cyanoacrylates), copolymers of PEG and PLA, poly(lactic-co-glycolic acid), poly(ortho esters) and hydrogels. Preferably, the polymeric material is pharmaceutically- acceptable, biodegradable, mucoadhesive or dermoadhesive and/or enhances the penetration of therapeutics across the skin and/or mucosal surface.
In one embodiment, the co-polymer/enhancer formulation further comprises one or more mucoadhesive or dermoadhesive agents. In one embodiment the mucoadhesive or dermoadhesive agent promotes adhesion of the co-polymer/enhancer formulation to the skin or mucosa membranes. Preferably, the mucoadhesive or dermoadhesive agent also enhances the penetration of therapeutics across the skin and/or mucosal surface.
Mucoadhesive or dermoadhesive agents useful according to this disclosure include, but are not limited to, polyols such as, propylene glycol, dipropylene glycol, polyethylene glycol, glycerine and butylene glycol; glycol derivatives with glycerol esters, such as, oleic acid esters of propylene glycol; and non-ionizable glycol ether derivatives, such as, ethoxydiglycol.
Mucoadhesive or dermoadhesive agents useful according to this disclosure, can also include polymers such as, polyethylene glycol caprylic/capric glycerides; vinyl polymers (e.g., polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polyvinyl pyrrolidone); cellulosic derivatives, such as, methyl cellulose, ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose; polysaccharides, such as, alginic acid and sodium alginate.
In one embodiment, the topical delivery formulation further comprises one or more penetration enhancers. Penetration enhancers useful according to this disclosure include, but are not limited to, laurocapram, diethylene glycol, monoethyl ether, n-decyl methyl sulfoxide, dimethyl sulfoxide, dimethylacetamidedimethylformamide, sucrose monooleate, amides and other nitrogenous compounds (e.g., urea, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine), organic acids (e.g., citric acid and succinic acid), N- methyl-2-pyrrolidine, borage oil, tetrahydropiperine (THP), alcohols (e.g., methanol, ethanol, propanol, octanol, benzyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol), fatty acids (e.g., oleic acid), fatty acid esters (e.g., isopropyl myristate, isopropyl palmitate), polyols (e.g., propylene glycol, polyethylene glycol, glycerol), polyethylene glycol monolaurate and lecithin.
Preferably, the co-polymer/enhancer formulation is solid or semi-solid at room temperature, begins to melt at temperatures slightly below, and completely melts at physiological temperatures. Generally, room temperature is below 30 °C, below 28 °C, below 25 °C, below 23 °C, below 20 °C, or below 18 °C.
In certain embodiments, the co-polymer/enhancer formulation melts, or begins to melt, at a temperature ranging from about 30 °C to 42 °C, 32 °C to 40 °C, 33 °C to 40 °C, 35 °C to 38 °C, or 34 °C to 37 °C. In certain embodiments, the co-polymer/enhancer formulation melts, or begins to melt, at a temperature above 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, or 37 °C. In certain embodiments, the biopolymer formulation melts, or begins to melt, at a temperature below 45 °C, 44 °C, 43 °C, 42 °C, 41 °C, 40 °C, 39 °C, 38 °C, 37 °C, 36 °C, 35 °C, or 34 °C.
The desired thermal property of the co-polymer/enhancer formulation can be achieved by adjusting the relative ratio (e.g., in terms of weight percentages or molar amounts) of various ingredients including, the thermo-sensitive polymeric material, the mucoadhesive agent, the penetration enhancer and/or the therapeutic agent.
In certain embodiments, the co-polymer/enhancer formulation comprises a polymeric material at a weight percentage of about 20% to about 95%, about 25% to about 90%, about 30% to about 85%, about 35% to about 80%, about 40% to about 70%, about 50% to about 90%, about 50% to about 85%, about 60% to about 80%, about 30% to about 40%, about 30% to about 50%, about 70% to about 90%, about 70% to about 85% or about 70% to about 80%.
In certain embodiments, the co-polymer/enhancer formulation comprises a mucoadhesive or deraioadhesive agent at a weight percentage of about 5% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 20%, about 5% to about 30%, about 5% to about 20%, about 5% to about 15% or about 15% to about 30%.
In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration ranging from about 1 to about 12 %, about 2 to about 11%, about 3 to about 10%, about 4 to about 9%, about 5 to about 8%, about 2 to about 9 %, about 3 to about 8%, about 4 to about 7%, about 2 to about 5%, or about 6 to about 7% by weight.
In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration above 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30% by weight.
In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration below 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6% or 5% by weight.
In certain specific embodiments, the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 100:0, 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 0: 100. In preferred embodiments, the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 70:30 (37 °C or core body temperature) or 50/50 (30-32 °C or skin temperature).
In certain embodiments, the co-polymer/enhancer formulation comprises laurocapram at a concentration of about 1 to about 12 %, about 2 to about 11%, about 3 to about 10%, about 4 to about 9%, about 5 to about 8%, about 2 to about 9 %, about 3 to about 8%, about 4 to about 7%, about 2 to about 5%, or about 6 to about 7% by weight. In a preferred embodiment, the co- polymer/enhancer formulation comprises about 12% laurocapram by weight. In another preferred embodiments, the co-polymer/enhancer formulation comprises about 2% laurocapram, by weight. In a another embodiment, the co-polymer/enhancer formulation comprises about <12%, <11%, <10%, <9%, <8%, <7%, <6%, <5%,<4%, <3%, <2%, or <1%, laurocapram by weight. It is contemplated that the amount of laurocapram can be selected to be a balance between a desired flux rate and negative side effects (e.g., irritation, toxicity).
The co-polymer/enhancer formulation can be used for topical delivery of a variety of small or large therapeutic agents not previously achieved using penetration enhancers including, but not limited to, large peptides and proteins greater than about 50 amino acids, (e.g., >53 amino acids, >60 amino acids, >70 amino acids), nucleic acids, compounds with unique
physicochemical structures and/or properties not considered amenable to passive transdermal or transmucosal delivery.
In one embodiment, hormones can include but not be limited to human or bovine growth hormone (hGH or bGH), or insulin-like growth factor 1 (IGF-1).
In certain embodiments, the co-polymer/enhancer formulation comprises a therapeutic agent at a concentration ranging from 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 0.1 mM to about 1.5 mM, about 0.5 mM to about 2 mM, or about 0.5 mM to about 1.5 mM, about 0.01 mM to about 30 mM, about 0.01 mM to about 20 mM, about 0.1 mM to about 15 mM, about 0.05 mM to about 20 mM, or about 0.05 mM to about 15 mM. Amounts of therapeutic agents incorporated into co-polymer/enhancer formulations disclosed herein can also be determined by those skilled in the art (e.g., based upon age, bioavailability of a therapeutic agent, etc.) such that the therapeutic agent is delivered to a subject in amounts that effect a therapeutic benefit to the subject.
In one embodiment the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation of this disclosure using any standard topical patch design or variations thereof, having in common the direct application (bio-interface) with the skin or mucosal surface. In a specific embodiment the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation comprising poloxamer 188 and propylene glycol, laurocapram and, optionally, one or more therapeutic agents.
The term "subject," as used herein, describes an organism, including mammals such as primates, to which treatment with the formulations according to the subject disclosure can be provided. Mammalian species that can benefit from the disclosed methods of treatment include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated
animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters.
In certain embodiments the co-polymer/enhancer formulation of this disclosure is administered to skin or mucosal surfaces including, but not limited to, cervix, vagina, anus, rectum, eye, ear, nose, thorax, vulva, larynx, and head and neck.
Embodiments of this disclosure allow for topical delivery of therapeutics across the full- thickness skin barrier including the keratinized apical layer of skin (stratum corneum), the epidermal cell layer, and the dermis, and/or mucosa. At least one embodiment allows for topical delivery of therapeutics across non-keratinized surface of skin and/or mucosa. At least one embodiment allows for topical delivery of therapeutics into, or across, multiple layers of cervical squamous epithelial cells. At least one embodiment allows for topical delivery of therapeutics to the basal keratinocytes of skin and/or mucosa.
At least one embodiment can be used as a non-invasive topical transdermal or transmucosal delivery system (or device) applied to normal skin or mucosal surfaces to obviate the need for subcutaneous injection of therapeutic compounds. A patch for topical transdermal delivery of a composition herein can include any suitable material (e.g., transdermal system, backings, liners, membranes and tapes, and the like) well known in the transdermal delivery art. Such materials are commercially available from various sources and known in the art. See for example, those available from 3M Drug Delivery Systems, St. Paul, MN.
Other aspects useful in application of this technology and embodiments herein are described in International Patent Application No. PCT/US2014/030259, incorporated by reference.
Formulations and Formulations for Topical Administration
The subject disclosure also provides for therapeutic or pharmaceutical formulations comprising the co-polymer/enhancer formulation in a form that can be combined with a pharmaceutically acceptable carrier. In a preferred embodiment the therapeutic or pharmaceutical formulation is solid at room temperature and transitions to a gel or liquid at desired physiological temperatures.
The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum oil such as mineral oil, vegetable oil such as peanut oil, soybean oil and sesame oil, animal oil or oil of synthetic origin.
Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The therapeutic formulation, if desired, can also contain minor amounts of wetting, emulsifying or pH buffering agents. These formulations can take the form of creams, foam, patches, lotions, drops, sprays, gel, oils, aerosol, powders, ointment, solutions, suspensions, emulsion and the like. The formulation can be formulated with traditional binders and carriers such as triglycerides. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such formulations contain a therapeutically effective amount of the therapeutic formulation, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
The subject disclosure also provides for the modification of the ingredient such that it is more stable once administered to a subject, i.e., once administered it has a longer time period of
effectiveness as compared to the unmodified form. Such modifications are well known to those of skill in the art, e.g., microencapsulation, etc.
The amount of the therapeutic or pharmaceutical formulation of this disclosure which is effective in the treatment of a particular disease, condition or disorder will depend on the route of administration and the seriousness of the disease, condition or disorder and should be decided according to the judgment of the practitioner and each patient's circumstances.
Further, at least one embodiment provides kits containing therapeutic compositions herein. Preferably, the formulations of this disclosure are stable in a wide range of temperatures below the desired melting temperature. In one embodiment the active therapeutic agents can be reconstituted by mixing pre-measured quantities of each component immediately prior to use. The kits can include a covering package material (e.g., plastic, foil, polymer material, etc.) suitable to protect the kit and its contents (e.g., active agent, patch, device) from degradation and contamination.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
EXAMPLES
Following are examples that illustrate procedures for practicing this disclosure. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.
EXAMPLE 1
There is a need for a convenient and affordable alternative to daily subcutaneous (sc) injections for a growing incidence and prevalence of childhood- and adult-onset human growth hormone (hGH) deficiency. hGH is also called somatotropin and growth hormone- 1 (GH- 1) to distinguish it from the related protein growth hormone-2 (GH-2). We sought to develop a convenient, non-invasive and affordable transdermal patch formulation capable of achieving passive delivery of large molecule drugs such as hGH and insulin for multiple days. We report a novel platform technology, a composition, applied to the transdermal delivery of hGH (22, 128 Da). This solution was lyophilized overnight. The lyophilized powder was reconstituted in an optimized formulation to create a stock solution. The formulation consisted of about 49% poloxamer 188, about 39% propylene glycol, and about 12% laurocapram (wt./wt./wt).
Formulations containing hGH at different concentrations were freshly prepared from the stock solution immediately prior to application as 50 μΐ^ gel to EpidermPT™ (EFT-300) tissue inserts, which are mitotically and metabolically active human skin equivalents (HSEs) when cultured in maintenance medium at 32°C. Formulations over the dose range of 0.0001- 1.0 mg/0.6 cm hGH were incubated at 32° C for 7-days. Equal volume of medium was sampled and replenished every 12 rs. hGH concentrations were measured using the Quantikine® ELISA kit (R&D Systems) as per manufacturer' s instructions. Steady-state hGH flux (Jss) was calculated using Pick' s first law. We observed a clear dose-response (FIG 1). We tested the feasibility of developing an effective extended- wear hGH patch capable of providing constant and consistent drug delivery to replace daily or weekly injections for therapy of growth hormone deficiency (GHD) in children and adults. Feasibility was demonstrated by using J„ from these in vitro
studies along with published pharmacokinetic (PK) data for hGH in humans to perform simulations using two different PK models as described in the figures below.
FIG 1: Passive transdermal delivery of human growth hormone (hGH, somatropin) continuously over 7-days using an embodiment of a formulation. Notably, hGH has a molecular weight (MW) of 22,124 Da, which is -3.8X larger than human insulin (5,808 Da). The flux of hGH exhibits a dose-response in the range of 0.0005-0.5 mg/0.6 cm over the course of a 7-day study in a highly robust human skin equivalent model (HSE). MatTek's EpiDermFT™ (EFT- 300) tissue inserts are barrier-enhanced (i.e. stratum corneum 3X the thickness of normal human skin), full-thickness, metabolically and mitotically active HSEs that remain viable for at least 7- days when maintained in serum-containing medium in a tissue culture incubator at 32° C (skin temperature). Continuous and consistent transdermal delivery was observed, as indicated by the linear accumulation plots (same amount of delivery each day characteristic of constant steady- state flux rates). Saturation was observed at an administered dose of 0.3 mg/0.6 cm , since the accumulation curves for the 0.3 mg/0.6 cm and 0.5 mg/0.6 cm doses are superimposable, although the true saturating dose may be between 0.2-0.3 mg/0.6 cm .
FIG 2: Table showing extrapolated serum hGH levels in humans as a determinant of hGH patch dimensions or surface area (cm ) and time (1-7 days). Extrapolated serum hGH levels are from flux observed for a 0.5 mg/0.6 cm saturating dose of an embodiment of an hGH formulation in EpiDermFT™ (EFT-300) accumulation dose-response studies using 2.5 ml of maintenance medium (FIG. 1), extrapolated to 5L adult blood volume.
Shadowing (light blue) in upper left quadrant corresponds to patch size and time required to remain in the normal range of random serum levels specific for Men (< 5 ng/mL or 226 pmol/L).
Shadowing (intermediate blue) in middle diagonal cells corresponds to additional patch size and time required to remain in normal range of random serum levels specific for Women: < 10 ng/mL (452 pmol/L).
Shadowing (darker blue) in right lower quadrant corresponds to patch size and time required to remain in normal range of random serum levels specific for Children 0-20 ng/mL (0- 904 pmol/L).
Shadowing (darkest blue) in right lower quadrant corresponds to patch size and time required to remain in normal range of random serum levels specific for Newborns: 5-40 ng/mL (226-1808 pmol/L).
The extrapolated serum hGH levels are derived from an in vitro tissue model that only assesses transdermal transport as a measure of accumulation of permeant as a function of time to demonstrate constant and consistent delivery (curve should be linear; slope defines dose- response). The values reflect a model of 100% drug metabolism/elimination each day since medium is removed and replaced with fresh medium every 24 hours for the duration of the 7-day study; this methodology is a requirement for creating "in sink" conditions for calculating steady- state flux from Fick's 1st Law of Diffusion.
FIG 3: Table showing extrapolated maximum hGH patch size carrying an equivalent absolute amount of hGH (upper limit) compared to weekly therapy with Genotropin® for GHD by injection.
Adult (age > 18): Assume dosing for average adult male of 70 kg
Pediatric (age < 18): Assume dosing for average 2-18 year old male of 30-70 kg, respectively.
Pediatric: maximum patch size between 3 x 3 cm (7.50 mg) and 4 x 4 cm (13.3 mg) can achieve normal range of random serum levels for a week.
Adults (Weighted): maximum patch size between 2 x 2 cm (3.33 mg) and 3 x 3 cm (7.5 mg) can achieve normal range of random serum levels for Adults (Men and Women). Adults (Unweighted): maximum patch size between l x l cm (0.83 mg) and 2 x 2 cm (3.33 mg) can achieve normal range of random serum levels for Adults (Men and Women) for a week.
FIG 4: Remarkably, the complex structure of skin morphology has not been fully elucidated. It was first proposed by Wertz, Swartzendruber, Madison and Downing (1983) that the fat layer of the stratum corneum extracellular space is composed of saturated long-chain ceramides, free fatty acids and cholesterol in a 1: 1: 1 molar ratio. Norlen (2001) proposed that the fat layer exists as a single and coherent gel phase. It was not until 2012 that Norlen' s team reported the use of very high magnification cryoelectron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation to determine the atomic structure of the stratum corneum lipid matrix in situ, in its near-native state. The structure is composed of stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety; the free fatty acid is associated with the long-chain fatty acid moiety of the ceramide.
FIG 5-7: Tables showing the results of a pharmacokinetic (PK) simulation model to demonstrate that hGH patch embodiments of reasonable patch dimensions, total patch dose, and maximum duration of action can achieve upper end of the range of normal random serum hGH levels within 12 hours after application for each age/gender group: a) FIG. 5 for men (5 ng/mL); b) FIG. 6 for women (10 ng/mL); and c) FIG.7 for children (20 ng/mL). Setting the target levels at the upper end of the normal range is intended to enhance the robustness of the proof-of-
concept PK simulations. Results are based on hGH steady-state flux observed for embodiments of hGH formulations over the dose range of 0.005-0.5 mg/0.6 cm in EpiDermFT™ (EFT-300) accumulation dose-response studies using 2.5 ml of maintenance medium (FIG 1). Pharmacokinetic calculations are based on non-compartmental analysis (NCA) when the elimination process follows first-order kinetics, as most of drugs do when they are used at their therapeutic doses (Foye's Principles of Medicinal Chemistry). The ideal simulation model of transdermal patch delivery would require use of published PK data from continuous subcutaneous infusion. We used the continuous intravenous infusion analysis function of the PKSolver 2.0 add-in PK software for Excel to simulate a NCA extravascular model using the formulas in FIG. 9.
FIG 8: Table showing comparison by age/gender of simulated hGH patch PK values. Notably, the values corresponding to the columns highlighted in red in FIG 5-7 indicate that patch dimensions are below 8 x 8 cm (upper limit of convenient size) and below 10 x 10 cm (upper limit of usage), and that the duration of action is up to 12-weeks. The latter supports the feasibility of developing an effective extended- wear hGH patch by a wide margin, certainly a 1-2 week patch that is the most practical life-span for extended-wear use.
FIG 9: Equations for pharmacokinetic modeling to predict patch size and duration of action. Although there is no steady-state level for serum hGH in normal individuals due to its wide fluctuation throughout the day, there is a range for random serum hGH measurements according to age/gender. The steady- state constant (Css) in equation 3 is utilized to define a hypothetical target serum steady-state level that can be achieved by constant and consistent delivery by an hGH patch in the setting of GHD.
Passive transdermal delivery of large molecule drugs (e.g., IGF-1, hGH) mediated by embodiments of formulations as disclosed herein is hypothesized to occur by the synergistic effects of its components (thermosensitive polymer, dermoadhesive agent, and a chemical penetration enhancer)— all of which contribute chemical penetration enhancing properties. The inclusion of a non-ionic amphipathic triblock copolymer (poloxamer 188) suggests the possibility of the formation of "pores" in which the lipophilic polyoxypropylene core interacts with the surrounding structure of the extracellular lipid matrix of the stratum corneum (as determined above), while the hydrophilic moieties of the flanking polyoxyethylene arms are partitioned in the center of the pore. The sizes of such putative pores might differ over a range in a stochastic distribution. The size distribution of such putative pores might follow a bell-shaped curve, such that small molecule drugs "pass through" all of the pores, intermediate-sized drugs (e.g. insulin) pass through the majority of pores constituting the pores with dimensions distributed across the central portion of the bell-shaped curve, and large drugs (e.g. hGH or larger) only pass through a smaller number of large pores at the upper size distribution of the bell-shaped curve. If this is the case, one strategy for increasing the flux of large molecules is to shift the bell-shaped curve towards the upper size distribution (i.e. "shift curve to the right").
EQUIVALENTS
The functions of several elements may, in alternative embodiments, be carried out by fewer elements, or a single element. Similarly, in some embodiments, any functional element may perform fewer, or different, operations than those described with respect to the illustrated embodiment.
While certain embodiments according to this disclosure have been described, this disclosure is not limited to just the described embodiments. Various changes and/or
modifications can be made to any of the described embodiments without departing from the spirit or scope of this disclosure. Also, various combinations of elements, steps, features, and/or aspects of the described embodiments are possible and contemplated even if such combinations are not expressly identified herein.
INCORPORATION BY REFERENCE
The entire contents of all patents, published patent applications, and other references cited herein are hereby expressly incorporated herein in their entireties by reference.
Claims
1. A composition comprising propylene glycol (PG), poloxamer 188 (P188), laurocapram (LP) and hGH.
2. The composition of claim 1, wherein the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 49:39: 12 (by weight).
3. The composition of claim 1, wherein the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 55:43:2 (by weight)
4. The composition of claim 1, wherein the ratio of propylene glycol (PG), poloxamer 188 (PI 88), and laurocapram (LP) is 56:44:0 (by weight)
5. The composition of claim 2, wherein the hGH is lyophilized hGH.
6. The composition of claim 2, wherein the hGH is present in a range of 0.1- 10 mg/50 μΙ_.
7. The composition of claim 1, further comprising IGF-1.
8. The composition of claim 5, wherein the IGF-1 is present in a range of 0.1-10 mg/50 μΙ_.
9. The composition of claim 1 that is devoid of azone.
10. A method of promoting growth in a subject comprising administration of the composition of claim 1 to the subject.
11. The method of claim 10, wherein the administration is topically.
12. The method of claim 11, wherein the hGH is administered at a range of 0.1-10 mg/50 μΙ_/οιη2.
13. The method of claim 11, wherein the administration of hGH is via a patch attached to the subject for up to 168 hours.
14. The method of claim 11, wherein the administration of hGH is via a patch attached to the subject for up to 24 hours.
15. The method of claim 11, wherein the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 24 hours after initial administration.
16. The method of claim 11, wherein the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 48 hours after initial administration.
17. The method of claim 11, wherein the permeation of hGH through EpiDermFT™ is at least 1 ng/cm /hr 72 hours after initial administration.
18. The method of claim 11, wherein the composition of claim 1 is in solid form.
19. The method of claim 11, wherein the composition of claim 1 is in gel form.
20. The method of claim 11, wherein the hGH is administered continuously and consistently over at least 7 days.
21. The method of claim 11, wherein the hGH is administered continuously and consistently over at least 3 days.
22. The method of claim 11, wherein the hGH is administered continuously and consistently over at least 24 hours.
23. The method of claim 11, wherein the hGH is administered such that serum hGH accumulation of at least 5-200 ng/niL is achieved over 24-168 consecutive hours.
24. The method of claim 11, wherein the hGH is administered such that serum hGH accumulation of at least 10-150 ng/niL is achieved over 24-168 consecutive hours.
25. The method of claim 11, wherein the hGH is administered such that serum hGH accumulation of at least 5-100 ng/niL is achieved over 24-168 consecutive hours.
26. The method of claim 11, wherein the hGH is administered such that serum hGH accumulation of at least 10-125 ng/niL is achieved over 24-168 consecutive hours.
27. The method of claim 11, wherein the hGH is administered at a dosage of 0.5-100 mg/wk.
28. The method of claim 11, wherein the hGH is administered at a dosage of 1-50 mg/wk.
29. The method of claim 11, wherein the hGH is administered at a dosage of 0.5-15 mg/wk.
30. A kit comprising a composition of claim 1 and a device for topical administration of the composition of claim 1.
31. The kit of claim 30, wherein the device is a patch.
32. The kit of claim 30, wherein the composition of claim 1 is in solid form.
33. The kit of claim 30, wherein the composition of claim 1 is in gel form
34. The kit of claim 31, wherein the patch further comprises an adhesive material.
35. The kit of claim 31, further comprising a cover material to protect the composition of claim 1 during shipping and storage.
36. The kit of claim 31, wherein the patch is no larger than 10 x 10 (cm x cm).
37. A device comprising a composition of claim 1 and a patch.
38. The device of claim 37, wherein the patch comprises a backing.
39. The device of claim 37, wherein the patch comprises an adhesive.
40. The device of claim 37, wherein the patch comprises a laminate coated with the composition of claim 1.
41. The device of claim 37, wherein the patch comprises a release liner.
42. The device of claim 37, wherein the patch comprises the composition of claim 1 in solid form.
43. The device of claim 37, wherein the patch comprises the composition of claim 1 in gel form.
44. The device of claim 37, wherein the patch is no larger than 10 x 10 (cm x cm).
45. The device of claim 37, wherein the patch is 1 x 1 (cm x cm).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462053122P | 2014-09-20 | 2014-09-20 | |
US62/053,122 | 2014-09-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016044750A1 true WO2016044750A1 (en) | 2016-03-24 |
Family
ID=55533917
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/050986 WO2016044750A1 (en) | 2014-09-20 | 2015-09-18 | Topical formulations of growth factors |
Country Status (2)
Country | Link |
---|---|
TW (1) | TW201628643A (en) |
WO (1) | WO2016044750A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004039428A2 (en) * | 2002-10-31 | 2004-05-13 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized medications |
US20040208916A1 (en) * | 2003-04-15 | 2004-10-21 | Nick Abbott | Patch for the transdermal administration of beneficial substances |
US20070141132A1 (en) * | 2005-11-02 | 2007-06-21 | Hagit Sacks | Human growth hormone patch formulations |
US20080208107A1 (en) * | 2002-03-11 | 2008-08-28 | Mcrae Stuart | Transdermal porator and patch system and method for using same |
WO2014145484A2 (en) * | 2013-03-15 | 2014-09-18 | Prometheon Pharma, Llc | Devices, systems, and methods for transdermal delivery of compounds |
-
2015
- 2015-09-18 WO PCT/US2015/050986 patent/WO2016044750A1/en active Application Filing
- 2015-09-18 TW TW104130908A patent/TW201628643A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080208107A1 (en) * | 2002-03-11 | 2008-08-28 | Mcrae Stuart | Transdermal porator and patch system and method for using same |
WO2004039428A2 (en) * | 2002-10-31 | 2004-05-13 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized medications |
US20040208916A1 (en) * | 2003-04-15 | 2004-10-21 | Nick Abbott | Patch for the transdermal administration of beneficial substances |
US20070141132A1 (en) * | 2005-11-02 | 2007-06-21 | Hagit Sacks | Human growth hormone patch formulations |
WO2014145484A2 (en) * | 2013-03-15 | 2014-09-18 | Prometheon Pharma, Llc | Devices, systems, and methods for transdermal delivery of compounds |
Also Published As
Publication number | Publication date |
---|---|
TW201628643A (en) | 2016-08-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5020061B2 (en) | Transdermal preparation | |
CA2633489C (en) | Compositions and methods for treating dermatological conditions | |
US20130022564A1 (en) | Compositions and methods for dermally treating infections | |
FI115034B (en) | Process for preparing a non-recrystallizable estradiol-containing patch | |
KR100445449B1 (en) | Skin Permeation Enhancer Compositions Using Acyl Lactylates | |
US8354121B2 (en) | Tape preparation | |
US5891461A (en) | Transdermal administration of olanzapine | |
EP2123274B1 (en) | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same | |
US20100267678A1 (en) | Flux-enabling compositions and methods for dermal delivery of drugs | |
JPH09505279A (en) | Monoglyceride / lactate permeation enhancer for oxybutynin | |
MX2011004454A (en) | Topical composition comprising a combination of at least two penetration enhancing agents. | |
CA2633472A1 (en) | Flux-enabling compositions and methods for dermal delivery of drugs | |
CN104797252B (en) | Alleviate the veterinary methods that noise is detested | |
JP2020511523A (en) | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene | |
JPH04338325A (en) | Composition that has reinforced permeability | |
JPH0667835B2 (en) | Pharmaceutical composition | |
El-Tokhy et al. | Transdermal delivery of second-generation antipsychotics for management of schizophrenia; disease overview, conventional and nanobased drug delivery systems | |
WO2016080533A1 (en) | Percutaneous absorption agent | |
WO2016044750A1 (en) | Topical formulations of growth factors | |
AU2016362979A1 (en) | Systems and methods for transdermal drug delivery | |
WO2017006974A1 (en) | Transdermal-absorption-type patch | |
CN115989025A (en) | Patch for alleviating or treating symptoms of neurodegenerative disease | |
US20080139513A1 (en) | Transdermal deliver of active agents | |
TW201636045A (en) | Compositions, methods of promoting or enhancing local hair fullness and thickness, or hair growth in a subject, kits and devices comprising such compositions | |
EP4338740A1 (en) | A transdermal patch for promoting or accelerating myelination and/or remyelination |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15842630 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15842630 Country of ref document: EP Kind code of ref document: A1 |