CN102247337A - Bufotalin dry powder inhalers and preparation method as well as application thereof - Google Patents
Bufotalin dry powder inhalers and preparation method as well as application thereof Download PDFInfo
- Publication number
- CN102247337A CN102247337A CN 201110147785 CN201110147785A CN102247337A CN 102247337 A CN102247337 A CN 102247337A CN 201110147785 CN201110147785 CN 201110147785 CN 201110147785 A CN201110147785 A CN 201110147785A CN 102247337 A CN102247337 A CN 102247337A
- Authority
- CN
- China
- Prior art keywords
- bufotalien
- lactose
- powder
- adjuvant
- formoterol fumarate
- 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
- 239000000843 powder Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- VOZHMAYHYHEWBW-NVOOAVKYSA-N Bufotalin Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@H](O)C[C@H]5CC[C@H]4[C@@]3(O)C[C@@H]2OC(=O)C)C=CC(=O)OC=1 VOZHMAYHYHEWBW-NVOOAVKYSA-N 0.000 title abstract 6
- VOZHMAYHYHEWBW-UHFFFAOYSA-N Bufotalin Natural products CC(=O)OC1CC2(O)C3CCC4CC(O)CCC4(C)C3CCC2(C)C1C=1C=CC(=O)OC=1 VOZHMAYHYHEWBW-UHFFFAOYSA-N 0.000 title abstract 6
- 239000003814 drug Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 7
- 208000037841 lung tumor Diseases 0.000 claims abstract description 6
- OBRNDARFFFHCGE-QDSVTUBZSA-N arformoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-QDSVTUBZSA-N 0.000 claims description 56
- 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 45
- 239000008101 lactose Substances 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 45
- 229960000193 formoterol fumarate Drugs 0.000 claims description 28
- 239000002775 capsule Substances 0.000 claims description 24
- 239000002671 adjuvant Substances 0.000 claims description 22
- 239000008187 granular material Substances 0.000 claims description 15
- 238000001694 spray drying Methods 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 238000010298 pulverizing process Methods 0.000 claims description 8
- 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 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 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 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 229940024606 amino acid Drugs 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 229920002988 biodegradable polymer Polymers 0.000 claims description 4
- 239000004621 biodegradable polymer Substances 0.000 claims description 4
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- 102000009027 Albumins Human genes 0.000 claims description 3
- 108010088751 Albumins Proteins 0.000 claims description 3
- 244000147568 Laurus nobilis Species 0.000 claims description 3
- 235000017858 Laurus nobilis Nutrition 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000005212 Terminalia tomentosa Nutrition 0.000 claims description 3
- 235000012000 cholesterol Nutrition 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- RYDFXSRVZBYYJV-TYYBGVCCSA-N (e)-but-2-enedioic acid;sodium Chemical compound [Na].OC(=O)\C=C\C(O)=O RYDFXSRVZBYYJV-TYYBGVCCSA-N 0.000 claims description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 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
- 239000004475 Arginine Substances 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 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 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine 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
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-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
- 229960003067 cystine Drugs 0.000 claims description 2
- 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 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- 239000003580 lung surfactant Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
- 229930182817 methionine Natural products 0.000 claims 1
- 210000004072 lung Anatomy 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 11
- 238000002347 injection Methods 0.000 abstract description 5
- 239000007924 injection Substances 0.000 abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 5
- 230000002588 toxic effect Effects 0.000 abstract description 5
- 238000010579 first pass effect Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 230000002440 hepatic effect Effects 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 230000009885 systemic effect Effects 0.000 abstract 1
- 230000002685 pulmonary effect Effects 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 15
- 241000283973 Oryctolagus cuniculus Species 0.000 description 15
- 229940079593 drug Drugs 0.000 description 13
- 230000008021 deposition Effects 0.000 description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 240000002853 Nelumbo nucifera Species 0.000 description 3
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 3
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FMMWHPNWAFZXNH-UHFFFAOYSA-N Benz[a]pyrene Chemical compound C1=C2C3=CC=CC=C3C=C(C=C3)C2=C2C3=CC=CC2=C1 FMMWHPNWAFZXNH-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to dry powder inhalers, in particular to dry powder inhalers prepared from bufotalin, a preparation method of the dry powder inhalers and application of the dry powder inhalers to preparation of medicaments for treating lung tumor medicaments. The bufotalin dry powder inhalers are characterized by consisting of bufotalin and a medically acceptable auxiliary material according to the mass ratio of (1:0.05)-(1:115). The bufotalin is prepared into the dry powder inhalers which can directly act on a focus of lung, so that toxic or side reaction is reduced, bioavailability of the medicament is improved, the defects of slow response, hepatic first-pass effect, systemic toxic or side effect, low bioavailability and the like of an oral preparation can be overcome, meanwhile, the problems of inconvenience for use, poor compliance of a patient and the like of injection can also be solved. Thus, the method of preparing the bufotalin into the dry powder inhalers has broad prospect on development of new medicaments.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of bufotalien, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Bufotalien is the main effective ingredient in the Venenum Bufonis, belongs to the cardiac glycoside material, and white crystals is liposoluble substance, and molecular formula is: C
26H
36O
6, have antitumor, pharmacological actions such as analgesia heart tonifying, antiinflammatory and enhance immunity.Oral liquid, the tablet that contains bufotalien at present has been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had curative effect preferably.Bufotalien toxicity is bigger, can produce the toxic and side effects of general after oral, and because the first pass effect of liver be unfavorable for drug accumulation in tumor locus, so onset is slow, the bioavailability of preparation is lower.
Lung has great surface area and abundant blood vessel, make drug molecule very easily enter blood, so the lung inhalation has plurality of advantages such as rapid-action, that untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have use convenient, absorb rapidly, no liver first, rapid release and the localized characteristics of targeting, be a kind of novel drug-supplying system.
Employing can directly act on bufotalien the focus of pulmonary carcinoma through the inhalant of lung administering mode, can improve bufotalien to the curative effect of pulmonary carcinoma and reduce its toxic and side effects to normal structure.Do not see at present the research report of bufotalien Foradil Aerolizer formoterol fumarate with resisting tumor of lung effect.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of bufotalien and preparation method thereof.Another object of the present invention provides the application of Foradil Aerolizer formoterol fumarate of the present invention in preparation treatment lung tumors medicine.
At the foregoing invention purpose, the invention provides following technical scheme:
A kind of bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is made up of bufotalien and medically acceptable adjuvant, and the mass ratio of bufotalien and described adjuvant is 1: 0.05-1: 115.
Described bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is to add the suction powder that adjuvant is made by bufotalien, and the particle diameter of powder is with D
50Meter is between the 0.5-1000 micron.
Described adjuvant is selected one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, the Pulvis Talci for use.
Described sugar can be selected one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose for use; Described alcohol can be selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol for use; Described aminoacid can be selected in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, the arginine one or more for use; Described phospholipid can be selected in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more for use; Described surfactant can be selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol for use; Described polymer substance, can select the macromolecule that meets safety requirements for use, preferred biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, the sodium alginate for example.
Preferred mode is that described adjuvant is the mixture of different-grain diameter lactose, preferred mode is that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the lactose granule mean diameter is at the 75-225 micron, micronization lactose mean diameter is at the 1-5 micron, the mass ratio of lactose granule and micronization lactose is 1000: 1-3: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-12: 1.
Described bufotalien Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufotalien is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus bufotalien and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in bufotalien and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
Preferred bufotalien Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufotalien by pulverizing or spray drying is made powder, is made suction with the mixture mix homogeneously of the lactose of different-grain diameter or lactose granule and micronization lactose and used powder, be packaged in capsule or bubble-cap or the Diskus.
The application of described bufotalien Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, lung has great surface area and abundant blood capillary, make drug molecule very easily enter blood, so the lung inhalation has plurality of advantages such as rapid-action, that untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have use convenient, patient dependence is high, absorptions is rapid, no liver head mistake, rapid release and the localized characteristics of targeting, is a kind of novel drug-supplying system.Existing Foradil Aerolizer formoterol fumarate is used for the treatment of the infection of respiratory tract and pulmonary more, does not see the treatment that is used for lung tumors.Simultaneously, the research with bufotalien Foradil Aerolizer formoterol fumarate of resisting tumor of lung effect does not appear in the newspapers yet.Oral liquid, the tablet that contains bufotalien at present has been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had curative effect preferably, and antitumor activity in vitro shows that its tumor control rate of preparation that contains bufotalien is 26.3-69%.Bufotalien is made Foradil Aerolizer formoterol fumarate, can directly act on pulmonary lesions, there is not simultaneously liver first-pass effect, can improve bioavailability of medicament, reduce the generation of toxicity, overcome medicine made oral formulations after, need through liver first-pass effect, shortcomings such as onset is slow, and the toxic and side effects of general is arranged, and the preparation bioavailability is lower.Therefore bufotalien is made Foradil Aerolizer formoterol fumarate, new drug development is had very big prospect.
2, in order to reach the granularity requirements of Foradil Aerolizer formoterol fumarate, need bufotalien is pulverized, find in the practical operation, when being crushed to certain particle size, bufotalien is easy to reunite because of electrostatic interaction, cohesiveness etc. between the powder influence medicine, therefore need carry out proportioning with adjuvant, overcome the problem that medicine is reunited, the applicant is known through a large amount of experiments, bufotalien and ratio of adjuvant are controlled in the particular range, and particularly adjuvant selects for use the mixture of lactose granule and micronization lactose can make the good Foradil Aerolizer formoterol fumarate of intake performance.
The specific embodiment
Below in conjunction with example the present invention is described in further detail, but scope of the present invention is not subjected to any restriction of these examples.
Embodiment 1
The preparation of inhalant: adopt comminution by gas stream to D bufotalien
50Below=6 microns, mix at 1: 9 by mass ratio, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant with the lactose of particle diameter at the 75-100 micron.
Embodiment 2
The preparation of inhalant: adopt comminution by gas stream to D bufotalien
50=4 microns, mix in 10: 90: 1 ratio at the leucine of 45-65 micron with lactose, the particle diameter of particle diameter at the 75-90 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 3
The preparation of inhalant: adopt comminution by gas stream to D bufotalien
50=4 microns, mix in 1: 9 ratio with the leucine of particle diameter 75-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: with bufotalien powder, lactose, mannitol, glycine, two Laurel phosphatidyl cholines, lecithin, magnesium stearate in 1: 3: 4: 3: 0.5: 0.5: 0.3 ratio was mixed, and comminution by gas stream is to powder D
50=6 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: with the bufotalien comminution by gas stream to powder D
50=5 microns are mixed in 1: 9: 1 ratio with lactose, cholesterol, and drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in bufotalien, add lactose, polyethylene glycol 6000, the albumin of 5 times, 2 times, 3 times of quality respectively, spray drying, powder D
50=8 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
The preparation of inhalant: bufotalien drug powder, the particle diameter of mean diameter at the 5-10 micron mixed in 7: 80: 12 ratio at mannitol, the micronization silica gel of 5-100 micron, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
The preparation of inhalant: bufotalien drug powder, mannitol, leucine are mixed in 8: 95: 7 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 5.0 microns powder, adding mean diameter is the lactose granule mixing of 125-200 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 9
The preparation of inhalant: bufotalien powder, mannitol, glycine are mixed in 9: 95: 6 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.0 microns powder, adding mean diameter is the lactose granule mixing of 80-100 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 10
1, the preparation of inhalant: with bufotalien powder (D
50=7.3 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=4.5 microns) mix in 2: 60: 4 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of bufotalien reaches 25.1%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate of bufotalien does not have significant change.
Embodiment 11
1, the preparation of inhalant: with bufotalien powder (D
50=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=5.5 microns) mix in 12: 87: 2 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of bufotalien reaches 26.2%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate of bufotalien does not have significant change.
Embodiment 12
1, the preparation of inhalant: with bufotalien powder (D
50=6.3 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=4.4 microns) mix in 4: 98: 1 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of bufotalien reaches 22.7%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate of bufotalien does not have significant change.
Embodiment 13
The preparation of inhalant: with bufotalien powder (D
50=7.0 microns), leucine (D
50=245 microns) mix in 1: 10 ratio, mix the particulate D in back
50Be 256 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: bufotalien is mixed comminution by gas stream, powder D with leucine in 1: 1 ratio
50Below 5 microns, this powder is mixed with the mannitol of 9 times of amounts again, mix the particulate D in back
50Be 289 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: bufotalien is mixed comminution by gas stream, powder D with poloxamer in 5: 1 ratio
50Below 5 microns, this powder is mixed with the lactose granule of 8 times of amounts, the magnesium stearate of 1 times of amount again, mix the particulate D in back
50Be 553 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the bufotalien comminution by gas stream, powder D
50=4 microns, this powder is mixed with the lactose granule of 13 times of amounts again, mix the particulate D in back
50Be 254 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 17
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 180 of modeling rats, is divided into 18 groups at random, 10 every group.Every day 1 time, medication 7 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 0.5mg bufotalien/kg; Irritate stomach for the 17th group and give bufotalien, dosage is 0.5mg bufotalien/kg; The 18th group is the normal saline matched group that contains 0.5% sodium carboxymethyl cellulose, lumbar injection 10mL/kg.Next day is put to death rat in drug withdrawal, dissects the rat lungs, observes the lung lesion situation.
Experimental result: it is 22% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or tuberosity pathological changes occurs minimum, is up to 37%; It is 59% that bufotalien is irritated the stomach group, and the normal saline group is 100%, and each group of inhalant administration is irritated the stomach group with bufotalien, the normal saline group has significant difference (P＜0.05) on the pulmonary lesion incidence rate.
Embodiment 18
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
1, the foundation of rabbit VX2 original position lung cancer model
1) the freezing cell suspension of the conventional recovery VX2 tumor of the making of lotus tumor kind rabbit makes 10
6The living cells suspension of/mL is got 1mL and is inoculated in 1 rabbit right rear leg outside intramuscular, 3 week the back can lay one's hand on and the lump of the about 30cm of a diameter in inoculation position, promptly make lotus tumor kind rabbit.
2) cut the intramuscular tumor in the lotus tumor kind rabbit leg outside under the preparation aseptic condition of piece of tissue suspension, get to be and oppress the eugonic tumor tissues of sample, be cut into the mud shape.30 mesh sieves were descended in the flushing of RPMI RPMI-1640, removed individual cells and too small piece of tissue, and 20 mesh sieves were descended in the flushing of RPMI RPMI-1640 in sieve top, removed excessive piece of tissue.Get the lower part of screen branch, after the centrifugation, taking precipitate 2mL adds the RPMI RPMI-1640 and is mixed with piece of tissue suspension 20mL.
3) all rabbit right thoracic wall depilations of inoculation in the lung, intramuscular injection speed is slept and is fixed after new mixture 0.8mL/kg anaesthetizes, routine disinfection, get aseptic three way cock, connecing No. 12 injection needles, suctions respectively has the 1mL syringe of rabbit self blood clot and the syringe that suction has VX2 tumor tissue suspension or cell suspension 1mL.Under X line perspective, No. 12 syringe needles are thrust in the rabbit inferior lobe of right lung, behind the resorption depletion of blood, inject 0.4mL piece of tissue suspension or cell suspension, inject 0.2mL rabbit self blood clot then, extract syringe needle, inoculation finishes.
4) the whole rabbit of the observation of growth of xenografted situation are from inoculating back the 3rd day, and carry out layer wide, bed thickness be 5mm CT scan to chest every day, observes transfer case in tumor growth, the thoracic cavity.
5) rabbit VX2 original position lung cancer model is set up as a result rabbit all tumor growth in the lung, success ratio of inoculation 100%.
2, pharmacodynamic experiment
Get successfully 180 of modeling rabbit, be divided into 18 groups at random, 10 every group.Every day 1 time, medication 12 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 0.5mg bufotalien/kg; Irritate stomach for the 17th group and give bufotalien, dosage is 0.5mg bufotalien/kg; The 18th group is the normal saline matched group that contains 0.5% sodium carboxymethyl cellulose, lumbar injection 10mL/kg.Next day is put to death rabbit in drug withdrawal, dissects the rabbit lungs, peels off tumor tissues, weighs.
Experimental result: the tumour inhibiting rate minimum of each group of inhalant administration is 42.1%, is up to 60.2%; The tumour inhibiting rate that bufotalien is irritated the stomach group is 31.7%, and normal saline does not almost suppress effect to tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate that bufotalien is irritated stomach group, normal saline group.
Claims (10)
1. bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is made up of bufotalien and medically acceptable adjuvant, and the mass ratio of bufotalien and described adjuvant is 1: 0.05-1: 115.
2. a kind of bufotalien Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that it is to add the suction powder that adjuvant is made by bufotalien, and the particle diameter of powder is with D
50Meter is between the 0.5-1000 micron.
3. a kind of bufotalien Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that described adjuvant selects one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, the Pulvis Talci for use.
4. a kind of bufotalien Foradil Aerolizer formoterol fumarate according to claim 3 is characterized in that described sugar, selects one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose for use; Described alcohol is selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol for use; Described aminoacid is selected in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, arginine, the methionine one or more for use; Described phospholipid can be selected in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more for use; Described surfactant is selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol for use; Biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, the sodium alginate.
5. a kind of bufotalien Foradil Aerolizer formoterol fumarate according to claim 3 is characterized in that described adjuvant is the mixture of different-grain diameter lactose or lactose and micronization lactose.
6. a kind of bufotalien Foradil Aerolizer formoterol fumarate according to claim 5, it is characterized in that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the mean diameter of lactose granule is at the 75-225 micron, micronization lactose mean diameter is at the 1-5 micron, and the mass ratio of lactose granule and micronization lactose is 1000: 1-3: 1.
7. adjuvant according to claim 6, the mass ratio that it is characterized in that lactose granule and micronization lactose is 100: 1-12: 1.
8. method for preparing the described a kind of bufotalien Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is as follows:
Bufotalien is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus bufotalien and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in bufotalien and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
9. method for preparing the described bufotalien Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is as follows:
Bufotalien by pulverizing or spray drying is made powder, is made suction with the mixture mix homogeneously of the lactose of different-grain diameter or lactose granule and micronization lactose and used powder, be packaged in capsule or bubble-cap or the Diskus.
10. the application of a kind of bufotalien Foradil Aerolizer formoterol fumarate of claim 1 in preparation treatment lung tumors medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110147785 CN102247337B (en) | 2011-06-02 | 2011-06-02 | Bufotalin dry powder inhalers and preparation method as well as application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110147785 CN102247337B (en) | 2011-06-02 | 2011-06-02 | Bufotalin dry powder inhalers and preparation method as well as application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102247337A true CN102247337A (en) | 2011-11-23 |
| CN102247337B CN102247337B (en) | 2013-03-13 |
Family
ID=44975148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110147785 Expired - Fee Related CN102247337B (en) | 2011-06-02 | 2011-06-02 | Bufotalin dry powder inhalers and preparation method as well as application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102247337B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743594A (en) * | 2018-09-05 | 2018-11-06 | 滨州医学院 | Application and its preparation of the bufotalien as anti-malignant mela noma drug |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1072183A (en) * | 1991-11-06 | 1993-05-19 | 张丽莎 | Extract the method for bufalin and the purposes of bufalin and relevant derivative thereof |
| CN1383851A (en) * | 2002-04-03 | 2002-12-11 | 张启玲 | Lung cancer treating medicine and its prepn |
| CN101485666A (en) * | 2009-02-16 | 2009-07-22 | 南京中医药大学 | Application of Gamabufotalin and salt thereof in preparing medicament for treating gynaecologic tumor |
| CN101491531A (en) * | 2009-02-16 | 2009-07-29 | 南京中医药大学 | Use of bufadienolides compound and bufadienolides salinization compound in preparing medicine for treating gynecological tumor |
| CN101785777A (en) * | 2010-03-30 | 2010-07-28 | 上海现代药物制剂工程研究中心有限公司 | Application of bufotalin std. in preparing medicament for treating lung tumors |
| CN101822832A (en) * | 2010-04-16 | 2010-09-08 | 马宏跃 | Composition with anti-tumor effect and application thereof in preparing medicament for treating tumor |
| WO2010104998A2 (en) * | 2009-03-11 | 2010-09-16 | Johns Hopkins University | Methods for treating heart failure by inhibiting the mitochondrial sodium-calcium exchanger (mnce) |
-
2011
- 2011-06-02 CN CN 201110147785 patent/CN102247337B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1072183A (en) * | 1991-11-06 | 1993-05-19 | 张丽莎 | Extract the method for bufalin and the purposes of bufalin and relevant derivative thereof |
| CN1383851A (en) * | 2002-04-03 | 2002-12-11 | 张启玲 | Lung cancer treating medicine and its prepn |
| CN101485666A (en) * | 2009-02-16 | 2009-07-22 | 南京中医药大学 | Application of Gamabufotalin and salt thereof in preparing medicament for treating gynaecologic tumor |
| CN101491531A (en) * | 2009-02-16 | 2009-07-29 | 南京中医药大学 | Use of bufadienolides compound and bufadienolides salinization compound in preparing medicine for treating gynecological tumor |
| WO2010104998A2 (en) * | 2009-03-11 | 2010-09-16 | Johns Hopkins University | Methods for treating heart failure by inhibiting the mitochondrial sodium-calcium exchanger (mnce) |
| CN101785777A (en) * | 2010-03-30 | 2010-07-28 | 上海现代药物制剂工程研究中心有限公司 | Application of bufotalin std. in preparing medicament for treating lung tumors |
| CN101822832A (en) * | 2010-04-16 | 2010-09-08 | 马宏跃 | Composition with anti-tumor effect and application thereof in preparing medicament for treating tumor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743594A (en) * | 2018-09-05 | 2018-11-06 | 滨州医学院 | Application and its preparation of the bufotalien as anti-malignant mela noma drug |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102247337B (en) | 2013-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5294509B2 (en) | Cycloastragenol monoglucoside, process for its production and use as a pharmaceutical composition | |
| CN102078312A (en) | Curcumin compound dry powder inhaler as well as preparation method and application thereof | |
| CN102058566A (en) | Dry powder inhaler with constituent rubescensin A as well as preparation method and application thereof | |
| CN103788043B (en) | The brilliant IV type of nicousamide, its method for making and its pharmaceutical composition and purposes | |
| CN110054659A (en) | The method for improving Antitumor Activity of Drugs | |
| CN109998996A (en) | Lipid composition and the method for improving Antitumor Activity of Drugs | |
| CN102247335B (en) | Bufalin dry powder inhalant as well as preparation method and application thereof | |
| CN102302477B (en) | Cinobufagin dry power inhaler and preparation method and application thereof | |
| CN102302475B (en) | Resibufogenin dry powder inhalant and preparation method and application thereof | |
| CN102247337B (en) | Bufotalin dry powder inhalers and preparation method as well as application thereof | |
| CN102961409B (en) | Toad skin extract dry powder inhaler | |
| CN102210712B (en) | Bufo bufo gargarizans cantor skin extract dry powder inhalant and preparation method and use thereof | |
| CN101322681A (en) | Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic | |
| CN102247336B (en) | Bufothionine dry powder inhaler, and its preparation method and application | |
| CN102210711B (en) | Senso fat-soluble extract dry powder inhalation, preparation method and application thereof | |
| CN102526038B (en) | Temozolomide brain-targeting pharmaceutical composition and application thereof | |
| CN103083286B (en) | Toad venom lipophilic extract dry powder inhaler, as well as preparation method and application thereof | |
| CN102961406B (en) | Toad skin extract dry powder inhaler, as well as preparation method and application thereof | |
| CN102302476B (en) | Dehydrobufotenine dry power inhaler and preparation method and application thereof | |
| CN103142652B (en) | Venenum bufonis fat-soluble extract dry powder inhaler, and preparation method and application thereof | |
| CN102961407B (en) | Toad skin extract dry powder inhaler, as well as preparation method and application thereof | |
| CN102961408B (en) | Toad skin extract dry powder inhaler | |
| CN102973605B (en) | Toad skin extract dry powder inhalant and preparation method and applications thereof | |
| CN103070885B (en) | Toad skin extract dry-powder inhalant and its preparation method and use | |
| CN102973604B (en) | Toad skin extract dry powder inhalant and preparation method and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130313 |