CN102302476A - Dehydrobufotenine dry power inhaler and preparation method and application thereof - Google Patents
Dehydrobufotenine dry power inhaler and preparation method and application thereof Download PDFInfo
- Publication number
- CN102302476A CN102302476A CN201110147769A CN201110147769A CN102302476A CN 102302476 A CN102302476 A CN 102302476A CN 201110147769 A CN201110147769 A CN 201110147769A CN 201110147769 A CN201110147769 A CN 201110147769A CN 102302476 A CN102302476 A CN 102302476A
- Authority
- CN
- China
- Prior art keywords
- dehydrobufotenine
- 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
- XRZDSPVDZKCARG-UHFFFAOYSA-O dehydrobufotenine Chemical compound C1=C(O)C([N+](C)(C)CC2)=C3C2=CNC3=C1 XRZDSPVDZKCARG-UHFFFAOYSA-O 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 51
- 239000003814 drug Substances 0.000 claims abstract description 28
- 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 54
- 239000000843 powder Substances 0.000 claims description 50
- 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
- 229960000193 formoterol fumarate Drugs 0.000 claims description 27
- 239000002775 capsule Substances 0.000 claims description 24
- 239000002671 adjuvant Substances 0.000 claims description 23
- 239000008187 granular material Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000001694 spray drying Methods 0.000 claims description 11
- 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 8
- 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
- 238000011282 treatment Methods 0.000 claims description 7
- 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
- 208000037841 lung tumor Diseases 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 6
- 235000001014 amino acid Nutrition 0.000 claims description 5
- 229940024606 amino acid Drugs 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000004471 Glycine Substances 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
- 230000008569 process Effects 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
- 206010028980 Neoplasm Diseases 0.000 abstract description 23
- 238000002347 injection Methods 0.000 abstract description 21
- 239000007924 injection Substances 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 17
- 230000002685 pulmonary effect Effects 0.000 abstract description 17
- 210000004072 lung Anatomy 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 238000009472 formulation Methods 0.000 abstract description 8
- 210000004185 liver Anatomy 0.000 abstract description 6
- 230000003902 lesion Effects 0.000 abstract description 5
- 238000010579 first pass effect Methods 0.000 abstract description 4
- 229940112141 dry powder inhaler Drugs 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 2
- 230000002411 adverse Effects 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 9
- 230000008021 deposition Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 241000269417 Bufo Species 0.000 description 3
- 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
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 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
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 206010003671 Atrioventricular Block Diseases 0.000 description 2
- 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 description 2
- 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 description 2
- 206010048610 Cardiotoxicity Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 2
- 208000007888 Sinus Tachycardia Diseases 0.000 description 2
- 206010040741 Sinus bradycardia Diseases 0.000 description 2
- 208000005392 Spasm Diseases 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
- 208000024780 Urticaria Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 230000007681 cardiovascular toxicity Effects 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 239000011780 sodium chloride Substances 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
- 230000004614 tumor growth Effects 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
- 241001415440 Bufo gargarizans Species 0.000 description 1
- 241000269420 Bufonidae Species 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 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
- 230000035617 depilation Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000037336 dry skin Effects 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
- 238000000338 in vitro Methods 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- -1 is to lung tumors Chemical compound 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000614 poison Toxicity 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000000779 thoracic wall Anatomy 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a dehydrobufotenine dry power inhaler, in particular to a dry power inhaler made of dehydrobufotenine, a preparation method of the dry power inhaler and application of the dry power inhaler in preparation of drugs for treating tumors of lung. The dehydrobufotenine dry power inhaler is characterized by consisting of the dehydrobufotenine and medically acceptable auxiliary materials, and the mass ratio of the dehydrobufotenine to the medically acceptable auxiliary materials is 1: 0.02 - 1:100. The dehydrobufotenine is prepared to be the dry powder inhaler, therefore, the dehydrobufotenine can be directly acted on pulmonary lesions, the happening of adverse actions is reduced, the bioavailability of the drug is enhanced, the defects of oral formulation including slow effect, first-pass effect to liver, low bioavailability and the like are overcome, and synchronously the problems of injection including inconvenience for use, bad compliance of patients and the like are also solved.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the method for preparing of the Foradil Aerolizer formoterol fumarate processed of dehydrobufotenine, said Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Cutis Bufonis is the dry skin of Bufonidae animal Bufo siccus Bufobufo gargarizans Cantor, has the effect of heat-clearing and toxic substances removing, diuretic relieving distension.The Cutis Bufonis water soluble part mainly contains dehydrobufotenine, N-phenyl-ethylnaphthalene amine, amino acids, and wherein dehydrobufotenine is the indole alkaloids, is its main component, and molecular formula is C
12H
14N
2O, antitumor activity in vitro show that dehydrobufotenine has tumors of higher and suppresses active.With water soluble ingredient in the Cutis Bufonis is the existing a plurality of listings of medicine of main exploitation, and present cinobufacin injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had curative effect preferably.Especially HUACHANSU ZHUSHEYE; Be from the water soluble preparation of Bufo siccus skin through being processed into; Treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.But injection need use in hospital, and administering mode is expensive, and patient compliance is poor, is difficult to carry out long-term treatment.In addition, though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister appearance; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in few part patient, possibly be that the cardiac toxicity that a spot of bufotalin produced in the cinobufacin causes.And the cinobufacin oral formulations need pass through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.Dehydrobufotenine is one of effective ingredient in cinobufacin injection and the oral formulations, but the content in injection and oral formulations is lower; And above-mentioned preparation can not directly act on lesions position, its inhibitory action to tumor can not be performed to maximum.
Alveolar wall is made up of cell monolayer, has great surface area, make drug molecule very easily get into 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 leans on patient's autonomous respiration to produce makes the medicine powder atomization; And then make drug powder be delivered to pulmonary; Have convenient in application, absorb the first mistake of rapid, no liver, rapid release, targeting location and the little characteristics of toxic and side effects; And can improve patient compliance, be specially adapted to the patient that former need carry out the long term injections treatment, be a kind of novel drug-supplying system.
The sickness rate of pulmonary carcinoma rises rapidly in worldwide, has become the first cancer killer.Present antitumor drug great majority all are drug administration by injection, and this whole body administering mode is unfavorable for drug accumulation in tumor locus, and untoward reaction increases, and cause the curative effect of medicine to reduce.
Adopt site-specific delivery of drugs that antitumor drug is transported to the tumor patient part of human body, medicine is improved in the concentration of patient part, the toxic and side effects that reduces medicine, the therapeutic effect that improves medicine are had great clinical value.Employing can directly act on dehydrobufotenine the focus of pulmonary carcinoma through the inhalant of lung administering mode, helps improving dehydrobufotenine 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 that the dehydrobufotenine Foradil Aerolizer formoterol fumarate with resisting tumor of lung effect is arranged.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of dehydrobufotenine and preparation method thereof.Another object of the present invention provides the application of Foradil Aerolizer formoterol fumarate according to the invention in preparation treatment lung tumors medicine.
To the foregoing invention purpose, the present invention provides following technical scheme:
A kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is made up of dehydrobufotenine and medically acceptable adjuvant, and the mass ratio of dehydrobufotenine and described adjuvant is 1: 0.02-1: 100.
Described dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is to add the suction powder that adjuvant is processed by dehydrobufotenine, 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 said adjuvant is the lactose of different-grain diameter; Preferred mode is that said adjuvant is for sucking the mixture with lactose granule and micronization lactose; Wherein the lactose granule mean diameter is that 45-225 micron micronization lactose mean diameter is the 1-5 micron; The mass ratio of lactose granule and micronization lactose is 1020: 1-1: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-6: 1.
Described dehydrobufotenine Foradil Aerolizer formoterol fumarate, its preparation process is following:
Dehydrobufotenine is processed powder through pulverizing or spray drying, and powder and adjuvant mix homogeneously are processed to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, process suction through pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus dehydrobufotenine and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in dehydrobufotenine and the prescription, through pulverizing or spray drying is processed powder, residue adjuvant mix homogeneously is processed to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
Preferred dehydrobufotenine Foradil Aerolizer formoterol fumarate, its preparation process is following:
Dehydrobufotenine through pulverizing or spray drying is processed powder, is processed suction with the mixture mix homogeneously of the lactose of different-grain diameter or micronization lactose and lactose and used powder, be packaged in capsule or bubble-cap or the Diskus.
The application of described dehydrobufotenine Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, lung is a kind of open organ, has great surface area, and alveolar wall is made up of cell monolayer, makes drug molecule very easily get into blood, thus the lung inhalation have rapid-action, untoward reaction is little and plurality of advantages such as easy to use.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation; DPIs) do not use propellant and solvent; The air-flow that leans on patient's autonomous respiration to produce makes the medicine powder atomization; And then make drug powder be delivered to pulmonary; Having convenient in application, absorb the first mistake of rapid, no liver, rapid release and the localized characteristics of targeting, is a kind of novel drug-supplying system.At present be used for treating the infection of respiratory tract and pulmonary more, but do not see treatment at lung tumors relevant for Foradil Aerolizer formoterol fumarate.Simultaneously, the research with dehydrobufotenine Foradil Aerolizer formoterol fumarate of resisting tumor of lung effect does not appear in the newspapers yet.Present Cutis Bufonis extract injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had effect preferably.Especially HUACHANSU ZHUSHEYE; Be from the water soluble preparation of Bufo siccus skin through being processed into; Treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister appearance; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in few part patient, and the possible cause of generation is the cardiac toxicity reaction that a spot of bufotalin produced in the cinobufacin.In addition, the use of injection need be used in hospital, and patient compliance is poor.Dehydrobufotenine is one of effective ingredient of cinobufacin injection and oral formulations, but the content in injection and oral formulations is lower.And above-mentioned preparation can not directly act on lesions position, dehydrobufotenine can not be performed to maximum to the inhibitory action of tumor, and oral formulations need pass through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.The Foradil Aerolizer formoterol fumarate that uses dehydrobufotenine mainly is to lung tumors, directly acts on focus, does not have liver first-pass effect simultaneously, and is rapid-action, and do not have above-mentioned untoward reaction, and new drug development is had very big prospect.
2, dehydrobufotenine is a water soluble ingredient, is prone to moisture absorption, needs to be mixed into Foradil Aerolizer formoterol fumarate with adjuvant.Find in the practical operation; When dehydrobufotenine is crushed to certain particle size because of influence such as electrostatic interaction, cohesiveness between the powder; Medicine and be easy to reunite; And because surface area increases; Hygroscopicity strengthens; Therefore need carry out proportioning with adjuvant; Overcome moisture absorption, easy problem of reuniting; The applicant is known through a large amount of experiments; Dehydrobufotenine 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 instance the present invention is done further explain, but scope of the present invention is not subjected to any restriction of these instances.
Embodiment 1
The preparation of inhalant: adopt comminution by gas stream to D dehydrobufotenine
90=7 microns, mix at 1: 9 by mass ratio with the lactose of particle diameter at the 45-105 micron, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 2
The preparation of inhalant: adopt comminution by gas stream to D dehydrobufotenine
90=5 microns, mix in 9: 80: 1 ratio at the leucine of 30-55 micron with lactose, the particle diameter of particle diameter at the 45-125 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 dehydrobufotenine
90=5 microns, mix in 1: 9 ratio with the leucine of particle diameter 50-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: with dehydrobufotenine powder, lactose, mannitol, glycine, two Laurel phosphatidyl cholines, lecithin, magnesium stearate in 1: 5: 5: 3: 0.5: 0.5: 0.2 ratio was mixed, and comminution by gas stream is to powder D
50=7 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: with the dehydrobufotenine comminution by gas stream to powder D
90=6 microns, mix in 1: 10: 1 ratio with lactose, cholesterol, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in dehydrobufotenine, add lactose, polyethylene glycol 6000, the albumin of 4 times, 2 times, 3 times of quality respectively, spray drying, powder D
50=9 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
The preparation of inhalant: dehydrobufotenine drug powder, the particle diameter of mean diameter at the 5-8 micron mixed in 10: 86: 4 ratio at mannitol, the micronization silica gel of 10-100 micron; Be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
The preparation of inhalant: dehydrobufotenine drug powder, mannitol, leucine are mixed in 9: 90: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 5.5 microns powder, adding mean diameter is the lactose mixing of 125-250 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 9
The preparation of inhalant: dehydrobufotenine powder, mannitol, glycine are mixed in 10: 100: 5 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.5 microns powder, adding mean diameter is the lactose mixing of 125-250 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 10
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.2 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.7 microns) mix in 6: 90: 6 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 dehydrobufotenine reaches 31.9%, and the room temperature condition held is after 18 months, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 11
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.1 microns) mix in 3: 120: 3 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 dehydrobufotenine reaches 29.9%, and the room temperature condition held is after 18 months, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 12
1, the preparation of inhalant: with dehydrobufotenine powder (D
90=6.8 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.4 microns) mix in 1: 70: 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 dehydrobufotenine reaches 28.6%, and the room temperature condition held is after 18 months, and the pulmonary deposition rate of dehydrobufotenine does not have significant change.
Embodiment 13
The preparation of inhalant: with dehydrobufotenine powder (D
50=7 microns), leucine (D
50=205 microns) mix in 1: 8 ratio, mix the particulate D in back
50Be 226 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: dehydrobufotenine is mixed comminution by gas stream, powder D with leucine in 1: 1 ratio
90Below 5 microns, this powder is mixed with the mannitol of 9 times of amounts again, mix the particulate D in back
50Be 276 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: dehydrobufotenine is mixed comminution by gas stream, powder D with poloxamer in 8: 1 ratio
90Below 8 microns, this powder is mixed with the lactose granule of 10 times of amounts, the magnesium stearate of 1 times of amount again, mix the particulate D in back
50Be 421 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the dehydrobufotenine comminution by gas stream, powder D
90=6 microns, this powder is mixed with the lactose granule of 13 times of amounts again, mix the particulate D in back
50Be 78 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 190 of modeling rats, is divided into 19 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 2mg dehydrobufotenine/kg; The 17th group of lumbar injection dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; Irritate stomach for the 18th group and give dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; The 19th group is physiology saline control group, 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 21% 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 38%; The dehydrobufotenine injection groups is 58%; It is 63% that dehydrobufotenine is irritated the stomach group; The normal saline group is 100%, and each group of inhalant administration is irritated the stomach group with dehydrobufotenine injection groups, dehydrobufotenine, 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 processes 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 process 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 appearance, 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 has tumor growth in the lung, success ratio of inoculation 100%.
2, pharmacodynamic experiment
Get successfully 190 of modeling rabbit, be divided into 19 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 2mg dehydrobufotenine/kg; The 17th group of lumbar injection dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; Irritate stomach for the 18th group and give dehydrobufotenine, dosage is 2mg dehydrobufotenine/kg; The 19th group is physiology saline control group, 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 45.1%, is up to 58.2%; The tumour inhibiting rate of dehydrobufotenine injection groups is 33.6%; The tumour inhibiting rate that dehydrobufotenine is irritated the stomach group is 28.5%; Normal saline does not almost have inhibitory action to tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate that dehydrobufotenine injection groups, dehydrobufotenine are irritated stomach group, normal saline group.
Claims (10)
1. dehydrobufotenine Foradil Aerolizer formoterol fumarate is characterized in that it is made up of dehydrobufotenine and medically acceptable adjuvant, and the mass ratio of dehydrobufotenine and described adjuvant is 1: 0.02-1: 100.
2. a kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that it is to add the suction powder that adjuvant is processed by dehydrobufotenine, and the particle diameter of powder is with D
50Meter is between the 0.5-1000 micron.
3. a kind of dehydrobufotenine 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 dehydrobufotenine 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 dehydrobufotenine Foradil Aerolizer formoterol fumarate according to claim 3 is characterized in that said adjuvant is the mixture of different-grain diameter lactose or lactose and micronization lactose.
6. a kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate according to claim 5; It is characterized in that said adjuvant is for sucking the mixture with lactose granule and micronization lactose; Wherein the lactose granule mean diameter is the 45-225 micron; Micronization lactose mean diameter is the 1-5 micron, and the mass ratio of lactose granule and micronization lactose is 1020: 1-1: 1.
7. adjuvant according to claim 6, the mass ratio that it is characterized in that lactose granule and micronization lactose is 100: 1-6: 1.
8. method for preparing the described a kind of dehydrobufotenine Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is following:
Dehydrobufotenine is processed powder through pulverizing or spray drying, and powder and adjuvant mix homogeneously are processed to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, process suction through pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus dehydrobufotenine and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in dehydrobufotenine and the prescription, through pulverizing or spray drying is processed powder, residue adjuvant mix homogeneously is processed 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 dehydrobufotenine Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is following:
Dehydrobufotenine through pulverizing or spray drying is processed powder, is processed 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 dehydrobufotenine Foradil Aerolizer formoterol fumarate of claim 1 in preparation treatment lung tumors medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110147769 CN102302476B (en) | 2011-06-02 | 2011-06-02 | Dehydrobufotenine dry power inhaler and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110147769 CN102302476B (en) | 2011-06-02 | 2011-06-02 | Dehydrobufotenine dry power inhaler and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102302476A true CN102302476A (en) | 2012-01-04 |
| CN102302476B CN102302476B (en) | 2013-09-25 |
Family
ID=45376466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110147769 Active CN102302476B (en) | 2011-06-02 | 2011-06-02 | Dehydrobufotenine dry power inhaler and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102302476B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1383851A (en) * | 2002-04-03 | 2002-12-11 | 张启玲 | Lung cancer treating medicine and its prepn |
| CN1813802A (en) * | 2005-02-04 | 2006-08-09 | 安徽金蟾生化股份有限公司 | Bufonid skin extract production process |
| CN1915363A (en) * | 2005-08-15 | 2007-02-21 | 张德友 | Composition of medication for treating tumor, preparation method and application |
| CN1931190A (en) * | 2006-09-13 | 2007-03-21 | 周亚球 | Toad skin extract and its medicine prepn and their prepn |
| CN101019891A (en) * | 2007-02-14 | 2007-08-22 | 周亚球 | Toad skin total alkaloid and its prepn, analysis and prepn process |
| 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 |
-
2011
- 2011-06-02 CN CN 201110147769 patent/CN102302476B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1383851A (en) * | 2002-04-03 | 2002-12-11 | 张启玲 | Lung cancer treating medicine and its prepn |
| CN1813802A (en) * | 2005-02-04 | 2006-08-09 | 安徽金蟾生化股份有限公司 | Bufonid skin extract production process |
| CN1915363A (en) * | 2005-08-15 | 2007-02-21 | 张德友 | Composition of medication for treating tumor, preparation method and application |
| CN1931190A (en) * | 2006-09-13 | 2007-03-21 | 周亚球 | Toad skin extract and its medicine prepn and their prepn |
| CN101019891A (en) * | 2007-02-14 | 2007-08-22 | 周亚球 | Toad skin total alkaloid and its prepn, analysis and prepn process |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 赵大洲等: "中华大蟾蜍蟾酥与蟾皮化学成分的比较分析", 《天津药学》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102302476B (en) | 2013-09-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| 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 | |
| CN103833713B (en) | Nicousamide brilliant type III, its method for making and its pharmaceutical composition and purposes | |
| CN102247335B (en) | Bufalin dry powder inhalant as well as preparation method and application thereof | |
| CN102302475B (en) | Resibufogenin dry powder inhalant and preparation method and application thereof | |
| CN102302477B (en) | Cinobufagin dry power inhaler and preparation method and application thereof | |
| CN102961409B (en) | Toad skin extract dry powder inhaler | |
| CN102247336B (en) | Bufothionine dry powder inhaler, and its preparation method and application | |
| CN102210712B (en) | Bufo bufo gargarizans cantor skin extract dry powder inhalant and preparation method and use thereof | |
| CN103664936A (en) | Compounds for treating traumatic brain injury diseases and application thereof | |
| CN102302476B (en) | Dehydrobufotenine dry power inhaler and preparation method and application thereof | |
| CN102526038B (en) | Temozolomide brain-targeting pharmaceutical composition and application thereof | |
| CN102247337B (en) | Bufotalin dry powder inhalers and preparation method as well as application thereof | |
| CN102961406B (en) | Toad skin extract dry powder inhaler, as well as preparation method and application thereof | |
| CN102210711B (en) | Senso fat-soluble extract dry powder inhalation, preparation method and application thereof | |
| CN103083286B (en) | Toad venom lipophilic extract dry powder inhaler, as well as 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 | |
| WO2017181816A1 (en) | Pharmaceutical composition for treating hepatitis, liver fibrosis and liver cancer | |
| CN103070885B (en) | Toad skin extract dry-powder inhalant and its preparation method and use | |
| CN103070886B (en) | Toad skin extract dry-powder inhalant and its preparation method and use | |
| CN103142652B (en) | Venenum bufonis fat-soluble extract dry powder inhaler, and preparation method and application thereof | |
| CN102973605B (en) | Toad skin extract dry powder inhalant and preparation method and applications thereof | |
| CN102988419A (en) | Toad skin extract powder inhalant, and preparation method and application thereof | |
| 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 | ||
| ASS | Succession or assignment of patent right |
Owner name: BEIJING XINLINGXIAN MEDICINE SCI-TECH DEVELOPMENT Free format text: FORMER OWNER: ZHANG ZHENHAI Effective date: 20140116 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 210028 NANJING, JIANGSU PROVINCE TO: 100083 HAIDIAN, BEIJING |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140116 Address after: 100083 Beijing city Haidian District Qinghua East Road No. 16 building 1403 yearhigh Patentee after: Beijing Xinlingxian Medical Technology Development Co., Ltd. Address before: 210028, cross street, Hongshan Road, Jiangsu, Nanjing, 100 Patentee before: Zhang Zhenhai |