JP6744821B2 - シルデナフィル液剤並びにその製造方法及び使用 - Google Patents
シルデナフィル液剤並びにその製造方法及び使用 Download PDFInfo
- Publication number
- JP6744821B2 JP6744821B2 JP2016558141A JP2016558141A JP6744821B2 JP 6744821 B2 JP6744821 B2 JP 6744821B2 JP 2016558141 A JP2016558141 A JP 2016558141A JP 2016558141 A JP2016558141 A JP 2016558141A JP 6744821 B2 JP6744821 B2 JP 6744821B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- sildenafil citrate
- liquid carrier
- water
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000007788 liquid Substances 0.000 title claims description 103
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title description 44
- 229960003310 sildenafil Drugs 0.000 title description 9
- 238000002360 preparation method Methods 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 229960002639 sildenafil citrate Drugs 0.000 claims description 131
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims description 129
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 127
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 86
- 239000008194 pharmaceutical composition Substances 0.000 claims description 57
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- 229960003511 macrogol Drugs 0.000 claims description 18
- -1 macrogol lauryl ethers Chemical class 0.000 claims description 16
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 12
- 229920002675 Polyoxyl Polymers 0.000 claims description 9
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 9
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 claims description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 6
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 3
- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 3
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 3
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 3
- KUXGUCNZFCVULO-UHFFFAOYSA-N 2-(4-nonylphenoxy)ethanol Chemical class CCCCCCCCCC1=CC=C(OCCO)C=C1 KUXGUCNZFCVULO-UHFFFAOYSA-N 0.000 claims description 3
- WITKSCOBOCOGSC-UHFFFAOYSA-N 2-dodecanoyloxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC WITKSCOBOCOGSC-UHFFFAOYSA-N 0.000 claims description 3
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 claims description 3
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 3
- 241000416162 Astragalus gummifer Species 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- 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 claims description 3
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 claims description 3
- 229920002884 Laureth 4 Polymers 0.000 claims description 3
- 229920001363 Polidocanol Polymers 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229920002669 Polyoxyl 20 Cetostearyl Ether Polymers 0.000 claims description 3
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920001615 Tragacanth Polymers 0.000 claims description 3
- 239000000679 carrageenan Substances 0.000 claims description 3
- 235000010418 carrageenan Nutrition 0.000 claims description 3
- 229920001525 carrageenan Polymers 0.000 claims description 3
- 229940113118 carrageenan Drugs 0.000 claims description 3
- 229960001777 castor oil Drugs 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 229950009789 cetomacrogol 1000 Drugs 0.000 claims description 3
- 229940096516 dextrates Drugs 0.000 claims description 3
- 229940099371 diacetylated monoglycerides Drugs 0.000 claims description 3
- UYAAVKFHBMJOJZ-UHFFFAOYSA-N diimidazo[1,3-b:1',3'-e]pyrazine-5,10-dione Chemical compound O=C1C2=CN=CN2C(=O)C2=CN=CN12 UYAAVKFHBMJOJZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 229940049654 glyceryl behenate Drugs 0.000 claims description 3
- 229940074045 glyceryl distearate Drugs 0.000 claims description 3
- 229940072106 hydroxystearate Drugs 0.000 claims description 3
- 229940061515 laureth-4 Drugs 0.000 claims description 3
- 229950006462 lauromacrogol 400 Drugs 0.000 claims description 3
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 3
- 229920000847 nonoxynol Polymers 0.000 claims description 3
- 229920002113 octoxynol Polymers 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229940068965 polysorbates Drugs 0.000 claims description 3
- 239000011118 polyvinyl acetate Substances 0.000 claims description 3
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229940116423 propylene glycol diacetate Drugs 0.000 claims description 3
- 229940026235 propylene glycol monolaurate Drugs 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 150000003445 sucroses Chemical class 0.000 claims description 3
- 235000010487 tragacanth Nutrition 0.000 claims description 3
- 229940116362 tragacanth Drugs 0.000 claims description 3
- 229920001664 tyloxapol Polymers 0.000 claims description 3
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 3
- 229960004224 tyloxapol Drugs 0.000 claims description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 3
- 102000009338 Gastric Mucins Human genes 0.000 claims description 2
- 108010009066 Gastric Mucins Proteins 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 claims description 2
- 239000000305 astragalus gummifer gum Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 91
- 238000010438 heat treatment Methods 0.000 description 56
- 239000000203 mixture Substances 0.000 description 54
- 238000002474 experimental method Methods 0.000 description 50
- 238000000034 method Methods 0.000 description 45
- 150000002576 ketones Chemical class 0.000 description 31
- 150000001298 alcohols Chemical class 0.000 description 20
- 235000019658 bitter taste Nutrition 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000006186 oral dosage form Substances 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- 208000010228 Erectile Dysfunction Diseases 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 201000001881 impotence Diseases 0.000 description 10
- 229940094720 viagra Drugs 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 235000015218 chewing gum Nutrition 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 239000000796 flavoring agent Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000006187 pill Substances 0.000 description 8
- 239000000341 volatile oil Substances 0.000 description 8
- 229940112822 chewing gum Drugs 0.000 description 7
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 208000002815 pulmonary hypertension Diseases 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000006199 nebulizer Substances 0.000 description 5
- 239000005022 packaging material Substances 0.000 description 5
- 229940039245 revatio Drugs 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 235000003092 Artemisia dracunculus Nutrition 0.000 description 4
- 240000001851 Artemisia dracunculus Species 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
- 239000000123 paper Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241001529734 Ocimum Species 0.000 description 3
- 235000010676 Ocimum basilicum Nutrition 0.000 description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229940071648 metered dose inhaler Drugs 0.000 description 3
- 229940100692 oral suspension Drugs 0.000 description 3
- 229940059096 powder for oral suspension Drugs 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 238000010257 thawing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 235000019501 Lemon oil Nutrition 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000010619 basil oil Substances 0.000 description 2
- 229940018006 basil oil Drugs 0.000 description 2
- 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 2
- 230000004064 dysfunction Effects 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000007897 gelcap Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 229940060367 inert ingredients Drugs 0.000 description 2
- 239000010501 lemon oil Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000010660 tarragon oil Substances 0.000 description 2
- OTYVBQZXUNBRTK-UHFFFAOYSA-N 3,3,6-trimethylhepta-1,5-dien-4-one Chemical compound CC(C)=CC(=O)C(C)(C)C=C OTYVBQZXUNBRTK-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002153 Anal fissure Diseases 0.000 description 1
- 208000016583 Anus disease Diseases 0.000 description 1
- 241000285470 Artemesia Species 0.000 description 1
- 241001184073 Basilicum Species 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 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
- 208000011231 Crohn disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010052337 Diastolic dysfunction Diseases 0.000 description 1
- 235000003550 Dracunculus Nutrition 0.000 description 1
- 241000316827 Dracunculus <angiosperm> Species 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000000289 Esophageal Achalasia Diseases 0.000 description 1
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
- 208000021663 Female sexual arousal disease Diseases 0.000 description 1
- 208000001362 Fetal Growth Retardation Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000009531 Fissure in Ano Diseases 0.000 description 1
- 206010070531 Foetal growth restriction Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 235000019687 Lamb Nutrition 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030136 Oesophageal achalasia Diseases 0.000 description 1
- 208000014174 Oesophageal disease Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 201000000621 achalasia Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 208000008445 altitude sickness Diseases 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008321 arterial blood flow Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000002302 brachial artery Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008355 dextrose injection Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 208000028299 esophageal disease Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000030941 fetal growth restriction Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000003168 generic drug Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000035168 lymphangiogenesis Effects 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 201000008312 primary pulmonary hypertension Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000037812 secondary pulmonary hypertension Diseases 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 235000021092 sugar substitutes Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000009489 vacuum treatment Methods 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
- A61K9/0058—Chewing gums
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01Q—ANTENNAS, i.e. RADIO AERIALS
- H01Q1/00—Details of, or arrangements associated with, antennas
- H01Q1/27—Adaptation for use in or on movable bodies
- H01Q1/28—Adaptation for use in or on aircraft, missiles, satellites, or balloons
- H01Q1/288—Satellite antennas
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01Q—ANTENNAS, i.e. RADIO AERIALS
- H01Q1/00—Details of, or arrangements associated with, antennas
- H01Q1/36—Structural form of radiating elements, e.g. cone, spiral, umbrella; Particular materials used therewith
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01Q—ANTENNAS, i.e. RADIO AERIALS
- H01Q5/00—Arrangements for simultaneous operation of antennas on two or more different wavebands, e.g. dual-band or multi-band arrangements
- H01Q5/50—Feeding or matching arrangements for broad-band or multi-band operation
- H01Q5/55—Feeding or matching arrangements for broad-band or multi-band operation for horn or waveguide antennas
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Physics & Mathematics (AREA)
- Physics & Mathematics (AREA)
- Astronomy & Astrophysics (AREA)
- Remote Sensing (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Aviation & Aerospace Engineering (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明のいくつかの好適な実施形態では、少なくとも7mg/mlの濃度で液体担体中に溶解したシルデナフィルクエン酸塩と一緒に、水及び少なくとも20%、少なくとも22.5%、少なくとも25%、少なくとも25%、または少なくとも30%の少なくとも1つのアルコールを含む液体担体を含む医薬組成物を提供する。水及び医薬組成物での使用に適切なアルコール(すなわち、ヒト消費に対して「安全」と考えられるアルコール)の両方へのシルデナフィルクエン酸塩の溶解性は7mg/mlをはるかに下回っているので、そのような組成物を製剤することが可能であるという事実は驚くべきことである。医薬組成物での使用に適切なアルコールの1つの例はエタノール(EtOH)である。
本発明のいくつかの好適な実施形態は、上記液体医薬組成物を非液体剤形中に組み込む。例えば、本発明のいくつかの実施形態に記載の経口用剤形は外側コーティング及び上記医薬組成物を含む液体コアを含む。このタイプの経口用剤形は、例えば、ジェルキャップまたはゲルカプセルとして提供される。
本発明のいくつかの好適な実施形態は、上記液体医薬組成物を口腔用剤形中に組み込む。経口粘膜経由する生理的活性物質の送達は、胃及び/または腸経由する同じ物質の送達より速い及び/またはより効果的であり得ることは確立している。本発明のいくつかの実施形態は、貯蔵中の組成物の液体担体の蒸発を防ぐように適合された包装材料中に提供される上記医薬組成物を含む担体を含む口腔用剤形に関する。本発明の様々な好適な実施形態に従えば、該担体は紙、ボール紙、不織布またはウェハー(例えば、デンプン系)である。
本発明のいくつかの好適な実施形態は、液体医薬組成物を治療キットで提供する。いくつかの実施形態では、該治療キットは、包装材料及び/または使用説明書を含む。本発明のいくつかの好適な実施形態では、使用説明書はシルデナフィルクエン酸塩固体物の用量から液剤中のシルデナフィルのより低い用量へ切り換えるためのガイダンスを提供する。
シルデナフィルクエン酸塩は苦い。錠剤などの従来の固体剤形を、通常、治療される患者により味がしないように迅速に飲み込む。上記液体組成物の経口投与及び/またはそのような液体組成物を含む剤形の口腔投与は、使用者がシルデナフィルクエン酸塩の苦味に対する感受性が高くなる可能性をより大きくする
図1は、一般的に100と示される上記液体医薬組成物の例示となる製剤方法の簡略化した流れ図である。示された例示となる方法100は、1つ以上のアルコール及び水から本質的に成る組合せにシルデナフィルクエン酸塩を入れて110混合物を得ること及び混合物を加熱120して少なくとも7mg/mlの濃度のシルデナフィルクエン酸塩液剤を得ることを含む。
図2は、一般的に200と示される上記液体医薬組成物の例示となる製剤方法の簡略化した流れ図である。示された例示となる方法200は、第一の体積のケトンを準備210し、1つ以上のアルコール及び水(例えば、組合せまたは混合物として)から本質的に成る第二体積を添加220して、総体積に対して少なくとも7mg/ml、少なくとも10mg/ml、少なくとも12.5mg/mlの濃度のシルデナフィルクエン酸塩液剤を溶解225することを含む。本発明の様々な好適な実施形態に従えば、溶解225は、210において前記第一の体積中に及び/または220において前記総体積中である。方法200の多くの実施形態で、シルデナフィルクエン酸塩の全てを加熱なしで溶液中に溶解することに注意することは重要である。NMRアッセイ(図3及び実施例4参照)により、シルデナフィルクエン酸塩が溶解により変化しなかったことを確認した。
本発明のいくつかの実施形態は、水、エタノール、及び30%未満のアセトンを含む液体担体及び少なくとも10mg/ml、少なくとも20mg/ml、少なくとも25mg/ml、少なくとも30mg/ml、少なくとも35mg/ml、少なくとも40mg/ml、少なくとも45mg/ml、少なくとも50mg/ml、少なくとも55mg/mlの濃度または中間の濃度またはより高濃度で該液体担体中に溶解したシルデナフィルクエン酸塩を含む医薬組成物に関する。いくつかの実施形態では、アセトン濃度は、25%未満または20%未満である。
図4は、一般的に400と示される勃起不全のための好適な治療方法の簡略化した流れ図である。
高濃度におけるシルデナフィルクエン酸塩液剤の製剤。
シルデナフィルクエン酸塩液剤の安定性。
加熱後の溶媒濃度。
加熱中のシルデナフィルクエン酸塩の溶解性
好適なケーススタディ
高濃度のさらなるシルデナフィルクエン酸塩液剤の製剤
追加のシルデナフィルクエン酸塩液剤の安定性
アセトン量を変化させたシルデナフィルクエン酸塩液剤。高濃度でのシルデナフィルクエン酸塩の溶解に対するアセトンの寄与を調査するために、比較的少量のアセトンを含む様々な比率のエタノール(EtOH)及び水を用いた追加の一連の13の実験を行った。
低アセトンシルデナフィルクエン酸塩液剤の安定性。実施例8の実験1〜13の各液剤の体積を、50%EtOH/水(実験1〜4);70%EtOH/水(実験5、7、8及び9〜13)及び95%EtOH/水(実験6)を用いて10mlまで調製した。全ての13の実験では、得られた液剤は透明であった。濃度は25mg/ml〜50mg/mlであった。
ケトンを含まないシルデナフィルクエン酸塩液剤。ケトンを含まないアルコール/水混合物中の高濃度でのシルデナフィルクエン酸塩の溶解の可能性を調査するために、アセトンを含有しない様々な比率のエタノール(EtOH)及び水を用いた追加の一連の8つの実験を行った。
アセトン非含有シルデナフィルクエン酸塩液剤の安定性
Claims (13)
- (a)水及び少なくとも35%のエタノールを含む液体担体;及び
(b)少なくとも7mg/mlの濃度で前記液体担体中に溶解したシルデナフィルクエン酸塩を含む医薬組成物。 - (a)水、エタノール、及び0.0075%〜20%のアセトンを含む液体担体;及び
(b)少なくとも10mg/mlの濃度で前記液体担体中に溶解したシルデナフィルクエン酸塩
を含む医薬組成物。 - 前記液体担体中に溶解したシルデナフィルクエン酸塩の前記濃度が少なくとも12.5mg/mlである、請求項1又は2記載の医薬組成物。
- 前記液体担体中に溶解したシルデナフィルクエン酸塩の前記濃度が少なくとも20mg/mlである、請求項3記載の医薬組成物。
- 前記液体担体が、水と少なくとも35%のエタノールから本質的に成る、請求項1記載の医薬組成物。
- 少なくとも50%のエタノールを含む、請求項5記載の医薬組成物。
- 少なくとも60%のエタノールを含む、請求項1又は2記載の医薬組成物。
- 少なくとも24時間安定である、請求項1又は2記載の医薬組成物。
- 前記液体担体のpHが4.4以上である、請求項1又は2記載の医薬組成物。
- 前記液体担体は、少なくとも2.5%のアセトンを含む、請求項2記載の医薬組成物。
- 前記液体担体は、少なくとも5%のアセトンを含む、請求項10記載の医薬組成物。
- 前記液体担体は、少なくとも10%のアセトンを含む、請求項10記載の医薬組成物。
- 安定化剤をさらに含み、前記安定化剤が、ジアセチル化モノグリセリド類、ジエチルグリコールモノパルミトステアレート、グリセリルベヘネート、グリセリルジステアレート、グリセリルモノリノレエート、グリセリルモノオレエート、グリセリルモノステアレート、自己乳化型グリセリルモノステアレート、マクロゴールセトステアリルエーテル類、セトマクロゴール1000、9ポリオキシル20セトステアリルエーテル、マクロゴール15ヒドロキシステアレート、マクロゴールラウリルエーテル類、ラウレス4、ラウロマクロゴール400、マクロゴールモノメチルエーテル類、マクロゴールオレイルエーテル類、ポリオキシル10オレイルエーテル、マクロゴールステアレート類、ポリオキシル40ステアレート類、メンフェゴール、モノ&ジグリセリド類、ノノキシノール類、オクトキシノール類、ポロキサマー類、ポリオキシルヒマシ油、ポリオキシル水素化ヒマシ油、ポリソルベート類、プロピレングリコールジアセテート、プロピレングリコールラウレエート類、プロピレングリコールジラウレート、プロピレングリコールモノラウレエート、プロピレングリコールモノパルミトステアレート、キラヤ、ソルビタンエステル類、ショ糖エステル類、チロキサポール、カラゲナン、セルロース、セラトニア、デキストレート類、エチルセルロース、胃ムチン、ヒプロロース(hyprolose)、ヒプロメロース、ヒプロメロースフタレート、メチルセルロース、ポリエチレンオキシド、ポリビニルアセテート、ポリビニルアルコール、シリカ類、デンプングリコール酸ナトリウム、トラガカント、及びキサンタンガムから成る群より選ばれる、請求項2記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461955299P | 2014-03-19 | 2014-03-19 | |
US61/955,299 | 2014-03-19 | ||
PCT/IB2015/052014 WO2015140748A2 (en) | 2014-03-19 | 2015-03-19 | Sildenafil solutions and methods of making and using same |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017508764A JP2017508764A (ja) | 2017-03-30 |
JP2017508764A5 JP2017508764A5 (ja) | 2018-05-10 |
JP6744821B2 true JP6744821B2 (ja) | 2020-08-19 |
Family
ID=54145440
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016558141A Expired - Fee Related JP6744821B2 (ja) | 2014-03-19 | 2015-03-19 | シルデナフィル液剤並びにその製造方法及び使用 |
Country Status (24)
Country | Link |
---|---|
US (2) | US9968609B2 (ja) |
EP (2) | EP3372083A1 (ja) |
JP (1) | JP6744821B2 (ja) |
KR (1) | KR20160137584A (ja) |
CN (1) | CN106132204B (ja) |
AU (2) | AU2015233006B2 (ja) |
CA (1) | CA2942628C (ja) |
CL (1) | CL2016002318A1 (ja) |
CY (1) | CY1120187T1 (ja) |
DK (1) | DK3119201T3 (ja) |
EA (1) | EA032819B1 (ja) |
ES (1) | ES2668915T3 (ja) |
HR (1) | HRP20180773T1 (ja) |
HU (1) | HUE038431T2 (ja) |
IL (1) | IL247840B (ja) |
LT (1) | LT3119201T (ja) |
MX (1) | MX371276B (ja) |
NO (1) | NO2723977T3 (ja) |
PL (1) | PL3119201T3 (ja) |
PT (1) | PT3119201T (ja) |
RS (1) | RS57206B1 (ja) |
SG (2) | SG11201607507VA (ja) |
SI (1) | SI3119201T1 (ja) |
WO (1) | WO2015140748A2 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NO2723977T3 (ja) | 2014-03-19 | 2018-03-10 | ||
JP6902372B2 (ja) * | 2017-02-28 | 2021-07-14 | ヱスビー食品株式会社 | 苦味抑制用組成物 |
CA3086881A1 (en) * | 2017-12-26 | 2019-07-04 | Ftf Pharma Private Limited | Liquid oral formulations for pde v inhibitors |
WO2020212931A1 (en) * | 2019-04-18 | 2020-10-22 | Vigorous Solutions Ltd. | Liquid sildenafil citrate compositions |
US20220387433A1 (en) * | 2019-11-12 | 2022-12-08 | American Regent, Inc. | Type v phosphodiesterase inhibitor compositions, methods of making them and methods of using them in preventing or treating elevated pulmonary vascular pressure or pulmonary hemorrhages |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5785984A (en) * | 1993-02-05 | 1998-07-28 | Kao Corporation | Taste-modifying method and bitterness-decreasing method |
WO1994017675A1 (en) * | 1993-02-05 | 1994-08-18 | Kao Corporation | Taste modifying method and bitter taste reducing method |
US6548490B1 (en) | 1997-10-28 | 2003-04-15 | Vivus, Inc. | Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction |
TWI223598B (en) | 1998-06-22 | 2004-11-11 | Pfizer Ireland Pharmaceuticals | An intranasal pharmaceutical composition for the treatment of male erectile dysfunction or female sexual disorders, an intranasal delivery system or device and sildenafil mesylate |
US6531114B1 (en) | 1999-04-06 | 2003-03-11 | Wm. Wrigley Jr. Company | Sildenafil citrate chewing gum formulations and methods of using the same |
US6552024B1 (en) | 1999-01-21 | 2003-04-22 | Lavipharm Laboratories Inc. | Compositions and methods for mucosal delivery |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
TWI224966B (en) | 1999-11-02 | 2004-12-11 | Pfizer | Pharmaceutical composition (I) useful for treating or preventing pulmonary hypertension in a patient |
AU3048501A (en) * | 1999-11-18 | 2001-05-30 | Natco Pharma Limited | An improved pharmaceutical composition for treating male erectile dysfunction |
KR100848344B1 (ko) | 2000-02-04 | 2008-07-25 | 유서홍 | 담즙산 함유 청정 수용액 제형의 제조 |
AU2001273545A1 (en) | 2000-07-19 | 2002-01-30 | Lavipharm Laboratories, Inc. | Sildenafil citrate solid dispersions having high water solubility |
US20030216407A1 (en) | 2002-01-31 | 2003-11-20 | Pfizer Inc. | Use of PDE5 inhibitors in the treatment of scarring |
US7611728B2 (en) | 2003-09-05 | 2009-11-03 | Supernus Pharmaceuticals, Inc. | Osmotic delivery of therapeutic compounds by solubility enhancement |
EP1781239A2 (en) | 2003-11-17 | 2007-05-09 | Patus Ltd | Compositions effective in altering the perception of malodor |
JP2007517803A (ja) | 2004-01-05 | 2007-07-05 | テバ ファーマシューティカル インダストリーズ リミティド | シルデナフィル塩基とクエン酸塩の製造方法 |
CN1925860A (zh) * | 2004-01-05 | 2007-03-07 | 特瓦制药工业有限公司 | 制备西地那非碱及其柠檬酸盐的方法 |
US7727565B2 (en) | 2004-08-25 | 2010-06-01 | Cadbury Adams Usa Llc | Liquid-filled chewing gum composition |
US7879828B2 (en) | 2005-03-14 | 2011-02-01 | Wyeth Llc | Tigecycline compositions and methods of preparation |
US7556487B2 (en) | 2006-03-29 | 2009-07-07 | Intergum Gida Sinayi ve Ticaret A.S. | Apparatus for making center-filled chewing gum pieces |
FR2906140B1 (fr) * | 2006-09-22 | 2008-12-05 | Philippe Perovitch | Forme galenique pour l'administration par voie trans-muqueuse de principes actifs |
DE502008002360D1 (de) | 2007-06-19 | 2011-03-03 | Symrise Ag | Aromakomposition zum Verringern oder Unterdrücken von unerwünschtem bitteren und adstringierenden Eindruck |
EP2072044A1 (en) * | 2007-12-19 | 2009-06-24 | Abbott GmbH & Co. KG | Pharmaceutical dosage form comprising a liquid or flowable core composition |
WO2009125415A1 (en) | 2008-04-07 | 2009-10-15 | Hetero Research Foundation | Amorphous form of sildenafil citrate |
FR2939321B1 (fr) | 2008-12-05 | 2011-08-26 | Philippe Perovitch | Dispositif de conditionnement et d'administration de principes actifs en solution hydro-alcoolique. |
US8642270B2 (en) | 2009-02-09 | 2014-02-04 | Vm Institute Of Research | Prognostic biomarkers to predict overall survival and metastatic disease in patients with triple negative breast cancer |
DE102010049708A1 (de) * | 2010-10-28 | 2012-05-03 | Hexal Ag | Orale pharmazeutische Filmformulierung für bitter schmeckende Arzneistoffe |
RU2611403C1 (ru) * | 2011-12-05 | 2017-02-21 | Суда Лимитед | Составы в форме спрея для перорального введения и способы введения силденафила |
GB2497933B (en) | 2011-12-21 | 2014-12-24 | Londonpharma Ltd | Drug delivery technology |
IN2014KN02583A (ja) * | 2012-05-16 | 2015-05-08 | Techfields Pharma Co Ltd | |
US9186361B2 (en) | 2013-03-15 | 2015-11-17 | Novartis Ag | Compounds and compositions for the treatment of parasitic diseases |
NO2723977T3 (ja) * | 2014-03-19 | 2018-03-10 |
-
2012
- 2012-04-16 NO NO12802846A patent/NO2723977T3/no unknown
-
2015
- 2015-03-19 EP EP18161634.3A patent/EP3372083A1/en not_active Withdrawn
- 2015-03-19 RS RS20180533A patent/RS57206B1/sr unknown
- 2015-03-19 SG SG11201607507VA patent/SG11201607507VA/en unknown
- 2015-03-19 LT LTEP15764710.8T patent/LT3119201T/lt unknown
- 2015-03-19 PT PT157647108T patent/PT3119201T/pt unknown
- 2015-03-19 EA EA201691871A patent/EA032819B1/ru unknown
- 2015-03-19 EP EP15764710.8A patent/EP3119201B1/en active Active
- 2015-03-19 CA CA2942628A patent/CA2942628C/en active Active
- 2015-03-19 HU HUE15764710A patent/HUE038431T2/hu unknown
- 2015-03-19 MX MX2016012154A patent/MX371276B/es active IP Right Grant
- 2015-03-19 AU AU2015233006A patent/AU2015233006B2/en not_active Ceased
- 2015-03-19 KR KR1020167029017A patent/KR20160137584A/ko not_active Application Discontinuation
- 2015-03-19 PL PL15764710T patent/PL3119201T3/pl unknown
- 2015-03-19 SI SI201530249T patent/SI3119201T1/en unknown
- 2015-03-19 WO PCT/IB2015/052014 patent/WO2015140748A2/en active Application Filing
- 2015-03-19 ES ES15764710.8T patent/ES2668915T3/es active Active
- 2015-03-19 CN CN201580013951.5A patent/CN106132204B/zh not_active Expired - Fee Related
- 2015-03-19 SG SG10201808038TA patent/SG10201808038TA/en unknown
- 2015-03-19 DK DK15764710.8T patent/DK3119201T3/en active
- 2015-03-19 JP JP2016558141A patent/JP6744821B2/ja not_active Expired - Fee Related
-
2016
- 2016-09-14 CL CL2016002318A patent/CL2016002318A1/es unknown
- 2016-09-15 US US15/265,897 patent/US9968609B2/en not_active Expired - Fee Related
- 2016-09-15 IL IL247840A patent/IL247840B/en active IP Right Grant
-
2018
- 2018-04-12 US US15/951,197 patent/US10211534B2/en active Active
- 2018-05-03 CY CY20181100459T patent/CY1120187T1/el unknown
- 2018-05-17 HR HRP20180773TT patent/HRP20180773T1/hr unknown
- 2018-10-16 AU AU2018250378A patent/AU2018250378B2/en not_active Ceased
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018250378B2 (en) | Sildenafil solutions and methods of making and using same | |
CN103269687B (zh) | 贝托斯汀组合物 | |
US9180124B2 (en) | Nicotine containing formulation | |
WO2019119720A1 (zh) | 一种福多司坦雾化吸入用溶液制剂及其制备方法 | |
JP2016506934A (ja) | 液体メントール組成物 | |
TWI620577B (zh) | 乙醯胺酚及曲馬多共溶複方止痛口服液 | |
WO2019091082A1 (zh) | 一种羧甲司坦雾化吸入用溶液制剂及其制备方法 | |
CN102166206B (zh) | 液体的磷酸奥司他韦组合物 | |
CN114159387B (zh) | 一种氢溴酸右美沙芬口服溶液 | |
JP2008260708A (ja) | ベンズイソキサゾール誘導体の経口ゼリー状医薬組成物 | |
US7632853B2 (en) | Soluble, stable and concentrated pharmaceutical composition compromising ritonavir and process for preparing thereof | |
KR102530365B1 (ko) | 아세트아미노펜 젤리 제제 | |
ES2338972B1 (es) | Composicion farmaceutica liquida de ibuprofeno y codeina para su administracion por via oral, su procedimiento de preparacion y utilizacionde la misma. | |
CN101869569A (zh) | 即用型恩替卡韦组合物 | |
RU2607965C1 (ru) | Жидкая лекарственная форма фенспирида и способ ее получения | |
JP2017523231A5 (ja) | ||
JP2017523231A (ja) | 癌治療用アファチニブ医薬キット | |
JP2003192574A (ja) | 弱アルカリで安定化される薬剤を含む医薬用液剤 | |
ES2475942A1 (es) | Composición farmacéutica de citrato de sildenafilo en forma de solución acuosa | |
RU2410088C2 (ru) | Фармацевтическая композиция в форме сиропа и способ ее получения | |
EP3863626A1 (en) | Oral liquid composition comprising triptan | |
WO2018070971A1 (ru) | Фармацевтическая композиция в форме оромукозного спрея для лечения эректильной дисфункции и легочной артериальной гипертензии |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180319 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20180319 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180319 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190212 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190510 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190813 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191210 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20200309 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200720 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200731 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6744821 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |