CN102727455A - Tadalafil oral disintegrating tablet and preparation method thereof - Google Patents
Tadalafil oral disintegrating tablet and preparation method thereof Download PDFInfo
- Publication number
- CN102727455A CN102727455A CN2012102362614A CN201210236261A CN102727455A CN 102727455 A CN102727455 A CN 102727455A CN 2012102362614 A CN2012102362614 A CN 2012102362614A CN 201210236261 A CN201210236261 A CN 201210236261A CN 102727455 A CN102727455 A CN 102727455A
- Authority
- CN
- China
- Prior art keywords
- solution
- tadalafil
- pharmaceutically
- oral cavity
- acceptable salts
- 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.)
- Granted
Links
- 229960000835 tadalafil Drugs 0.000 title claims abstract description 33
- 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 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 32
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 239000000945 filler Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000001694 spray drying Methods 0.000 claims abstract description 13
- 239000000853 adhesive Substances 0.000 claims abstract description 3
- 230000001070 adhesive effect Effects 0.000 claims abstract description 3
- 239000007921 spray Substances 0.000 claims description 22
- 210000000214 mouth Anatomy 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 17
- 239000011230 binding agent Substances 0.000 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 239000002671 adjuvant Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 238000009835 boiling Methods 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000011859 microparticle Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 238000007907 direct compression Methods 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- -1 hydroxypropyl Chemical group 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
- 235000010489 acacia gum Nutrition 0.000 claims description 4
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 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
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 xylitol Drugs 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 101100273639 Carassius auratus ccna1 gene Proteins 0.000 claims 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 claims description 2
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 claims description 2
- 101000652736 Homo sapiens Transgelin Proteins 0.000 claims description 2
- 239000004831 Hot glue Substances 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 244000147568 Laurus nobilis Species 0.000 claims description 2
- 235000017858 Laurus nobilis Nutrition 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229910000503 Na-aluminosilicate Inorganic materials 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 235000005212 Terminalia tomentosa Nutrition 0.000 claims description 2
- 102100031013 Transgelin Human genes 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229920005601 base polymer Polymers 0.000 claims 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 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
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- 235000010980 cellulose Nutrition 0.000 claims description 2
- 235000009508 confectionery Nutrition 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class 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 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
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- 239000008101 lactose Substances 0.000 claims description 2
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- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000000429 sodium aluminium silicate Substances 0.000 claims description 2
- 235000012217 sodium aluminium silicate Nutrition 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
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- 238000005507 spraying Methods 0.000 claims description 2
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
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- 229940082509 xanthan gum Drugs 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 16
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- 239000000463 material Substances 0.000 abstract 1
- 239000006186 oral dosage form Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
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- 238000001514 detection method Methods 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
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- 239000011248 coating agent Substances 0.000 description 2
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- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
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- 229940094720 viagra Drugs 0.000 description 2
- PPWLAQVKIFDULF-UHFFFAOYSA-N 2-phenyl-1h-pyrrolo[2,3-b]pyridine Chemical compound N1C2=NC=CC=C2C=C1C1=CC=CC=C1 PPWLAQVKIFDULF-UHFFFAOYSA-N 0.000 description 1
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
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- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products 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 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
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- 239000007884 disintegrant Substances 0.000 description 1
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- 210000003296 saliva Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 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 description 1
- 210000002784 stomach Anatomy 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to the improvement of the shortcomings that the existing tadalafil and pharmaceutically acceptable salt thereof in the aspect of oral dosage form and provides an oral disintegrating tablet preparation of tadalafil and pharmaceutically acceptable salt thereof. The oral disintegrating tablet is convenient to take, and fast in absorption and action, good in taste and high in bioavailability. Being different from common spray drying, the oral disintegrating tablet disclosed by the invention is subject to spray drying together with main auxiliary materials, including disintegrating agent, adhesive, filling agent, etc., thus the objectionable flavors of the medicament can be masked better; and meanwhile, the oral disintegrating tablet can be quickly disintegrated and can also be quickly disintegrated without an effervescent tablet.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of have rapid delivery of pharmaceuticals and the good orally disintegrating tablet preparation of taste, is the tadalafil oral cavity disintegration tablet specifically.
Background technology
In recent years; (sexual impotence, representative drugs ED) have three types to the treatment male sexual dysfunction of research: (1) phosphodiesterase inhibitor (representative drugs is tadalafil-viagra) (2) a-receptor blocking agent (representative drugs is a phentolamine mesylate) (3) dopamine-receptor stimulant (representative drugs is an apomorphine) in the world.
Research shows; Libido can make neurocyte secretion nitric oxide (NO), sees through the spongy body VSMC through diffusion, activates guanylate cyclase; But guanylate cyclase catalysis GTP generates cGMP; CGMP is the second message,second messenger of cellular signal transduction, can make the penis smooth muscle relaxation, finally makes erection.CGMP can generate 5GMP through the catalysis of 5 type phosphodiesterases (PDE-5), loses second message,second messenger's effect.Tadalafil is the special inhibitor of 5 type phosphodiesterases (PDE-5); And tadalafil (Vardenafil) has another name called Vardenafil, is the up-to-date medicine in up-to-date in the world at present disorder of erection function (ED) treatment field; Be that Bayer (Bayer) is developed through years'development with GlaxoSmithKline PLC (Glaxo Smith Kline) company; Be acting through suppressing 5 type PDEs (PDE-5), same tadalafil (viagra) is compared, and it has following advantage: consumption is few; Only need 20mg, and tadalafil needs 120mg-150mg.Onset time is fast, and average onset time is about 16 minutes, takes back 2 hours PC peakings, 18～48 hours half-life.Side effect is little, but because of the difference of individuality, still has the people of less than 2% can slightly feel slight headache.Vardenafil obtains drugs approved by FDA in the U.S. in August, 2003, and European Union also goes on the market.
Oral cavity disintegration tablet is meant not to be needed water or only needs low amounts of water, need not to chew, and tablet places lingual surface, meets after saliva separates rapidly or collapse, and borrows and swallows power, and medicine can be gone into the tablet of stomach onset.The characteristics of oral cavity disintegration tablet are that absorption is fast, bioavailability is high, and intestinal is residual few, and side effect is low, avoids liver first-pass effect etc.
Summary of the invention
The objective of the invention is to improve existing tadalafil and pharmaceutically acceptable salt thereof aspect peroral dosage form deficiency, a kind of taking convenience is provided, absorbs rapid-action, good mouthfeel and high tadalafil and the pharmaceutically acceptable salt orally disintegrating tablet preparation thereof of bioavailability.
The tadalafil that reaches according to the invention and the oral cavity disintegration tablet of pharmaceutically-acceptable salts thereof, according to weight ratio, the 5-50% of tadalafil and pharmaceutically-acceptable salts thereof; Binding agent 1-10%, filler 20-90%, disintegrating agent 5-45%; Effervescent 0-30%, fluidizer 0-5%, lubricant 0-3%.
The tadalafil of further being addressed and the oral cavity disintegration tablet of pharmaceutically-acceptable salts thereof, according to weight ratio, the 10-20% of tadalafil and pharmaceutically-acceptable salts thereof; Binding agent 3-5%; Filler 40-90%, disintegrating agent 10-40%, effervescent 0-30%; Also can comprise fluidizer 0-5%, lubricant 0-3%.
Further, the oral cavity disintegration tablet of above-mentioned Da Nafei and pharmaceutically-acceptable salts thereof, according to weight ratio, effervescent 5-20% also can comprise fluidizer 3-5%, lubricant 1-3%.
Wherein, Binding agent includes but are not limited to day hot glue family macromolecule polymer such as starch, pregelatinized Starch, dextrin, maltodextrin, sucrose, arabic gum or gelatin, hydrophilic cellulose base polymer, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthan gum, hydroxypropyl cellulose and hydroxypropyl emthylcellulose (HPMC); Can use use also capable of being combined separately.Be preferably polyvinylpyrrolidone (PVP), arabic gum, gelatin, hypromellose.
Filler is tasteless or sweet cpd; Include but are not limited to mannitol, xylitol, sorbitol, maltose 、 Chi ?alcohol, microcrystalline Cellulose,
SMCC, polymerization sugar
coupling sugar, glucose, lactose, sucrose, dextrin and starch etc.; Can use separately, also can Combination application.Be preferably mannitol, xylitol, sorbitol.
Disintegrating agent includes but are not limited to crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), low substituted hydroxy-propyl methylcellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa) and soybean polysaccharide
etc.; Can use use also capable of being combined separately.Be preferably crospolyvinylpyrrolidone (PVPP).
Fluidizer includes but are not limited to micropowder silica gel, Pulvis Talci, Cab-O-sil, Arosil, hydrated sodium aluminosilicate.Lubricant includes but are not limited to magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, Polyethylene Glycol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium laurylsulfate, lauryl alcohol sulphuric acid younger sister, Stepanol MG and Pulvis Talci etc.; Can use use also capable of being combined separately.
Effervescent includes but are not limited to the mixture of malic acid, citric acid or citric acid and sodium bicarbonate or sodium carbonate.
Above-mentioned oral cavity disintegration tablet, it promptly carries out spray drying treatment with medicine, each adjuvant successively through special method for preparing in same container, obtain being mixture Powdered or the microparticle shape.Except fluidizer and lubricant, the adjuvant of all the other kinds, for example binding agent, filler, disintegrating agent, three's order can change arbitrarily or or will wherein a kind ofly join in other two kinds with arbitrary proportion.Also can take same processing when increasing other kind adjuvants.
Concrete method for preparing comprises:
1. with medicine, filler, disintegrating agent mixed dissolution in solvent, be called solution 1 respectively, solution 2, solution 3.
2. solution 1 is carried out spray drying in fluid bed or spray dryer earlier, make medicine be " boiling " state after, spray into solution 2 and solution 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, mix direct compression or granulation with other adjuvants.
Need to prove that the order that above-mentioned solution 2 and 3 sprays into is unrestricted, only need spray into successively.Preferably, spray into disintegrating agent solution 3 at last.
Preferably, above-mentioned method for preparing can be divided equally disintegrating agent equivalent or arbitrary proportion is dissolved in each solution, in the ie in solution 1 and 2, and refabrication solution 3 not.
Preferably, above-mentioned method for preparing can with the part adhesive be dissolved in the solvent form solution 4 after, the 2. in the step, spray into after solution 1 makes medicine be " boiling " state spraying into.Can also equivalent or arbitrary proportion be dissolved in the solution 2,3 and spray into together.
Likewise, above-mentioned method for preparing is treated to spray into after medication medication is " boiling " state after also can also can taking said method to form solution 5 correctives, can also equivalent or arbitrary proportion be dissolved in solution 2,3, spray into together in 4.
Different with common spray drying is that the present invention comprises disintegrating agent with medicine and main adjuvant, after binding agent, filler etc. get into spray drying successively, can cover the bad of medicine better and ask that simultaneously, disintegrate is rapid.Also disintegrate fast under the situation that does not need effervescent.
Preferably; Having under the situation of effervescent; Add in 3. in above-mentioned steps, perhaps one of them adds in the solution with equivalent or arbitrary proportion with acid moieties/alkali part in 2. in step, and remaining alkali part/acid moieties mixes perhaps tabletting after the granulation of back direct compression with other adjuvants.Owing to adopt the spray-dired mode of layering, when the effect of part coating is arranged and disintegrate rapid, and the dissolving that can take the lead in of exposed drug moiety is followed successively by the coating part, the core is thought of as Concentraton gradient preferably, making it medicine can fully be absorbed.Therefore, inapplicable effervescent perhaps uses a small amount of effervescent just can realize the quick disintegrate stripping of medicine.
Need explanatorily be when taking pelletizing press sheet technology, when selecting fluidizer, lubricant are arranged, after granulation, to add.
Preferably, prescription is formed, and according to weight ratio is:
Wherein, above-mentioned adjuvant can use preferred other adjuvants to replace.
Above-mentioned oral cavity disintegration tablet, its preparation method comprises:
1. tadalafil, filler, disintegrating agent, binding agent are dissolved in respectively in the solvent, are called solution A 1 respectively, solution A 2, solution A 3.
2. solution A 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution A 2 and solution A 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, mix direct compression with other adjuvants.
Further, prescription is formed, and according to weight ratio is:
Wherein, above-mentioned adjuvant can use preferred other adjuvants to replace.
Above-mentioned oral cavity disintegration tablet, its preparation method comprises:
1. tadalafil, filler, disintegrating agent, binding agent are dissolved in respectively in the solvent, are called solution A 1 respectively, solution A 2, solution A 3.Simultaneously, one of them is dissolved in solution A 2 or A3 with citric acid/sodium bicarbonate, perhaps is dissolved in solution A 2 and A3 behind the five equilibrium.
2. solution A 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution A 2 and solution A 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, mix direct compression with other adjuvants.
In the present invention, related solvent promptly makes to be not limited to particular types by dissolved solvents such as medicine, adjuvant, as long as make that chemical compound can good solvent, can select organic solvent, and for example acetone, ethanol etc. also can be selected water.
The specific embodiment
Below come further to explain or explanation content of the present invention through embodiment.Described embodiment has been merely and has helped to understand content of the present invention, should not be understood that the qualification to purport of the present invention and protection domain.
Embodiment 1
Prescription is formed, and according to weight ratio is:
Method for preparing comprises:
1. tadalafil, binder/disintegrant, filler are dissolved in 95% ethanol, are called solution B 1 respectively, solution B 2, solution B 3.
2. solution B 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution B 2 and solution B 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, mix direct compression after the intermediate content detection with magnesium stearate.
Embodiment 2
Prescription is formed, and according to weight ratio is:
Method for preparing comprises:
1. tadalafil, binding agent, disintegrating agent/filler are dissolved in the acetone solvent, are called solution C 1 respectively, solution C 2, solution C 3.
2. solution C 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution C 2 and solution C 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, after the intermediate content detection, mix direct compression with magnesium stearate.
Embodiment 3
Prescription is formed, and according to weight ratio is:
Method for preparing comprises:
1. tadalafil, binding agent, filler are dissolved in the acetone, are called solution D 1 respectively, solution D 2, solution D 3 adds solution D 2 respectively with branches such as disintegrating agents, solution D 3.
2. solution D 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution D 2 and solution D 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. the solids that obtains of step mix, granulate, 50 ℃ of dryings are crossed 20 mesh sieves, after the intermediate content detection, mix tabletting with magnesium stearate.
Embodiment 4
Prescription is formed, and according to weight ratio is:
Method for preparing comprises:
1. tadalafil, binding agent, filler are dissolved in the acetone, are called solution E 1 respectively, solution E 2, solution E 3 adds solution E 2 respectively, solution E 3 with disintegrating agent and one of them five equilibrium of citric acid/sodium bicarbonate.
2. solution E 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution E 2 and solution E 3 more successively, drying obtains being solids Powdered or the microparticle shape.
3. with the 2. after the solids that obtains of step and the residue adjuvant mixing intermediate content detection, mix tabletting with magnesium stearate.
The foregoing description sample is detected: place 2m1 water, measure complete disintegration time and mouthfeel.See following table for details.
The disintegration time of each embodiment tadalafil of table 1
What need explanation is that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (10)
1. the oral cavity disintegration tablet of tadalafil and pharmaceutically-acceptable salts thereof, according to weight ratio, tadalafil and pharmaceutically-acceptable salts 5-50% thereof, binding agent 1-10%, filler 20-90%, disintegrating agent 5-45%, fluidizer 0-5%, lubricant 0-3%.
2. the oral cavity disintegration tablet of tadalafil and pharmaceutically-acceptable salts thereof according to claim 1, according to weight ratio, tadalafil and pharmaceutically-acceptable salts 10-20% thereof; Binding agent 3-5%, filler 40-90%, disintegrating agent 10-40%; Fluidizer 0-5%, lubricant 0-3%.
3. the oral cavity disintegration tablet of tadalafil and pharmaceutically-acceptable salts thereof according to claim 1 or claim 2 according to weight ratio, also can comprise effervescent 5-20%.
4. like each described oral cavity disintegration tablet of claim 1-3; Said binding agent is selected from day hot glue family macromolecule polymer such as starch, pregelatinized Starch, dextrin, maltodextrin, sucrose, arabic gum or gelatin, hydrophilic cellulose base polymer, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthan gum, hydroxypropyl cellulose and hydroxypropyl emthylcellulose (HPMC); Can use use also capable of being combined separately; Filler is tasteless or sweet cpd; Include but are not limited to mannitol, xylitol, sorbitol, maltose 、 Chi ?alcohol, microcrystalline Cellulose,
SMCC, polymerization sugar
coupling sugar, glucose, lactose, sucrose, dextrin and starch; Can use separately, also can Combination application; Disintegrating agent selects crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), low substituted hydroxy-propyl methylcellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa) and soybean polysaccharide
can use use also capable of being combined separately; Fluidizer is selected from micropowder silica gel, Pulvis Talci, Cab-O-sil, Arosil, hydrated sodium aluminosilicate; Lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, Polyethylene Glycol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium laurylsulfate, lauryl alcohol sulphuric acid younger sister, Stepanol MG and Pulvis Talci; Can use use also capable of being combined separately.
5. the oral cavity disintegration tablet of said tadalafil of claim 4 and pharmaceutically-acceptable salts thereof, binding agent is polyvinylpyrrolidone (PVP), arabic gum, gelatin, hypromellose; Filler is mannitol, xylitol, sorbitol; Disintegrating agent is crospolyvinylpyrrolidone (PVPP); Lubricant is magnesium stearate, calcium stearate.
6. the oral cavity disintegration tablet of said tadalafil of claim 3 and pharmaceutically-acceptable salts thereof, effervescent includes but are not limited to the mixture of malic acid, citric acid or citric acid and sodium bicarbonate or sodium carbonate.
7. the oral cavity disintegration tablet of said tadalafil of claim 1-5 and pharmaceutically-acceptable salts thereof is write out a prescription and is formed, and according to weight ratio is:
Principal agent tadalafil 15-20%,
Binding agent and disintegrating agent polyvinylpyrrolidone (PVP) 10-15%,
Filler mannitol 40-80%,
Fluidizer magnesium stearate 1-2%.
8. the oral cavity disintegration tablet of claim 3 or 6 said tadalafils and pharmaceutically-acceptable salts thereof is write out a prescription and is formed, and according to weight ratio is:
9. the method for preparing of the oral cavity disintegration tablet of said tadalafil of claim 1-8 and pharmaceutically-acceptable salts thereof comprises:
1. with medicine, filler, disintegrating agent mixed dissolution in solvent, be called solution 1 respectively, solution 2, solution 3;
2. solution 1 is carried out spray drying earlier, make medicine be " boiling " state after, spray into solution 2 and solution 3 more successively, drying obtains being solids Powdered or the microparticle shape;
3. with the 2. the solids that obtains of step mix, mixes the direct compression or the tabletting afterwards of granulating with other adjuvants;
Wherein, above-mentioned steps 2. in, solution 2 and 3 the order that sprays into are unrestricted, and only are to spray into successively;
Perhaps, step 1. in, disintegrating agent equivalent is divided equally or arbitrary proportion is dissolved in each solution, in the ie in solution 1 and 2, and refabrication solution 3 not.
10. like the method for preparing of the said oral cavity disintegration tablet of claim 9; The part adhesive is dissolved in formation solution 4 in the solvent; The 2. in the step, after making medicine be " boiling " state, solution 1 sprays into or equivalent or arbitrary proportion are dissolved in and spray into together in the solution 2,3 spraying into;
Likewise, above-mentioned method for preparing is treated to spray into after medication medication is " boiling " state after also can also can taking said method to form solution 5 correctives, can also equivalent or arbitrary proportion be dissolved in solution 2,3, spray into together in 4.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191075A (en) * | 2013-04-28 | 2013-07-10 | 南京海融医药科技有限公司 | Oral medicinal preparation of tadalafil |
| CN105213333A (en) * | 2014-06-30 | 2016-01-06 | 深圳海王药业有限公司 | A kind of tadanafil pharmaceutical composition and preparation method thereof |
| CN109157520A (en) * | 2018-09-07 | 2019-01-08 | 苏州科技城医院 | Tadalafei tablet and preparation method thereof |
| CN115154429A (en) * | 2021-04-06 | 2022-10-11 | 南京科默生物医药有限公司 | Tadalafil oral disintegrating composition |
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| CN101141950A (en) * | 2005-03-01 | 2008-03-12 | 拜耳医药保健股份公司 | Pharmaceutical forms with improved pharmacokinetic properties |
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101141950A (en) * | 2005-03-01 | 2008-03-12 | 拜耳医药保健股份公司 | Pharmaceutical forms with improved pharmacokinetic properties |
| WO2011030351A2 (en) * | 2009-09-03 | 2011-03-17 | Rubicon Research Private Limited | Taste - masked pharmaceutical compositions |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191075A (en) * | 2013-04-28 | 2013-07-10 | 南京海融医药科技有限公司 | Oral medicinal preparation of tadalafil |
| CN103191075B (en) * | 2013-04-28 | 2015-04-08 | 南京海融医药科技有限公司 | Oral medicinal preparation of tadalafil |
| CN105213333A (en) * | 2014-06-30 | 2016-01-06 | 深圳海王药业有限公司 | A kind of tadanafil pharmaceutical composition and preparation method thereof |
| CN109157520A (en) * | 2018-09-07 | 2019-01-08 | 苏州科技城医院 | Tadalafei tablet and preparation method thereof |
| CN109157520B (en) * | 2018-09-07 | 2021-04-02 | 苏州科技城医院 | Tadalafil tablet and preparation method thereof |
| CN115154429A (en) * | 2021-04-06 | 2022-10-11 | 南京科默生物医药有限公司 | Tadalafil oral disintegrating composition |
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