WO2005107754A2 - Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds - Google Patents
Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds Download PDFInfo
- Publication number
- WO2005107754A2 WO2005107754A2 PCT/EP2005/051401 EP2005051401W WO2005107754A2 WO 2005107754 A2 WO2005107754 A2 WO 2005107754A2 EP 2005051401 W EP2005051401 W EP 2005051401W WO 2005107754 A2 WO2005107754 A2 WO 2005107754A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- iontophoretic
- use according
- pharmaceutically acceptable
- piperazinyl
- Prior art date
Links
- KPGBJPZISGYNSG-UHFFFAOYSA-N 3-piperazin-1-yl-1,3-benzoxazol-2-one Chemical class O=C1OC=2C=CC=CC=2N1N1CCNCC1 KPGBJPZISGYNSG-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 229940002612 prodrug Drugs 0.000 claims abstract description 16
- 239000000651 prodrug Substances 0.000 claims abstract description 16
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 10
- 208000005793 Restless legs syndrome Diseases 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000003792 electrolyte Substances 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- -1 3-pyridylmethyl Chemical group 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- YVPUUUDAZYFFQT-UHFFFAOYSA-N 7-(4-methylpiperazin-1-yl)-3h-1,3-benzoxazol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC2=C1OC(=O)N2 YVPUUUDAZYFFQT-UHFFFAOYSA-N 0.000 claims description 15
- 239000012528 membrane Substances 0.000 claims description 13
- 230000037317 transdermal delivery Effects 0.000 claims description 12
- VADWZGDBNPPHCY-UHFFFAOYSA-N 7-(4-benzylpiperazin-1-yl)-3h-1,3-benzoxazol-2-one Chemical compound C=12OC(=O)NC2=CC=CC=1N(CC1)CCN1CC1=CC=CC=C1 VADWZGDBNPPHCY-UHFFFAOYSA-N 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- PYAJIYSYVSUDBJ-UHFFFAOYSA-N 7-(4-benzylpiperazin-1-yl)-3h-1,3-benzoxazol-3-ium-2-one;methanesulfonate Chemical compound CS(O)(=O)=O.C=12OC(=O)NC2=CC=CC=1N(CC1)CCN1CC1=CC=CC=C1 PYAJIYSYVSUDBJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 238000004891 communication Methods 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- 230000001965 increasing effect Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000003860 storage Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
- 150000003254 radicals Chemical class 0.000 claims 1
- 210000003491 skin Anatomy 0.000 description 35
- 239000003814 drug Substances 0.000 description 34
- 229940079593 drug Drugs 0.000 description 32
- 230000004907 flux Effects 0.000 description 20
- 238000009792 diffusion process Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 210000000434 stratum corneum Anatomy 0.000 description 11
- 230000032258 transport Effects 0.000 description 11
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000012377 drug delivery Methods 0.000 description 8
- 239000007979 citrate buffer Substances 0.000 description 7
- NQRIKTDKFHAOKC-UHFFFAOYSA-N 7-(4-methylpiperazin-1-yl)-3h-1,3-benzoxazol-2-one;hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=CC=CC2=C1OC(=O)N2 NQRIKTDKFHAOKC-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910021607 Silver chloride Inorganic materials 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002716 delivery method Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000003939 Membrane transport proteins Human genes 0.000 description 2
- 108090000301 Membrane transport proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000027520 Somatoform disease Diseases 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000000017 hydrogel Substances 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
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000009061 membrane transport Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 208000027753 pain disease Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 210000004003 subcutaneous fat Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229940100640 transdermal system Drugs 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- WJTCHBVEUFDSIK-NWDGAFQWSA-N (2r,5s)-1-benzyl-2,5-dimethylpiperazine Chemical compound C[C@@H]1CN[C@@H](C)CN1CC1=CC=CC=C1 WJTCHBVEUFDSIK-NWDGAFQWSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- IKYKEVDKGZYRMQ-PDBXOOCHSA-N (9Z,12Z,15Z)-octadecatrien-1-ol Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCO IKYKEVDKGZYRMQ-PDBXOOCHSA-N 0.000 description 1
- 125000006602 (C1-C3) alkylsulfonylamino group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 description 1
- 0 *N(CC1)CCN1c1cccc(N2)c1OC2=O Chemical compound *N(CC1)CCN1c1cccc(N2)c1OC2=O 0.000 description 1
- MXDYUONTWJFUOK-UHFFFAOYSA-N 1-(azepan-1-yl)dodecan-1-one Chemical compound CCCCCCCCCCCC(=O)N1CCCCCC1 MXDYUONTWJFUOK-UHFFFAOYSA-N 0.000 description 1
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- ZZNDQCACFUJAKJ-UHFFFAOYSA-N 1-phenyltridecan-1-one Chemical compound CCCCCCCCCCCCC(=O)C1=CC=CC=C1 ZZNDQCACFUJAKJ-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 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
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- IBYKYYZAEVHVLS-UHFFFAOYSA-N Hexamethylenglykol-dipalmitat Natural products CCCCCCCCCCCCCCCC(=O)OCCCCCCOC(=O)CCCCCCCCCCCCCCC IBYKYYZAEVHVLS-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- MMOXZBCLCQITDF-UHFFFAOYSA-N N,N-diethyl-m-toluamide Chemical compound CCN(CC)C(=O)C1=CC=CC(C)=C1 MMOXZBCLCQITDF-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033372 Pain and discomfort Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 description 1
- 229960003338 crotamiton Drugs 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940068939 glyceryl monolaurate Drugs 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940116335 lauramide Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- KRTSDMXIXPKRQR-AATRIKPKSA-N monocrotophos Chemical compound CNC(=O)\C=C(/C)OP(=O)(OC)OC KRTSDMXIXPKRQR-AATRIKPKSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YYZUSRORWSJGET-UHFFFAOYSA-N octanoic acid ethyl ester Natural products CCCCCCCC(=O)OCC YYZUSRORWSJGET-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229920005573 silicon-containing polymer Polymers 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- KLBOFRLEHJAXIU-UHFFFAOYSA-N tributylazanium;chloride Chemical compound Cl.CCCCN(CCCC)CCCC KLBOFRLEHJAXIU-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0432—Anode and cathode
- A61N1/044—Shape of the electrode
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0432—Anode and cathode
- A61N1/0436—Material of the electrode
Definitions
- the present invention relates to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula
- R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo- ⁇ Cs-rJ-alkylmethyl optionally substituted with one or more fluorine atoms or benzyl, 2-pyr ⁇ dylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, optionally substituted with one or more substituents from the group consisting of halogen, hydroxyl, cya ⁇ o, amino, mono- or di-C ⁇ .
- the invention is related to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (l) wherein R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo-(C 3 .7)-alkylmethyl optionally substituted with one or more fluorine atoms or benzyl, 2-pyridylmethyl, 3- pyridylmethyl or 4-pyridylmethyl, which groups may be substituted with one or more substituents from the group consisting of halogen, hydroxyl, cyano, amino, mono - or di-C ⁇ -3-alkyIamino, CF 3 , OCF 3 , SCF 3> C ⁇ - 4 -alkyl, C ⁇ - 3 -alkylsulfonyl amino.
- R is methyl, ethyl, ethyl substituted with one or more fluorine atoms, or cyclo-(C 3 .7)-alkyl
- the invention is related to transdermal iontophoretic delivery of pharmaceutical compounds of the general formula (I) wherein R is methyl or benzyl optionally substituted with 1-3 substituents from the group hydroxyl and halogen.
- R is methyl or benzyl optionally substituted with 1-3 substituents from the group hydroxyl and halogen.
- Most preferred compounds in the present invention are compounds wherein R is methyl or benzyl.
- the invention is related to the use of at least one compound of the general formula I as defined above, or mixtures thereof, for the manufacture of an iontophoretic device for the treatment of pain disorders, especially restless leg syndrome and CNS disorders, especially Parkinson's disease.
- the present invention also relates to the use of compounds of the general formula (1) for the preparation of (a) a solution for use in a device for transdermal administration by iontophoresis or kits containing cartridges which contain the compound ready for use in said device, (b) a device suitable for transdermal administration by iontophoresis, wherein said transdermal device has a reservoir containing the compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte, which device can be used in a meth od for controlling the delivery profile of pharmaceutical compounds of the general formula (I) and compositions thereof, and the use of said controlled delivery profiles in the treatment of pain disorders, especially restless leg syndrome and CNS disorders , especially Parkinson's disease.
- transdermal delivery may provide an advantageous method of delivering that compound. This is the case, for example, for Parkinson's disease, where there is a need to administer medication to patients who are sleeping, comatose or anaesthetized. Further, there is growing evidence that continuous dopamine stimulation avoids the development of problems associated with intermittent dosing and where continuous drug delivery has been shown to decrease the incidence of "off' periods (P. Niall and W.H. Oertel, Congress Report of 7 th International Congress of Parkinson's Disease and Movement Disorders, Miami, Florida, November 10-14, 2002). In general, transdermal administration also has its problems, since it is not always easy to get drugs to cross the skin.
- Iontophoretic transdermal delivery relates to introducing ions or soluble salts of pharmaceutically active compounds into tissues of the body under the influence of an applied electric field.
- iontophoretic transdermal delivery may provide an advantageous method of delivering that compound.
- Further iontophoretic transdermal delivery has the major advantage that the administered amount can be regulated precisely and can be used to easily titrate patients up to a certain level of administration over a period of up to several weeks.
- iontophoretic methods appear limited as the drug delivery profile of a particular method depends heavily on the particular drug administered. Although a lot of experiments have been done with the iontophoretic delivery of various active substances, specific information allowing a person skilled in the art to tailor the delivery profile of a specific drug is not always available. As it has appeared that it is very difficult to develop transdermal patches with an acceptable size for compounds with the general formula (I), there is a need for an iontophoretic delivery method for said compounds that allows variable rate delivery of said compounds tailored to a specific treatment.
- the present invention relates to iontophoretic transdermal technology that provides for the delivery of the compounds of the general formula (1) and compositions thereof through human skin.
- compositions suitable for use in a device for transdermal administration by iontophoresis wherein said composition comprises the compound of formula I and optionally a pharmaceutically acceptable electrolyte.
- the composition manufactured is suitable for use in a device for transdermal administration by iontophoresis for the treatment of Parkinson's disease and restless leg syndrome.
- an object of the subject invention is to provide the use of the compounds of the general formula (I) and pharmaceutically acceptable salts and prodrugs thereof for the manufacture of a device suitable for transdermal administration by iontophoresis for the treatment of Parkinson's disease and restless leg syndrome, wherein said transdermal device has a reservoir containing the compound of formula I or a composition thereof and optionally a pharmaceutically acceptable electrolyte.
- this device is applied to the skin of a living body and electrical current is caused to flow through the skin, the compounds of the general formula (I) and pharmaceutically acceptable salts and prodrugs thereof are iontophoretically delivered through the skin.
- Another object of the invention is to provide an iontophoretic system for the delivery of the compounds of the general formula (I) and compositions thereof through the skin, wherein the system includes a transdermal delivery device attachable to the skin, the device including a first electrode and a second electrode, and a reservoir for containing a pharmaceutically acceptable electrolyte and the compounds of the general formula (I) and compositions thereof in electrical communication with the first and second electrodes; and an electrical power source connected to the first and second electrodes; wherein the reservoir contains the compounds of the general formula (I) and compositions thereof and optionally a pharmaceutically acceptable electrolyte.
- kits comprising the iontophoretic system combined with one or more cartridges comprising the compound of the general formula (I) or a kit containing one or more cartridges comprising the compound of the general formula (I) to be used for refilling the reservoir of the iontophoretic system.
- the amount of cartridges in the kits is preferably between 2 and 91, more preferably between 7 and 28 and most preferably between 14 and 28.
- the skin through which the delivery has to take place is animal skin, for example human skin.
- Figure 1 plots the flux of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazoIone across human stratum corneum as a function of the active compound concentration versus time.
- Figure 2 plots the flux of 7-(4-methyl-1-piperazinyl) ⁇ 2(3H)-benzoxazolone across human stratum corneum as a function of the electrolyte concentration versus time.
- Figure 3 plots the flux of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone across human stratum corneum as a function of active compound concentration versus time in the presence of 4 g/l NaCI.
- Figure 4 plots the flux of 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate across hairless rat skin as a function of active compound concentration versus time in the presence of 30 millimolar ( M) NaCI.
- Figure 5 plots the flux of 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate across hairless rat skin as a function of the current density in the presence of 30 mM NaCI.
- Figure 6 depicts a schematic presen tation of the iontophoretic set-up used for the tests with 7-(4-methyl-1-piperazi ⁇ yl)-2(3H)-be ⁇ zoxazolone.
- An iontophoretic transdermal delivery system may comprise a first (donor) electrode containing an electrolytically available active compound within a suitable vehicle or carrier and optionally a penetration enhancer, a counter electrode and a power source, the first and second electrodes each being in electrically conductive communication with the power source.
- the first and second electrodes can be adapted for spaced apart physical contact with the skin whereby, in response to a current provided by the power source through the electrodes, a therapeutic amount of tine active compound is administered through the skin to a patient.
- the iontophoretic delivery (dose and profile) by which a particular active compound of the general formula (I) is administered to a patient may be controlled by suitable combination of the initial concen tration of the drug and electrolyte and the applied current (constant variable) in the iontophoretic system.
- the combination of current density (constant/variable) and the initial amount of electrolyte may lead to an iontophoretic device with a very reasonable size that allows the drug delivery profile to be adjusted.
- the ability to tailor the drug delivery profile in iontophoresis may provide increased control of the drug's effects on the user. Additionally, the ability to tailor drug delivery profile in iontophoresis may make the iontophoretic delivery of the compounds of formula (I) a more practically effective mode of administration.
- permeation profile means a plot of the flux of the active compound versus time for a given delivery period.
- the term "cartridge” means a container containing the active compound that is used for storage of the active compound before it is delivered by the device.
- a cartridge can be selected for its user-friendliness. Any means for packaging the active compound separately from the iontophoretic device may be considered a "cartridge.”
- detachable and replaceable reservoirs may be used to deliver active compound to the device.
- the electrolytes used in the methods of the present invention may include u ⁇ ivalent or divalent ions, for example.
- electrolytes used in our method include all Ci" donating compounds that are water soluble, such as HCI, NaCI, KCI, CaCI 2 , MgCI 2 , triethylammonium chloride and tributylammonium chloride.
- the electrolyte comprises NaCI.
- the required amount of electrolyte may depend on factors such as the transport area of the devi ce, the volume of the vehicle or earner, the concentration of the active compound, the current density, the duration of the iontophoresis and the efficiency of the transport.
- the electrolyte may be present in amounts of, for example, at least about 0.005 mmole, at least about 0.01 mmole, or at least about 0.05 mmole.
- the electrolyte may be present in amounts of, for example, not more than about 2 mmole, not more than about 1.0 mmole, or not more than about 0.3 mmole.
- the initial amount of electrolyte may be expressed as a concentration of, for example, at least about 0.005 M, at least about 0.01 M, or at least about 0.03 M.
- the initial amount of electrolyte may be expressed as a concentration of, for example, not more than about 2 M, not more than about 0.2 M, or not more than about 0.2 M.
- Prodrugs of the compounds mentioned above are within the scope of the present invention.
- Prodrugs are therapeutic agents which are inactive per se but are transformed into one or more active metabolites.
- Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are n ot limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F. D. King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P.
- Pro-drugs i.e., compounds which when administered to humans by any known route, are metabolized to compounds having formula (I), belong to the invention. In particular this relates to compounds with primary or secondary amino or hydroxy groups.
- Such compounds can be reacted with organic acids to yield compounds having formula (I) wherein an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl - methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
- an additional group is present which is easily removed after administration, for instance, but not limited to amidine, enamine, a Mannich base, a hydroxyl - methylene derivative, an 0-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone.
- the compounds of formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. Salts of prodrugs also fall within the scope of this invention.
- pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well -known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
- the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
- Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isothionate), lactate, maleate, mesylate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene
- acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succ inic acid and citric acid.
- Active drugs that may be administered by the method described herein include, but are not limited to, compounds such as 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt (SLV308, see Drugs of the Futu re 2001, 26, 128-32) and 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate salt (SLV318).
- compounds such as 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt (SLV308, see Drugs of the Futu re 2001, 26, 128-32) and 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate salt (SLV318).
- 7-(4-methyl-1-piperazinyl)-2(3H)- benzoxazolone or its monohydrochloride salt and 7- (4-benzyl-1-piperazinyI)-2(3H benzoxazolone or its monomesylate salt are suitable for the treatment of restless leg syndrome or Parkinson's disease.
- the pH of the solution in the drug reservoir may be at least about 3.0 in some embodiments. In other embodiments, the pH may be less than or equal to about 7.5. In still other embodiments, the pH may range from about 4.0 to about 6.5.
- the pH can be maintained on a constant level by means of a buffer such as a citrate buffer or a phosphate buffer.
- a useful pH ranges from about 5.0 to about 6.0. Another possible pH for said compound is about 5.5.
- the pH may range, for example, from about 3.5 to about 6.0. Another useful pH for said compound is about 4.0.
- the current may be caused to flow by applying a constant or variable, such as pulsed, or alternating voltage/current.
- the current may be caused to increase during the delivery period in order to titrate an increasing concentration of the compound of formula (I).
- the voltage charged in the current application step is selected in the range of voltage that does not injure the skin of a living body and that does not disadvantage the rate of the transdermal absorption of the active compound.
- the voltage can be, for example, at least about 0.1 V, or at least about 0.5 V, or at least about 1 V.
- the voltage also can be, for example, less than about 40 V, or less than about 20 V, or less than about 10 V.
- the pulsed or alternating voltage may have a frequency of, for example, at least about 0.01 Hz, or at least about 100 Hz, or at least about 5 kHz.
- the pulsed or alternating voltage may have a frequency of, for example, no more than about 200 kHz, or no more than about 100 kHz, or no more than about 80 kHz.
- the pulsed or alternating voltage may use substantially any type of waveform shape, including for example, sine, square, triangular, sawtooth, rectangular, etc.
- the pulsed or alternating voltage may be applied on a duty cycle less than 100%.
- the current density can be, for example, at least about 0.001 mA cm 2 , or at least about 0.005 mA cm 2 , or at least about 0.025 mA/cm 2 .
- the current density also can be, for example, not more than about 1.0 mA cm 2 , not more than about 0.8 mA/cm 2 or not more than about 0.5 mA cm 2 .
- the drug reservoir contains the drug and optional electrolyte with, as the vehicle or carrier, either an aqueous solution or a (hydro)gel.
- the reservoir gel may be comprised of water soluble polymers or hyd rogels. In principle any gel can be used. Gels can be selected so that they do not adversely affect the skin (corrosion and irritation).
- Gels may exhibit suitable properties, such as good skin contact (adhesiveness) and electroconductive property.
- suitable properties such as good skin contact (adhesiveness) and electroconductive property.
- No ⁇ -limiting examples include agar, agarose, polyvinyl alcohol, or crosslinked hydrogels, such as Hydroxypropylmethylcellulose (HPMC), Methylcellulose (MC), Hydoxyethylcellulose (HEC), Carboxymethylcellulose (CMC) and Polyvinylpyrrolidone (PVP) and Polyvinyl Acetate Phthalate (PVAP).
- HPMC Hydroxypropylmethylcellulose
- MC Methylcellulose
- HEC Hydoxyethylcellulose
- CMC Carboxymethylcellulose
- PVAP Polyvinylpyrrolidone
- PVAP Polyvinyl Acetate Phthalate
- Suitable skin penetration enhancers include those well known in the art, and for example, include C 2 -C 4 alcohols such as ethanol and isopropanol; surfactants, e.g., anionic surfactants such as salts of fatty acids of 5 to 30 carbon a oms, e.g. sodium lauryl sulphate and other sulphate salts of fatty acids, cationic surfactants such as alkylamines of 8 to 22 carbon atoms, e.g.
- oleylamine, and nonionic surfactants such as polysorbates and polyoxamers
- aliphatic monohydric alcohols of 8 to 22 carbon atoms such as decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, linolenyl alcohol and oleyl alcohol
- fatty acids of 5 to 30 carbon atoms such as oleic acid, stearic acid, linoleic acid, palmitic acid, myristic acid, lauric acid and capric acid and their esters such as ethyl caprylate, isopropyl myristate, methyl laurate, hexamethylene palmitate, glyceryl monolaurate, polypropylene glycol monolaurate and polyethylene glycol monolaurate
- alkyl methyl sulfoxides such as decyl methyl sulfoxide and dimethyl sulfoxide
- the carrier or vehicle i s separated from the skin by a membrane.
- This membrane may be chosen, for example, to have a low resistance against the electric current, and/or to avoid substantially raising the barrier against the transport of the active compound, and/or to contain the carrier within the device during storage and transport.
- a low resistance against the electronic cu ent may be defined in one embodiment as 20% of the resistance of the skin.
- the barrier against transport of the active compound is not substantially raised by the membrane when the flux of active compound in the membrane containing device is, for example, more than 75% compared with the device not containing a membrane.
- membranes that can be used are e.g., the membranes having low electrical resistance as disclosed in D.F. Stamiatialis et al., J.
- Controlled Release 2002, 81, 335-345 such a the membranes CT-10 kDA, CT-20 kDA, PES-30 kDA and PSf-100 kDA of Sartorius, Dialysis -5 kDA of Diachema, CA-10 kDa, CA-25 kDa, CA-50 kD and CA-100 kDa of Amika and NF-PES-10 and NF-CA-30 of Nadir Filtration.
- the iontophoretic systems used to practice the subject invention may include devices and/or components selected from a wide variety of commercially available devices or components and/or from a wide range of methods and materials such as taught, for example, by patents and publications relating to such iontophoretic systems.
- the iontophoretic transdermal system may comprise an iontophoretic device such as is available from The Alza corporation of Mountain View, California, U.S.A. (E-trans® Transdermal Technology), Birch Point Medical Inc. of St. Paul, Minnesota U.S.A. (e.g., lontoPatchTM working according to the Wearable Electronic Disposable Delivery (WEDDTM) technology), lomed of Salt Lake City, Utah, U.S.A.
- WEDDTM Wearable Electronic Disposable Delivery
- IOMEDTM Phoresor devices using IOGEL®, TransQ®Flex, TransQ®E, TransQ®1&2 or Numby Stuff® electrodes and the GelSponge® containment medium e.g. IOMEDTM Phoresor devices using IOGEL®, TransQ®Flex, TransQ®E, TransQ®1&2 or Numby Stuff® electrodes and the GelSponge® containment medium
- a device such as manufactured by Vyteris of Fair Lawn, New Jersey, U.S.A. (Active Transdermal system) or a device such as manufactured by Empi of St. Paul, Minnesota (e.g. Empi DUPELTM), or a device known as the LECTROTM Patch, manufactured by General Medical Device Corp. of Los Angeles, California.
- the electrodes may comprise reactive or non -reactive electrodes.
- reactive electrodes are those made from metal salts, such as silver chloride or materials described in US 4,752,285.
- the silver chloride electrodes can be prepared based on the knowledge of a person skilled in the art or are available from lomed.
- Alternative reactive electrodes can be made from a combination of ion -exchange resins, exemplified by electrodes available from Empi.
- non -reactive electrodes are those made from metals such as gold or platinum, or from carbon particles dispersed in polymeric matrices such as one used in the LECTROTM Patch.
- Adhesives used to fix the iontophoretic device to the skin may comprise pressure sensitive adhesives used in passive transdermal delivery systems, such those derived from silicone or acrylic polymers, or those derived from rubbers such as polyisobutylene.
- pressure sensitive adhesives used in passive transdermal delivery systems, such those derived from silicone or acrylic polymers, or those derived from rubbers such as polyisobutylene.
- a combination of pressure sensitive and conductive adhesives can also be used, such as those described EPA 0542294.
- the concentration of the drug may be, for example, at least about 0.1 mg/ml.
- the concentration of the drug in the drug reservoir may be, for example, not more than about 90 mg/ml.
- the concentration for 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone or its monohydrochloride salt is, for example, about 10 to about 75 mg/ml. In other embodiments, that concentration ranges from about 20 to about 55 mg/ml.
- the concentration for 7-(4-benzyl-1-piperazinyl)-2(3H)-benzoxazolone or its monomesylate is, for example, about 1 to about 30 mg/ml. In other embodiments, that concentration can range from about 5 to about 10 mg/ml.
- the drug reservoir of the iontophoretic system may include further additives.
- additives can be chosen from those that are well known and conventional in the iontophoresis art.
- additives include, for example, antimicrobial agents, preservatives, antioxidants, penetration enhancers and buffers.
- a unit dosage that may be delivered during a s ingle delivery period may vary in amount.
- a unit dosage in one embodiment may be at least about 0.05 mg.
- the unit dosage in another embodiment may be, for example, no more than about 100 mg.
- a unit dosage for 7-(4-methyl-1-piperazinyI)-2(3H)- benzoxazolone or its monohydrochloride in some embodiments can range from about 0.05 to about 60 mg. In other embodiments, that concentration can range from about 0.05 to about 30 mg.
- the unit dosage that is delivered may be determined on the basis of on e or more of a wide range of factors, including, for example, the compound, condition, age, body weight, clearance, etc.
- the flux rate of delivery through the skin of at least one compound of formula I can be, for example, at least about 50 ⁇ g per hour. In other embodiments, the flux rate of delivery through the skin can be, for example, no more than about 4000 ⁇ g per hour.
- the iontophoretic delivery method of pharmaceutical compounds comprises a drug delivery treatment protocol that includes periodically applying an iontophoretic transdermal device at intervals that may be as frequent as twice daily or as infrequent as once a week or once a month.
- a single treatment step the d evice is applied, the drug is iontophoretically delivered and the device is then removed.
- the absolute quantity of the drug delivered may vary substantially, a unit dosage is herein defined to be that quantity of drug, however large or small, that is delivered during a single treatment step by a single device application at an individual site.
- the drug may be delivered constantly or during defined intervals.
- the intervals may range, for example, from about 10 minutes to 24 or 48 hours. In some cases it may be advantageous to omit delivery during a part of the day and night cycle, e.g., during the night for 6, 7 or 8 hours.
- a linear or stepwise increase of the drug over a certain time starting with a low amount of drug up to the normal maintenance dose, which time is also referred to as titration time.
- the period for titration can be, for example, at least 3 days or not more than 42 days.
- the period for titration can range between 7 and 21 days in some embodiments, and in still other embodiments around 14 days.
- the iontophoretic delivery method according to the present invention may be useful for such a linear or stepwise increase of the drug administration as the administered amount of drug can be regulated by linear or stepwise increase of the current density.
- the iontophoretic system comprises
- a transdermal delivery device attachable to the skin, the device comprising a first electrode and a second electrode, and a reservoir capable of comprising a compound of the formula I as set forth above, and optionally a pharmaceutically acceptable electrolyte, in electrical communication with the first and second electrodes, and
- the electrical power source may be any appropriate source, such as for example, a battery, a rechargeable battery, or electrical power delivered by an electrical ou tlet.
- the means for connecting the electrical power source may comprise any suitable conductor, conduit, or carrier of electrical energy.
- the means may comprise, for example, wiring, a power adaptor, a power controller, a power monitor, or a combination of two or more of the foregoing.
- the iontophoretic system may comprise still other methods and materials, such as described in WO 92/17239, EPA 0547482 and US 4,764,164, the entire contents of which are incorporated herein by reference.
- the transport area of the device can be at least about 1.0 cm 2 . In other embodiments, the transport area might be no more than about 30 cm 2 . In still other embodiments, the transport area can range from about 2 to about 15 cm 2 , and in still other embodiments from about 5 to about 10 cm 2 .
- the drug reservoir of the iontophoretic system is delivered empty to the user and the reservoir is filled just before or after application of the system to the skin.
- the iontophoretic system is combined with one or more cartridges containing the compound of general formula I as defined above, including a salt or prodrug thereof, or a composition of two or more thereof and optionally a pharmaceutically acceptable electrolyte.
- This combination of an iontophoretic system and one or more cartridges may be defined as a starter kit .
- the number of cartridges in one kit can range, for example, from 7 to 91, and in other embodiments from 14 to 28.
- the compound and the optional electrolyte may be in the form of a solid crystalline, amorphous or lyophilized material which material has to be dissolved in water before filling of the reservoir of the iontophoretic device, or in the form of a solution ready for use.
- the iontophoretic system may be refilled with a fresh solution for example every 3-48 hours, or for example once every 24 hours.
- a kit which is intended for more than one treatment step, as long as the iontophoretic syste m is working properly contains only one or more of cartridges comprising the compound of general formula I as defined above, including a salt or prodrug thereof, or a composition thereof and optionally a pharmaceutically acceptable electrolyte may be present.
- the term "about” when modifying a value indicates the variability inherent in that value that would be understood by one of ordinary skill in the art. For example, “about” indicates that significant digits, rounding errors, and the like provide a range of values about the recited number that falls within the scope of the disclosure of that number.
- HSC Human Stratum Corneum
- HSC Remaining trypsin activity was blocked by bathing HSC in a 0.1% trypsin inhibitor solution in PBS, pH 7.4. HSC was washed several times in water and stored in a silica gel containing desiccator in a N z environment to inhibit oxidation of lipids.
- Hairless rats were euthanized by inhalation of carbon dioxide using an exposure chamber designed for such use half hour before start of experiment.
- the skin from the abdomen was carefully removed, making sure no muscle or fat was attached to the skin.
- the skin was then cut into small squares to fit the Franz diffusion set (Membrane Transport System, PermeGear, U.S.A) and placed in 0.1 M potassium phosphate buffer until mounted.
- Franz diffusion set Membrane Transport System, PermeGear, U.S.A
- 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolo ⁇ e hydrochloric acid salt was synthesized as described in WO00/29397 and Drugs of the Future 2001 , 26, 128-32.
- 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone mesylate was prepared as described in WO01/85725 and WO02/066449.
- the silver plate and silver/silver chloride electrodes can be prepared according to chapter 3.4.3. of Ajay K. Banga, Electrically Assisted Transdermal and Topical Drug Delivery, Taylor and Francis Group Ltd., London UK, 1998, ISBN 0-7484-0687-5. or can be purchased from a commercial supplier such as lomed.)
- Parafilm rings were added for making a tight connection between the compartments.
- the temperature of the acceptor chamber was 37 °C.
- the flow of PBS through the acceptor chamber was kept approximately constant for each cell during the experiment: 6 - 8 ml per hour.
- the current was switched on.
- passive diffusion post iontophoresis was carried out.
- the current density was 0.5 mA cm 2 .
- the total resistance of the stratum corneum sheets was monitored during the experiment with two additional silver electrodes. A very low resistance is indicative of leakage of the stratum corneum in a cell. When this was observed, the diffusion data obtained were discarded. All conditions were repeated at least 3 times.
- the number of skin donors used for each condition was at least 3.
- Iontophoresis experiments with 7-(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone Iontophoresis experiments with 7-(4-benzyl-1-piperazinyl)-2(3H) ⁇ benzoxazolone were performed using vertical Franz diffusion cells (Membrane Transport System, PermeGear, U.S.A) hooked up to a Keithley 2400 source meter and the current monitored using a multimeter. The donor half was of the cell was exposed to room temperature (25°C) while the receptor half was maintained at 37° C. Receptor compartment was continuously stirred.
- vertical Franz diffusion cells Membrane Transport System, PermeGear, U.S.A
- Freshly excised hairless rat skin was mounted on the vertical diffusion cells, after the receptor compartment had been filled with a suitable receptor media, which can maintain the sink condition.
- the receptor media had the same composition as the donor solution wi thout the drug, so that the sink conditions could be maintained.
- the formulation was placed in the donor compartment.
- a silver wire was used as the anode in the donor and a silver/silver chloride wire was used as the cathode in the receptor.
- Current was applied for 3 hours using a constant current power source. However, sampling was continued till 24 hrs to see if enhanced delivery will stop on terminating current. Samples were taken at pre -determined time intervals from the receptor and analyzed by the HPLC as described below. Samples were replaced with fresh receptor medium and this was taken into consideration in the calculations.
- Example 2 Iontophoresis of 7-(4-methyI-1-piperazinyl)-2(3H)-be ⁇ zoxazolone monohydrochloride with varying active substance concentration
- Example 3 Iontophoresis of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride with varying active electrolyte concentration
- 7-(4-methyl-1-piperazi ⁇ yl)-2(3H)-benzoxazolone monohydrochloride was dissolved in 10 mM sodium citrate solution. The pH was adjusted to pH 5.5 with 10 mM citric acid. Sodium chloride was added resulting in solutions of either 0, 2 or 4 mg/ml NaCI.
- the 7-(4-methyl-1 -piperazinyl)-2(3H)-benzoxazolone monohydrochloride concentration was kept constant, namely 35 mg/ml.
- the selected 7 -(4-methyl-1- piperazi ⁇ yl)-2(3H)-benzoxazolone monohydrochloride concentration is 80% of its maximum solubility. The solubility of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride increases with reducing NaCI concentration.
- Figure 2 illustrates that, after switching on the current, there is a steep increase in 7- (4-methyl-1-piperazinyl)-2(3H)-benzoxazolone flux.
- the mean transport during the iontophoretic period was 471 ⁇ 65, 377 ⁇ 37 and 424 ⁇ 50 ⁇ g/hr/cm 2 (averages ⁇ s.e.m.) for the sodium chloride concentrations 0, 2, 4 mg/ml, respectively. There was no significant difference between these values as 5 tested by one way ANOVA (p-value between all groups > 0.05).
- the pH of the donor solution did not change more than 0.2 pH units during the experiment. The strong increase and decrease during switching on and off the current indicates that a large variation in transport can be achieved by iontophoresis.
- Example 4 Iontophoresis of 7-(4-methyl-1-piperazinyl)-2(3H)-benzoxazolone monohydrochloride with varying active substance concentration in the presence of 4 g/l NaCI.
- Figure 3 shows that in the presence of NaCI the iontophoretic flux of 7 -(4-methyl-1- piperazinyl)-2(3H)-benzoxazolone monohydrochloride was slightly dependent on its concentration flux.
- the fluxes were 409 ⁇ 47, 467 ⁇ 74 and 580 ⁇ 87 ⁇ g/hr/cm 2 for the donor concentrations of 20, 35 and 55 mg/ml respectively (averages ⁇ s.e.m.). 25
- the pH of the donor solution did not change more than 0.2 pH units during the experiment.
- Example 5 Iontophoresis of 7 -(4-benzyl-1-piperazinyl)-2(3H)- benzoxazolone varying active substance concentration in the presence of 30 mM NaCI.
- Example 6 Iontophoresis of 7-(4-benzyl-1-pi ⁇ erazinyl)-2(3H)- benzoxazolone at a concentration of 5 mg/ml, varying current density in the presence of 30 mM NaCI.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Electrotherapy Devices (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05768713A EP1742632A2 (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
JP2007504423A JP2007530512A (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2 (3H) -benzoxazolone compounds |
CA002558113A CA2558113A1 (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
CN2005800098780A CN1938030B (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
BRPI0508848-8A BRPI0508848A (en) | 2004-03-26 | 2005-03-25 | use of at least one compound, iontophoretic system for administration of a compound through the skin, cartridge, and kit |
AU2005239833A AU2005239833B2 (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds |
IL177684A IL177684A (en) | 2004-03-26 | 2006-08-24 | Use of piperazinyl-2(3h)-benzoxazolone compounds for the preparation of an iontophoretic device for the treatment of parkinson's disease and restless legs syndrome |
NO20064865A NO20064865L (en) | 2004-03-26 | 2006-10-25 | Transdermal ionophoretic delivery of piperazinyl-2 (3H) benzoxazolone compounds |
HK07104262.6A HK1098048A1 (en) | 2004-03-26 | 2007-04-24 | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US55637504P | 2004-03-26 | 2004-03-26 | |
US60/556,375 | 2004-03-26 | ||
EP04101253A EP1595542A1 (en) | 2004-03-26 | 2004-03-26 | Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds |
EP04101253.5 | 2004-03-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005107754A2 true WO2005107754A2 (en) | 2005-11-17 |
WO2005107754A3 WO2005107754A3 (en) | 2005-12-29 |
Family
ID=34928930
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/051401 WO2005107754A2 (en) | 2004-03-26 | 2005-03-25 | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
Country Status (13)
Country | Link |
---|---|
EP (2) | EP1595542A1 (en) |
JP (1) | JP2007530512A (en) |
CN (1) | CN1938030B (en) |
AR (1) | AR048186A1 (en) |
AU (1) | AU2005239833B2 (en) |
BR (1) | BRPI0508848A (en) |
CA (1) | CA2558113A1 (en) |
HK (1) | HK1098048A1 (en) |
RU (1) | RU2371179C2 (en) |
SA (1) | SA05260067A (en) |
TW (1) | TW200536839A (en) |
UA (1) | UA87493C2 (en) |
WO (1) | WO2005107754A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009082268A2 (en) | 2007-12-21 | 2009-07-02 | Alla Chem, Llc | LIGANDS OF α-ADRENOCEPTORS AND OF DOPAMINE, HISTAMINE, IMIDAZOLINE AND SEROTONIN RECEPTORS AND THE USE THEREOF |
WO2009106516A1 (en) * | 2008-02-25 | 2009-09-03 | Solvay Pharmaceuticals B.V. | Compositions, kits and methods for a titration schedule for pardoprunox compounds |
WO2010024717A1 (en) | 2008-08-22 | 2010-03-04 | Алла Xem, Ллс | Ligand with a broad spectrum of pharmacological activity, a pharmaceutical composition, a medicinal agent and a method of treatment |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102309481A (en) * | 2011-09-30 | 2012-01-11 | 山西医科大学 | Application of compound 4-o-methyl-benzenesulfonyl-2(3H)-benzoxazolone and pharmaceutically acceptable salt thereof in preparing non-steroidal anti-inflammatory and analgesic medicines |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0529510A1 (en) * | 1991-08-23 | 1993-03-03 | Boehringer Ingelheim Kg | Sintered transdermal iontophoresis application of active therapeutical agents |
EP0522062B1 (en) * | 1990-03-30 | 1996-09-04 | Alza Corporation | Activity controlled electrotransport drug delivery device |
WO2000029397A1 (en) * | 1998-11-13 | 2000-05-25 | Duphar International Research Bv | New piperazine and piperidine compounds |
WO2001085725A1 (en) * | 2000-05-12 | 2001-11-15 | Solvay Pharmaceuticals B.V. | Piperazine and piperidine compounds |
WO2001085168A1 (en) * | 2000-05-12 | 2001-11-15 | Solvay Pharmaceuticals B.V. | Use of compounds having combined dopamine d2, 5-ht1a and alpha adrenoreceptor agonistic action for treating cns disorders |
EP1336406A1 (en) * | 2002-02-14 | 2003-08-20 | Solvay Pharmaceuticals B.V. | Partial dopamine-D2 receptor agonist plus serotonin and/or noradrenaline inhibitory activity |
US20040013620A1 (en) * | 1996-02-19 | 2004-01-22 | Monash University | Transdermal delivery of antiparkinson agents |
WO2004045509A2 (en) * | 2002-11-18 | 2004-06-03 | Pharmacia Corporation | Method of using a cox-2 inhibitor and a 5-ht1a receptor modulator as a combination therapy |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5207752A (en) * | 1990-03-30 | 1993-05-04 | Alza Corporation | Iontophoretic drug delivery system with two-stage delivery profile |
AU1280701A (en) * | 1999-11-17 | 2001-05-30 | Novartis Ag | Iontophoretic transdermal delivery of peptides |
EP1448263B1 (en) * | 2001-10-24 | 2009-01-07 | Power Paper Ltd. | Device for controlled delivery of active substance into the skin |
-
2004
- 2004-03-26 EP EP04101253A patent/EP1595542A1/en not_active Withdrawn
-
2005
- 2005-03-23 AR ARP050101147A patent/AR048186A1/en not_active Application Discontinuation
- 2005-03-24 TW TW094109105A patent/TW200536839A/en unknown
- 2005-03-25 WO PCT/EP2005/051401 patent/WO2005107754A2/en active Application Filing
- 2005-03-25 BR BRPI0508848-8A patent/BRPI0508848A/en not_active IP Right Cessation
- 2005-03-25 UA UAA200611249A patent/UA87493C2/en unknown
- 2005-03-25 AU AU2005239833A patent/AU2005239833B2/en not_active Ceased
- 2005-03-25 CN CN2005800098780A patent/CN1938030B/en not_active Expired - Fee Related
- 2005-03-25 RU RU2006137714/15A patent/RU2371179C2/en not_active IP Right Cessation
- 2005-03-25 JP JP2007504423A patent/JP2007530512A/en active Pending
- 2005-03-25 EP EP05768713A patent/EP1742632A2/en not_active Withdrawn
- 2005-03-25 CA CA002558113A patent/CA2558113A1/en not_active Abandoned
- 2005-03-26 SA SA05260067A patent/SA05260067A/en unknown
-
2007
- 2007-04-24 HK HK07104262.6A patent/HK1098048A1/en not_active IP Right Cessation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0522062B1 (en) * | 1990-03-30 | 1996-09-04 | Alza Corporation | Activity controlled electrotransport drug delivery device |
EP0529510A1 (en) * | 1991-08-23 | 1993-03-03 | Boehringer Ingelheim Kg | Sintered transdermal iontophoresis application of active therapeutical agents |
US20040013620A1 (en) * | 1996-02-19 | 2004-01-22 | Monash University | Transdermal delivery of antiparkinson agents |
WO2000029397A1 (en) * | 1998-11-13 | 2000-05-25 | Duphar International Research Bv | New piperazine and piperidine compounds |
WO2001085725A1 (en) * | 2000-05-12 | 2001-11-15 | Solvay Pharmaceuticals B.V. | Piperazine and piperidine compounds |
WO2001085168A1 (en) * | 2000-05-12 | 2001-11-15 | Solvay Pharmaceuticals B.V. | Use of compounds having combined dopamine d2, 5-ht1a and alpha adrenoreceptor agonistic action for treating cns disorders |
EP1336406A1 (en) * | 2002-02-14 | 2003-08-20 | Solvay Pharmaceuticals B.V. | Partial dopamine-D2 receptor agonist plus serotonin and/or noradrenaline inhibitory activity |
WO2004045509A2 (en) * | 2002-11-18 | 2004-06-03 | Pharmacia Corporation | Method of using a cox-2 inhibitor and a 5-ht1a receptor modulator as a combination therapy |
Non-Patent Citations (3)
Title |
---|
GAI LING LI ET AL: "IONTOPHORETIC DELIVERY OF APOMORPHINE IN VITRO: PHYSICOCHEMIC CONSIDERATIONS" PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 18, no. 11, November 2001 (2001-11), pages 1509-1513, XP001149891 ISSN: 0724-8741 * |
See also references of EP1742632A2 * |
TYLE P: "IONTOPHORETIC DEVICES FOR DRUG DELIVERY" PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 3, no. 6, 1 December 1986 (1986-12-01), pages 318-326, XP000576948 ISSN: 0724-8741 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009082268A2 (en) | 2007-12-21 | 2009-07-02 | Alla Chem, Llc | LIGANDS OF α-ADRENOCEPTORS AND OF DOPAMINE, HISTAMINE, IMIDAZOLINE AND SEROTONIN RECEPTORS AND THE USE THEREOF |
WO2009106516A1 (en) * | 2008-02-25 | 2009-09-03 | Solvay Pharmaceuticals B.V. | Compositions, kits and methods for a titration schedule for pardoprunox compounds |
WO2010024717A1 (en) | 2008-08-22 | 2010-03-04 | Алла Xem, Ллс | Ligand with a broad spectrum of pharmacological activity, a pharmaceutical composition, a medicinal agent and a method of treatment |
Also Published As
Publication number | Publication date |
---|---|
AR048186A1 (en) | 2006-04-05 |
EP1595542A1 (en) | 2005-11-16 |
AU2005239833A1 (en) | 2005-11-17 |
JP2007530512A (en) | 2007-11-01 |
AU2005239833B2 (en) | 2010-02-25 |
EP1742632A2 (en) | 2007-01-17 |
SA05260067A (en) | 2005-12-03 |
RU2371179C2 (en) | 2009-10-27 |
CN1938030A (en) | 2007-03-28 |
TW200536839A (en) | 2005-11-16 |
BRPI0508848A (en) | 2007-08-28 |
CA2558113A1 (en) | 2005-11-17 |
RU2006137714A (en) | 2008-05-10 |
CN1938030B (en) | 2010-10-20 |
WO2005107754A3 (en) | 2005-12-29 |
HK1098048A1 (en) | 2007-07-13 |
UA87493C2 (en) | 2009-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7596407B2 (en) | Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds | |
EP2285362B1 (en) | Composition for transdermal delivery of cationic active agents | |
AU2004255059A1 (en) | Method, apparatus, and kit for onychomycosis treatment using electrokinetic transport of substances | |
AU2008358026B2 (en) | Polyamine enhanced formulations for triptan compound iontophoresis | |
JP2002525307A (en) | Iontophoresis device containing piperidine derivative | |
FR2734728A1 (en) | DEVICE FOR THE ADMINISTRATION OF FENTANYL OR SUFENTANIL BY TRANSDERMAL ELECTROTRANSPORT | |
AU2005239833B2 (en) | Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds | |
WO2008102349A2 (en) | Terbinafine formulation for iontophoresis | |
JP3261501B2 (en) | Drug delivery method by improved iontophoresis | |
JP2921987B2 (en) | Ion electrophoretic delivery of antimigraine drugs | |
MXPA06011018A (en) | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds | |
KR20070012432A (en) | Transdermal iontophoretic delivery of piperazinyl-2(3h)-benzoxazolone compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006/07105 Country of ref document: ZA Ref document number: 200607105 Country of ref document: ZA Ref document number: 177684 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2558113 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12006501717 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007504423 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2006/011018 Country of ref document: MX Ref document number: 3522/CHENP/2006 Country of ref document: IN Ref document number: DZP2005000476 Country of ref document: DZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200580009878.0 Country of ref document: CN |
|
NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005768713 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005239833 Country of ref document: AU Ref document number: 1020067022368 Country of ref document: KR Ref document number: 2006137714 Country of ref document: RU |
|
ENP | Entry into the national phase in: |
Ref document number: 2005239833 Country of ref document: AU Date of ref document: 20050325 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2005239833 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 2005768713 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1020067022368 Country of ref document: KR |
|
ENP | Entry into the national phase in: |
Ref document number: PI0508848 Country of ref document: BR |