CN102850426B - A kind of 21 is the glucocorticosteroid of N-acetylcystein ester - Google Patents
A kind of 21 is the glucocorticosteroid of N-acetylcystein ester Download PDFInfo
- Publication number
- CN102850426B CN102850426B CN201110184121.2A CN201110184121A CN102850426B CN 102850426 B CN102850426 B CN 102850426B CN 201110184121 A CN201110184121 A CN 201110184121A CN 102850426 B CN102850426 B CN 102850426B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical compositions
- compound
- formula
- diketone
- acetyl
- 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.)
- Active
Links
- -1 N-acetylcystein ester Chemical class 0.000 title claims abstract description 31
- 239000003862 glucocorticoid Substances 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 238000002360 preparation method Methods 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 20
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 54
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 43
- 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 38
- 239000008101 lactose Substances 0.000 claims description 37
- 229960001375 lactose Drugs 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 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 30
- 238000009472 formulation Methods 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 235000019359 magnesium stearate Nutrition 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002775 capsule Substances 0.000 claims description 17
- 239000000843 powder Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 12
- 150000001720 carbohydrates Chemical class 0.000 claims description 12
- 235000014633 carbohydrates Nutrition 0.000 claims description 12
- 230000032050 esterification Effects 0.000 claims description 12
- 238000005886 esterification reaction Methods 0.000 claims description 12
- 230000001105 regulatory effect Effects 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 12
- 239000000443 aerosol Substances 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 8
- 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 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 7
- 235000011187 glycerol Nutrition 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 235000000346 sugar Nutrition 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229960000502 poloxamer Drugs 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 238000007910 systemic administration Methods 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 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 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose 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-DCSYEGIMSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 claims description 4
- 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 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 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 4
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 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 4
- 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 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000002016 disaccharides Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229960000193 formoterol fumarate Drugs 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000001647 drug administration Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 230000003068 static effect Effects 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
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 2
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose 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)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 claims description 2
- 206010015943 Eye inflammation Diseases 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
- 239000004471 Glycine Substances 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- ZIJKGAXBCRWEOL-SAXBRCJISA-N Sucrose octaacetate Chemical compound CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1 ZIJKGAXBCRWEOL-SAXBRCJISA-N 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
- 239000001344 [(2S,3S,4R,5R)-4-acetyloxy-2,5-bis(acetyloxymethyl)-2-[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxyoxolan-3-yl] acetate Substances 0.000 claims description 2
- 208000037883 airway inflammation Diseases 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
- 229920002301 cellulose acetate Polymers 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
- 238000004090 dissolution Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000003094 microcapsule Substances 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- 229940013883 sucrose octaacetate Drugs 0.000 claims description 2
- 229930195724 β-lactose Natural products 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 5
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000002245 particle Substances 0.000 description 23
- 239000003595 mist Substances 0.000 description 22
- 239000000463 material Substances 0.000 description 16
- 208000006673 asthma Diseases 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 206010036790 Productive cough Diseases 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 208000024794 sputum Diseases 0.000 description 10
- 210000003802 sputum Anatomy 0.000 description 10
- 150000003431 steroids Chemical class 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 7
- 239000008108 microcrystalline cellulose Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 206010062717 Increased upper airway secretion Diseases 0.000 description 6
- 229920000881 Modified starch Polymers 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 208000026435 phlegm Diseases 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011122 softwood Substances 0.000 description 6
- 235000020985 whole grains Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 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 description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960001660 histamine phosphate Drugs 0.000 description 4
- ZHIBQGJKHVBLJJ-UHFFFAOYSA-N histamine phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.NCCC1=CNC=N1 ZHIBQGJKHVBLJJ-UHFFFAOYSA-N 0.000 description 4
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 4
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013256 coordination polymer Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 3
- 239000002075 main ingredient Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940099259 vaseline Drugs 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 239000004034 viscosity adjusting agent Substances 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical class NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960005233 cineole Drugs 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000003777 experimental drug Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 238000010832 independent-sample T-test Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 235000001510 limonene Nutrition 0.000 description 2
- 229940087305 limonene Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940038384 octadecane Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N sec-butylidene Natural products CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- 235000007586 terpenes Nutrition 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- YSAVKGQYEXDTTL-UHFFFAOYSA-N C(CC)OC(=O)C1=CC=C(O)C=C1.C(C)C1=C(C(=O)O)C=CC(=C1)O Chemical compound C(CC)OC(=O)C1=CC=C(O)C=C1.C(C)C1=C(C(=O)O)C=CC(=C1)O YSAVKGQYEXDTTL-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 229920013701 VORANOL™ Polymers 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229940082484 carbomer-934 Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940100242 glycol stearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000059 polyethylene glycol stearate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000000534 thyroid cartilage Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of 21 is the glucocorticosteroid of N-acetylcystein ester, N-acetylcystein is combined the formula of being formed (I) compound with glucocorticosteroid, and the application of acceptable solvated compounds in preparation treatment people or inflammation in mammals medicine on formula (I) compound and physiology thereof.
Description
Technical field:
The present invention relates to a kind of novel glucocorticosteroid and synthetic method thereof and preparing the application in the medicine for the treatment of diseases related.
Background technology:
It is well-known that glucocorticosteroid has antiinflammatory property, and be widely used in inflammatory disorders or diseases associated with inflammation as the treatment of asthma, rhinitis, eczema etc., play the effect of relief of symptoms, in the treatment of these diseases, often need long-term prescription, so also can cause the various untoward reactions of whole body, how improving curative effect of medication thus to reduce drug use, the generation reducing untoward reaction just becomes the key of medicament research and development.
The phlegm dissolving agent of N-acetylcystein system, has stronger phlegm dissolving effect.In its molecule, contained sulfydryl (-SH) can make the disulfide linkage (-S-S-) in phlegm in glycoprotein polypeptide chain rupture, and reduces the viscosity of phlegm, and makes it liquefaction.This product can also make the DNA fiber in purulent sputum rupture, therefore can not only dissolve the sticky phlegm of white and can dissolve purulent sputum.
In glucocorticoid treatment respiratory tract disease, extensive employing inhalation is treated, but because respiratory disease patient often has denseer sputum in respiratory tract, glucocorticosteroid major part in by respiratory tract process is adhered to by sputum, cannot play a role.
Summary of the invention:
Contriver is by constantly research, N-acetylcystein is combined with glucocorticosteroid and forms novel formula (I) compound, effectively reduce the absorption of sputum to glucocorticosteroid, improve the curative effect of anti-inflammatory, be highly suitable for general action and long-time use.
The invention provides a kind of formula (I) compound,
R2=OH ,-OCOR6, R6 is alkyl within six carbon or furyl;
R3=H, OH or methyl;
R2，R3＝
R4=H or halogen;
R5=H, halogen or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
Preferred:
R2=H ,-COR6, R6 is alkyl within three carbon or 2-furyl;
R3=H or methyl;
R2，R3＝
R4=H or F;
R5=H, F or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
More preferably:
R2=H ,-COR6, R6 is methyl or 2-furyl;
R3＝H；
R2、R3＝
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
Further preferably:
R2=H ,-COR6, R6 is methyl;
R3＝H；
R2，R3＝
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows double bonds.
Further preferably following several:
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl;
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-chloro-16 Alpha-Methyls of Cys ester-9-;
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester;
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester;
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-];
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)];
Two hydroxyl-the 21-(N-acetyl) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
Most preferably following several:
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-];
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)];
Two hydroxyl-the 21-(N-acetyl) of pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
The invention also discloses a kind of synthetic method of formula (I) compound:
Synthetic method:
By formula (II) compound dissolution to N, in dinethylformamide, be warming up to 60 DEG C, add 4-dimethylaminopyridine, dicyclohexylcarbodiimide, N-acetylcystein, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, obtain formula (I) compound.
Substituting group cotype (I) compound of formula (II) compound.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or Mammals medicine on described formula (I) compound and physiology thereof.
The invention also discloses the application of acceptable solvated compounds in preparation treatment people or inflammation in mammals medicine on described formula (I) compound and physiology thereof.React particularly preferably in preparation treatment people or mammal skin inflammation such as eczema, psoriasis, allergic dermatitis, neurodermatitis, itch and hypersensitivity; Airway inflammation is as bronchial asthma, rhinallergosis, chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary fibrosis; Eye inflammation is as conjunctivitis; Inflammatory bowel is as ulcerative colitis or Crohn disease; And autoimmune disease is as the application in the medicine of the diseases such as rheumatic arthritis, rheumatoid arthritis, lupus erythematosus, pemphigus." treatment " of the present invention can extend to prevention and the diagnosis of disease.
The dosage of formula disclosed by the invention (I) compound in treatment people or mammalian diseases medicine is 0.2 μ g-50mg/kg/ days, preferably 1 μ g-2mg/kg/ days.During disease as treatment people, the body weight of people generally calculates according to 50kg, so people described in the present invention can calculate according to ABW with dosage, also can calculate according to above-mentioned dosage × 50.
The invention also discloses a kind of pharmaceutical composition, it is characterized in that containing any one or a few the compound described in the formula (I) as activeconstituents and one or more pharmaceutical excipients.
The pharmaceutical composition being activeconstituents with formula (I) compound disclosed in this invention includes but are not limited to the composition being applicable to Formulations for systemic administration, topical, the described composition being applicable to Formulations for systemic administration includes but are not limited to the pharmaceutical composition being applicable to oral administration, drug administration by injection, orally administering, sublingual administration, parenteral admin, local or rectal administration, the pharmaceutical composition of preferred oral administration or drug administration by injection.
The preparation of oral administration is common has tablet, capsule, oral liquid formulations, suspensoid, aqua etc. by the preparation of gastrointestinal absorption, and injecting and administering preparations is common has injection, infusion solution etc. by the preparation of muscle, venous absorption.
The described pharmaceutical composition being suitable for topical includes but are not limited to inhalation as aerosol, Foradil Aerolizer formoterol fumarate, sprays; Nasal formulations such as nasal spray, nasal drop, external preparation comprise as ointment, ointment, gelifying agent, lotion, foaming agent, patch, powder; The tablet that orally administering preparation maybe can be sucked as chewed or pill, oral cavity sticking tablet; Local cavity preparation is as suppository, vaginal suppository, enema,retention; Ophthalmic preparation is as eye drops; And liposome or microcapsule formulation.Be preferably inhalation, nasal formulations and external preparation.
Described is that pharmaceutical composition dosage when treating people or mammalian diseases of activeconstituents counts 0.2 μ g-5mg/kg/ days with formula (II) compound, preferably 1 μ g-2mg/kg/ days with formula (I) compound.Described pharmaceutical composition treatment people or Mammals supersensitivity, diseases associated with inflammation dosage count 0.2 μ g-5mg/kg/ days with formula (II) compound, preferably 1 μ g-2mg/kg/ days, described pharmaceutical composition adopts the administering mode of every day 1 time or more in use, preferred every day 1 ~ 3 time, also can adopt medication in many days administering mode once, dosage is the superposition of Dan Tian.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes oral or injection, described pharmaceutically acceptable auxiliaries is the pharmaceutical excipient of traditional oral or injection, and concrete kind and relevant method for making can see relevant textbook or documents.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound is made as the aerosol of inhalation, described pharmaceutically acceptable auxiliaries is propellent and one or more low volatility component.
Described propellent can include but are not limited to fluorochloroparaffins, hydrocarbon polymer, fluorohydrocarbon class, pressurized gas, one or more in ethers, comprise 1, 1, 1, 2-Tetrafluoroethane (HFA134a) and 1, 1, 1.2, 3, 3, 3-heptafluoro-propane (HFA227), Trichloromonofluoromethane (CCl3F), chlorodifluoromethane (CCl2F2), dichloro tetrafluoro ethane (CClF2-CClF2), propane (C3H8, ), Trimethylmethane (iso-C4H10), normal butane (n-C4H10), carbonic acid gas, nitrous oxide, nitrogen, be preferably one or more in fluorohydrocarbon compounds.Be particularly preferably the one in HFA134a and HFA227 or its combination.Most preferably be HFA134a.
Described low volatility component can include but are not limited to, one or more in solvent, latent solvent, suspending agent, stablizer, correctives, sanitas.And also can be applicable to aerosol or the sprays of non-suction.
The described latent solvent be applicable to can be but be not limited only to ethanol or oleic acid, and preferably use ethanol, applicable solvent is glycerine, and propylene glycol or polyoxyethylene glycol, preferably use glycerine.Solvent and latent solvent also can be referred to as thinner herein.
Described low volatiles can also be but be not limited only to following component, comprise other alcohol and glycol, such as alkanol, as the sugar alcohol of decyl alcohol (decyl alcohol), Sorbitol Powder, mannitol, Saccharum lactis, maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol, comprise vegetables oil, organic acid as comprised dodecylic acid and the saturated carboxylic acid such as tetradecanoic acid and stearic acid; Comprise Sorbic Acid, particularly the unsaturated carboxylic acid such as oleic acid.Known be applied to aerosol, the stablizer of sprays, suspending agent, correctives as asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as ethyl cellulose, dextran; Antioxidant as Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Polymkeric substance is as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
When described pharmaceutical composition makes aerosol, screening formulation is: active component content is 1-8mg/ml; Ethanol weight percent content as latent solvent is 5-20%, and the propellent of surplus.
Should be appreciated that because known reason, as the retention of activeconstituents in suction apparatus, the amount of often kind of activeconstituents that patient sucks can be different from the amount of metering.Therefore the applicating ratio between activeconstituents can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.
The pharmaceutical composition that is activeconstituents with formula (I) compound of the present invention is made as the powder inhalation of inhalation, and described powder inhalation is made up of dried powder, and described excipient substance comprises carrier and additives.
Obtain the method for dried powder for pulverize activeconstituents of the present invention and pharmaceutical excipient with known breaking method such as mechanical disintegration or spray-dired mode,
The preferred median size of preferred described activeconstituents micro mist is 1 ~ 8 μm, and particularly preferably median size is 2 ~ 5 μm, and the median size of preferably described carrier micro mist is 20 ~ 60 μm.
Median size of the present invention is mass median diameter (massmeandiameter).
Described carrier is one or more in carbohydrate carrier, amino acid, and described amino acid includes but are not limited to glycine, α-amino-isovaleric acid.Described carbohydrate comprises monose, disaccharides and/or its derived carbohydrate, described monose includes but are not limited to N.F,USP MANNITOL, fructose, glucose, described disaccharides includes but are not limited to maltose, trehalose, cellobiose, lactose, sucrose, described derived carbohydrate includes but are not limited to eight cellulose acetate two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid marine alga sugar esters, described derived carbohydrate can also with reference to derived carbohydrate example disclosed in the specification sheets of international monopoly WO99/33853, preferably as carrier in derived carbohydrate is eight acetic acid-D-cellobiose esters, in above-mentioned various carrier, most preferably carrier is lactose.Described lactose is alpha-lactose monohydrate, β-lactose hydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, particularly preferably crystallizing and drying lactose.
Preferably in described carrier micro mist, add additives, described additives include but are not limited to tensio-active agent, lubricant, static inhibitor.The consumption of described additives and kind can with reference to any known prior art and documents, disclosed in " pharmaceutics " (Cui Fude etc., 2006-11-1, People's Health Publisher).
The preferred poloxamer of described tensio-active agent.Activeconstituents: poloxamer weight ratio is 1: 0.01 ~ 5.Poloxamer is also as static inhibitor.Described lubricant can also include but are not limited to one or more in Magnesium Stearate, micropowder silica gel, talcum powder, and consumption is 0.01% ~ 1% of carrier micropowder weight.
Described activeconstituents and the weight ratio of carrier are 1: 10 ~ 1000; Preferably 1: 10 ~ 200.
The method of micronization of described activeconstituents can adopt spray-drying process, fluidized-bed supersonic jet mill method, and speed lapping method, ball milled, fluid energy mill method, solvent method etc., preferably adopt spray-drying process.
Powder inhalation provided by the invention can adopt the packaged of single or multiple dosage, and preferably adopt the mode packing of capsule, each capsule contains the above-mentioned powder inhalation of 5 ~ 40mg.Preferably containing the above-mentioned powder inhalation of 10 ~ 30mg.
Capsule containing powder inhalation provided by the invention can adopt known powder inhalation capsule inhaler to suck.Described sucker is such as disclosed in WO94/28958.
Activeconstituents micro mist is changed into the micro mist of 0.5 ~ 10 μm by the preparation method of powder inhalation of the present invention, then carrier and additives micro mist is changed into the micro mist of 20 ~ 60 μm, by above-mentioned two kinds of micro mists mixing, is contained in capsule after crossing 200 mesh sieve 3 times
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes nasal formulations, described pharmaceutically acceptable auxiliaries can include but are not limited to pH adjusting agent, carrier, osmotic pressure regulator, viscosity modifier, suspending agent, antioxidant, tensio-active agent, stablizer, bacteriostatic preservative etc. all be applicable to local nose administration pharmaceutical excipient in one or more.
Described carrier can include but are not limited to one or more in water, propylene glycol, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, whiteruss, vegetables oil, Vaseline, lanolin, CP.When described pharmaceutical composition makes gelifying agent, described carrier contains water and crosslinked acrylic resin, and the CP used is preferably carbomer resin, is particularly preferably carbomer 934, consumption is 0.1% ~ 1% of pharmaceutical composition weight, preferably 0.2% to 0.5%.The consumption of water is 90% to 99% of pharmaceutical composition weight.
Described pH adjusting agent can be enumerated but be not limited only to phosphoric acid and salt, boric acid and salt thereof, Citric Acid and salt, acetic acid and salt thereof, tartrate and salt, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, tromethane etc.
Described suspending agent can include but are not limited to, asccharin, xitix, cyclamic acid, amino acid or aspartame; Alkane is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as one or more in ethyl cellulose, dextran.
Described antioxidant can include but are not limited to Yoshinox BHT, Sodium Pyrosulfite, butylated hydroxyanisol; Amine is as thanomin, diethanolamine, trolamine; Steroid class is as cholesterol, cholesteryl ester.
Described osmotic pressure regulator with include but are not limited to osmotic pressure regulator and can enumerate but be not limited only to glycerine, propylene glycol, sodium-chlor, Repone K, Sorbitol Powder, N.F,USP MANNITOL one or more etc.
Described viscosity modifier can enumerate but be not limited only to polyvinyl alcohol, carboxy vinyl polymer, Polyvinylpyrolidone (PVP) one or more, foregoing CP, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, also can be used as viscosity modifier.
Described stablizer can include but are not limited to ethylenediamine tetraacetic acid (EDTA) and alkaline metal salt thereof, preferred disodium ethylene diamine tetraacetate.
Described tensio-active agent can be enumerated but be not limited only to tween-80, HCO60, polyoxyethylene glycol-stearate, Macrogol 4000, Yelkin TTS, sucrose ester, Voranol EP 2001, polyoxy stearate, one or more in polyoxyethylene, polyoxypropylene diols and analogue thereof.
Described bacteriostatic preservative can include but are not limited to, one or more in benzalkonium chloride, benzethonium chloride, Sorbic Acid, potassium sorbate, methyl p-hydroxybenzoate (Tegosept M), nipagin A (ethyl p-hydroxybenzoate) propylparaben (propylben), chlorobutanol.
Propylene glycol in described pharmaceutically useful auxiliary material, glycerine can also replace with other alcohols, available alcohols can include but are not limited to other alcohols and glycols, such as alkanol, as decyl alcohol (decyl alcohol), comprise Sorbitol Powder, mannitol, Saccharum lactis, the sugar alcohol of maltose alcohol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol.
When the described pharmaceutical composition that is activeconstituents with formula (I) compound makes external preparation, preferably make ointment, described pharmaceutically acceptable auxiliaries includes but are not limited to the antioxidant for pharmaceutical composition described in preservation, pH buffer reagent, wetting Agent for Printing Inks, oil-phase component, antibiotic antiseptic, also has the water of surplus.
Described oil-phase component comprises one or more in solid in oil-phase component, consistency modifiers, emulsifying agent.
Solid in described oil-phase component include but are not limited to stearic acid, paraffin, beeswax, higher alcohols one or more, described higher alcohols is the monohydroxy-alcohol of 16 ~ 22 carbon atoms, preferred hexadecanol and/or stearyl alcohol, described consistency modifiers includes but are not limited to one or more in Vaseline, whiteruss, vegetables oil, preferred Vaseline and/or Liquid Paraffin, described emulsifying agent, include but are not limited to the derivative of soap class emulsifying agent, Soxylat A 25-7, described higher alcohols also plays the effect of tensio-active agent in emulsifiable paste simultaneously.
The composition of the above pharmaceutical composition is not limited only to described in technical solution of the present invention, also comprise any composition that may be used for the pharmaceutical excipient of above-mentioned preparation, the composition of described pharmaceutical excipient can with reference to " pharmaceutics " (the 5th edition, Cui Fude, within 2003, publish, People's Health Publisher) in disclosed scheme.
Compared with glucocorticosteroid of the prior art, new formula (I) compound provided by the invention, beyond thought effect is created when inhalation, be used alone with glucocorticosteroid, N-acetylcystein and compare, curative effect all increases, and is conducive to reducing dosage, is conducive at life-time service, meanwhile, new formula (I) compound provided by the invention also can be prepared into Formulations for systemic administration preparation (as oral preparations) and uses for whole body.
Embodiment:
Pillar layer separation method in the present invention:
The minimum 70cm of length of chromatographic column, inner filling 254-silica gel, and will the organism be separated be needed entirely to be dissolved in minimum chloroform: methyl alcohol=1: in 1, with minimum 254-silica gel, this solution is absorbed the top being placed on silica gel in chromatography column, use moving phase wash-out, connect with several 10ml test tubes the solution obtained through column chromatography under chromatography column, coutroi velocity is 10ml/3min, the solution HPLC of each test tube is analyzed, test tube solution identical for retention time merged and carries out recrystallization, obtaining corresponding product.Elution flow adopts chloroform mutually: methyl alcohol=1: the mixed solvent of 3 (volume ratios).
Determine the method for target compound: by different products respectively refining laggard row element analysis and
13c-NMR analyzes, with the chemical structure of deterministic compound
Analytical instrument: HP1084B liquid chromatograph, HP79850BLC terminal and UV detector
Column material: HypersilC18,5 μm, 150 × 4.6mm
Determined wavelength: 242nm
Moving phase: methyl alcohol: water=5.5: 4.5
Column temperature: 45 DEG C
Flow velocity: about 1.2ml/ divides
DMF is DMF
D90 is the particle diameter corresponding when reaching 90% of the cumulative particle sizes distribution number of a sample.
The pregnant steroid of embodiment 1-Isosorbide-5-Nitrae-diene-3,20-diketone-11,17,21-trihydroxy--21-(N-acetyl)-Cys ester
By pregnant steroid-1,4-diene-3,20-diketone-11,17,21-trihydroxy-(II-1) 10mmol puts in 80mlDMF, be warming up to 60 DEG C, add 0.30g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.8mmol.
Ultimate analysis: C, 61.53; H, 6.99; N, 2.79; O, 22.31; S, 6.38
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.4 | 90.1 | 207.5 | 68.4 | 172.1 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant steroid of embodiment 2-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--9 α-fluoro-16 Beta-methyls (II-2) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.33g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.3mmol.
Ultimate analysis: C, 60.18; H, 6.77; F, 3.54; N, 2.63; O, 20.90; S, 5.98
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 71.2 | 90.9 | 205.9 | 68.4 | 172.3 | 53.0 | 26.9 | 180.2 | 23.5 |
The pregnant steroid of embodiment 3-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester (II-3) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.34g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.1mmol.
Ultimate analysis: C, 61.30; H, 6.83; N, 2.56; O, 23.43; S, 5.88
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.1 | 101.9 | 211.9 | 68.5 | 171.9 | 53.0 | 26.8 | 179.2 | 23.5 |
The pregnant steroid of embodiment 4-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl
By pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--6 Alpha-Methyl 10mmol (II-4) is put in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, stir and carry out esterification, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filters after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.7mmol.
Ultimate analysis: C, 62.40; H, 7.18; N, 2.70; O, 21.55; S, 6.17
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.2 | 90.0 | 207.4 | 68.4 | 172.0 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant steroid of embodiment 5-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-chloro-16 Alpha-Methyls of Cys ester-9-
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-(2-furans)-manthanoate-9-chloro-16 Alpha-Methyls (II-5) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.0mmol.
Ultimate analysis: C, 59.43; H, 5.99; Cl, 5.85; N, 2.31; O, 21.15; S, 5.29
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 70.4 | 100.3 | 211.4 | 67.6 | 172.1 | 53.2 | 26.9 | 179.1 | 23.3 |
The pregnant Gona-4-ene-3 of embodiment 6,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester
By pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy-(II-6) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, reacts 24 hours under room temperature, and reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.2mmol.
Ultimate analysis: C, 61.49; H, 7.36; N, 2.76; O, 22.08; S, 6.32
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 68.4 | 90.0 | 207.5 | 68.3 | 172.1 | 53.1 | 26.9 | 179.6 | 23.3 |
The pregnant Gona-4-ene-3 of embodiment 7,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester
By pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester (II-7) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, reacts 24 hours under room temperature, and reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 5.9mmol.
Ultimate analysis: C, 62.340; H, 7.51; N, 2.42; O, 22.17; S, 5.55
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 68.3 | 101.5 | 211.5 | 68.4 | 172.0 | 53.1 | 26.9 | 179.4 | 23.4 |
| C position | 27 | 28 | 29 | 30 | |||||
| Numerical value | 173.9 | 36.8 | 18.5 | 13.5 |
Two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of the pregnant steroid of embodiment 8-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-]
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] (II-8) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.1mmol.
Ultimate analysis: C, 64.35; H, 7.37; N, 2.27; O, 20.80; S, 5.22
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.1 | 100.9 | 203.9 | 68.8 | 172.5 | 53.2 | 26.8 | 179.3 | 23.4 |
| C position | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 16 | |
| Numerical value | 101.6 | 36.4 | 24.3 | 26.2 | 26.0 | 26.2 | 24.3 | 84.9 |
The pregnant steroid of embodiment 9-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)]
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(R, S) propylmethylene] two (oxygen)] (II-9) 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.4mmol.
Ultimate analysis: C, 62.59; H, 7.18; N, 2.43; O, 22.23; S, 5.57
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.2 | 100.8 | 203.8 | 68.8 | 172.5 | 53.3 | 26.7 | 179.2 | 23.3 |
| C position | 27 | 28 | 29 | 30 | 16 | ||||
| Numerical value | 98.1 | 36.6 | 13.2 | 14.5 | 84.5 |
Two hydroxyl-the 21-(N-acetyl) of the pregnant steroid of embodiment 10-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
By pregnant steroid-1, 4-diene-3, 20-diketone-11 β, the two hydroxyl-16 of 21-, 17-[(methyl ethylidene) two (oxygen)] 10mmol puts in 100mlDMF, be warming up to 60 DEG C, add 0.35g4-dimethyl aminopyridine, 4g dicyclohexylcarbodiimide, N-acetylcystein 15mmol, esterification is carried out in stirring, Temperature fall under room temperature after 30 minutes, react 24 hours under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, product pillar layer separation, recrystallizing methanol obtains title compound 4.4mmol.
Ultimate analysis: C, 61.99; H, 7.00; N, 2.49; O, 22.80; S, 5.72
13C-NMR：
| C position | 11 | 17 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Numerical value | 69.0 | 97.5 | 203.6 | 68.7 | 172.0 | 53.1 | 26.7 | 179.1 | 23.3 |
| C position | 27 | 28 | 29 | 16 | |||||
| Numerical value | 111.9 | 26.6 | 26.6 | 81.8 |
Example of formulations 1
Activeconstituents
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11,17,21-trihydroxy--21-(N-acetyl)-Cys ester (I-1) 100.0g auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 2
Activeconstituents:
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-fluoro-16 Beta-methyls (I-2) 5.0g
Auxiliary material:
Activeconstituents, Microcrystalline Cellulose, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 3
Activeconstituents: pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-acetic ester-21-(N-acetyl)-Cys ester (I-3) 100.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 4
Activeconstituents: pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester-6 Alpha-Methyl (I-4) 40.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 5
Pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, two hydroxyl-the 21-(N-acetyl) of 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)] (I-5) 2g, white vaseline 30g, stearyl alcohol 120g, glyceryl monostearate 20g, whiteruss 10g, peregal A-2050g, glycerine 120g, EDTA-2Na2g, phenylcarbinol 5g, hydroxypropylcellulose, 3g, purified water 639g
By above proportioning accurate weighing, moisture is two portions: 380g and 259g, gets ready, and emulsifiable paste process for preparation is as follows:
(1) oil phase preparation:, get white vaseline, stearyl alcohol, glyceryl monostearate, whiteruss, peregal A-20 is placed in container, is heated to melting, and temperature remains on 72 ± 2 DEG C;
(2) aqueous phase preparation: by above proportioning accurate weighing, get glycerine, EDTA-2Na and 380g water is placed in container, heating, temperature remains on 70 ± 2 DEG C;
(3) phase is closed: poured into by the oil phase that step (1) is prepared in the aqueous phase that step (2) prepares, stir, maintain the temperature at 75 ± 2 DEG C, add phenylcarbinol;
(4) main ingredient suspension: activeconstituents, 259g water, polyvinylpyrrolidone are placed in container, stirring or ultrasonic, obtains main ingredient suspension;
(5) control temperature is at 60 ± 2 DEG C, and added by the main ingredient suspension obtained in step (4) in the solution that step (3) obtains, limit edged stirs, and is cooled to cream.Obtain emulsifiable paste 1kg.
Example of formulations 6
Activeconstituents:
) pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-chloro-16 Alpha-Methyl 10.0g of manthanoate-21-(N-acetyl)-Cys ester-9-
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 7
Activeconstituents:
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--21-(N-acetyl)-Cys ester (I-6) 200.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 8
Activeconstituents:
Pregnant Gona-4-ene-3,20-diketone-11 β, 17,21-trihydroxy--17-butyric ester-21-(N-acetyl)-Cys ester (I-7) 50.0g
Auxiliary material:
Activeconstituents, pregelatinized Starch, Microcrystalline Cellulose, lactose is taken according to recipe quantity, cross 60-100 mesh sieve respectively, after mixing, add polyvidone aqueous solution softwood processed in right amount, 20 mesh sieve particles, drying, whole grain, adds, Magnesium Stearate, carboxymethylstach sodium, micropowder silica gel, mixes rear employing and is applicable to punch die and is pressed into tablet.
Example of formulations 9-1
Activeconstituents:
Pregnant steroid-1,4-diene-3, two hydroxyl-21-(N-the acetyl)-Cys ester-16,17-[(R) cyclohexylmethylene] two (oxygen) of 20-diketone-11 β, 21-] (I-8) (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 9-2
Activeconstituents:
Pregnant steroid-1, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 4-diene-3,20-diketone-11 β, 21-, 17-[(R, S) propylmethylene] two (oxygen)] (I-9) (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Example of formulations 9-3
Activeconstituents:
Pregnant steroid-1,4-diene-3,20-diketone-11 β, 17,21-trihydroxy--17-(2-furans)-chloro-16 Alpha-Methyls (I-5) of manthanoate-21-(N-acetyl)-Cys ester-9-(particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 1
Activeconstituents:
Ciclesonide (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 2
Activeconstituents:
Budesonide (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 3
Activeconstituents:
Furoic acid momisone (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Preparations. Control embodiment 4
Activeconstituents:
N-acetylcystein (particle diameter is the micro mist of D90≤5 μm) 100mg
Auxiliary material:
Lactose (particle diameter is D90 at the micro mist of 30 μm) 20g
Magnesium Stearate 0.5g
Make 1000 altogether
Activeconstituents, lactose are crossed 80 mesh sieves respectively, after mixing, adds the Magnesium Stearate of recipe quantity, mix in rear loading suitable capsule and get final product.
Pharmacological Examples 1
Comparative formulations embodiment 9-1 to 9-3, preparations. Control embodiment 1-4 suck the impact of histamine induced rat asthma attack
1. laboratory animal: choose healthy infant rats, body weight 180 ~ 220g, male and female are not limit.
2 laboratory apparatuss: the bell glass of air compressor, aerosol shower nozzle, mercury manometer, base, 4L
3 experimental drugs: 2% Ovisot, 0.1% histamine phosphate, example of formulations 9-1 (A group), 9-2 (B group), 9-3 (C group), preparations. Control embodiment 1 (D group), preparations. Control embodiment 2 (E group), preparations. Control embodiment 3 (F group), preparations. Control embodiment 4 (G group)
4 data processing: the independent samples t-test adopting SAS system.
Three, experimental technique
Choose infant rats, male and female, body weight is 180-220g, puts into the lens of about 5 liters, sprays into 2% Ovisot and 0.1% histamine phosphate's volume mixed solution 15 second with the pressure of 400mmHg.After spraying stops, observing the asthmatic latent period (namely asthma occur, breathe be the devil, until twitch time of falling) of rat, draw and breathe heavily the rat that the latent phase is greater than 120 seconds and will not select.Learn from else's experience and measure the qualified rat 120 of asthmatic latent period, 6 groups are divided into by asthmatic latent period stochastic averagina, give A-G group medicine respectively, after inhalation 30min, spraying gives 0.25% 2 hydrochloric acid histamine respectively, observes the change (draw animal when breathing heavily and do not occur in 6 minutes that the person of falling take asthmatic latent period as 360s) of asthmatic latent period and tic incidence before and after drug
Four, experimental result: a few treated animal generation asthma until the time of falling of twitching have difference, in table 1:
Table 1 sucks the impact of induced asthma outbreak to histamine phosphate's spraying
(n＝20，
)
Shown by this experiment, compound of the present invention all can the asthmatic latent period that brought out by histamine phosphate of significant prolongation rat compared with control group, (P < 0.01), and under Isodose, to use after the administration of asthmatic latent period and contrast D-G group after the administration of the A-C tetra-groups of the compounds of this invention asthmatic latent period respectively compared with, all there is significance (P < 0.05), illustrating that the present invention provided by the invention has more significant effect when treating asthma compared with the medicine of existing approximate construction thus.
Pharmacological Examples 2 sputum secretion test (phenol red method)
1. laboratory animal: choose Kunming mouse, male and female are not limit.
2 laboratory apparatuss: the bell glass of air compressor, aerosol shower nozzle, mercury manometer, base, 4L
3 experimental drugs: example of formulations 9-1 (A group), 9-2 (B group), 9-3 (C group), preparations. Control embodiment 1 (D group), preparations. Control embodiment 2 (E group), preparations. Control embodiment 3 (F group), preparations. Control embodiment 4 (G group)
4 data processing: the independent samples t-test adopting SAS system.
Three, experimental technique
Kunming mouse 160, male and female half and half, be divided into 8 groups at random, namely blank group, A-G group, then give A-G group medicine respectively, inhalation 30min, blank group gives the micro mist lactose that 0.8mgD90 particle diameter is 30 μm, every day 1 time, successive administration 3d, after last administration 0.5h, by abdominal injection 0.5% phenol red solution 0.5mL/ only.After 30min, cervical dislocation puts to death mouse, facing upward position is fixed on operation plate, cut off throat skin, be separated tracheae, peel off tracheae surrounding tissue, cut one section of tracheae to tracheae bifurcation from thyroid cartilage, put in the test tube filling 3mL physiological saline and rinse, then add 5% sodium hydrogen carbonate solution 0.1mL.By centrifugal for lavage of trachea liquid, get supernatant liquor, measure OD value (optical density(OD)) OD value height by microplate reader (wavelength 570nm) and represent that in discharge sputum, phenol red total amount is higher, also show that sputum discharge total amount is higher, the index that eliminates the phlegm is each experimental group OD value and the blank ratio organized.
Shown by this experiment, compound of the present invention all significantly can increase the eliminating of mouse sputum compared with control group D-F, (P < 0.01), and under Isodose, after using A-C tri-groups of administrations of the compounds of this invention, expectoration amount is compared with after the administration of contrast D-F tri-groups, all there is significance (P < 0.05), but expectoration amount is not enough to some extent compared with control group G after using A-C tri-groups of administrations of the compounds of this invention, illustrate thus compound provided by the invention compared with the medicine of existing approximate construction in sputum discharge time have more significant effect.
Claims (43)
1. a formula (
) compound,
Formula (
)
R2=OH ,-OCOR6, R6 is alkyl within six carbon or furyl;
R3=H, OH or methyl;
R2、R3=
；
R4=H or halogen;
R5=H, halogen or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
2. formula as claimed in claim 1 (
) compound, it is characterized in that
R2=-OCOR6, R6 are alkyl within three carbon or 2-furyl;
R3=H or methyl;
R2、R3=
；
R4=H or F;
R5=H, F or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
3. compound as claimed in claim 1, is characterized in that
R2=-OCOR6, R6 are methyl or 2-furyl;
R3=H；
R2、R3=
；
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows singly-bounds or double bonds.
4. formula as claimed in claim 1 (
) compound, it is characterized in that
Wherein
R2=-OCOR6, R6 are methyl;
R3=H；
R2、R3=
；
R4=H or F;
R5=H or methyl;
1,2 represented by dotted arrows double bonds.
5. formula as claimed in claim 1 (
) compound is pregnant steroid-1, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-Cys ester-9 α-pregnant steroid-1 of fluoro-16 Beta-methyl, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-acetic ester-21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant steroid-1 of Cys ester-6 Alpha-Methyl, 4-diene-3, 20-diketone-11 β, 17, 21-trihydroxy--17-(2-furans)-manthanoate-21-(N-acetyl)-pregnant Gona-4-ene-3 of chloro-16 Alpha-Methyl of Cys ester-9-, 20-diketone-11 β, 17, 21-trihydroxy--21-(N-acetyl)-pregnant Gona-4-ene-3 of Cys ester, 20-diketone-11 β, 17, 21-trihydroxy--17-butyric ester-21-(N-acetyl)-pregnant steroid-1 of Cys ester, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] pregnant steroid-1, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R, S) propylmethylene] two (oxygen)] pregnant steroid-1, 4-diene-3, 20-diketone-11 β, two hydroxyl-21-(N-acetyl)-Cys ester-16 α of 21-, 17-[(methyl ethylidene) two (oxygen)].
6. as claimed in claim 1 formula (
) compound is:
Pregnant steroid-1,4-diene-3,20-diketone-11 β, two hydroxyl-21-(N-the acetyl)-Cys ester-16 of 21-, 17-[(R) cyclohexylmethylene] two (oxygen)] pregnant steroid-1,4-diene-3,20-diketone-11 β, 21-two hydroxyl-21-(N-acetyl)-Cys ester-16,17-[(R, S) propylmethylene] two (oxygen)] pregnant steroid-1,4-diene-3, two hydroxyl-the 21-(N-acetyl) of 20-diketone-11 β, 21--Cys ester-16 α, 17-[(methyl ethylidene) two (oxygen)].
Formula as described in 7. as arbitrary in claim 1-6 (
) synthetic method of compound, its synthetic method be by formula II compound dissolution in DMF, be warming up to 60 DEG C, add 4-dimethylaminopyridine, dicyclohexylcarbodiimide, N-acetylcystein, esterification is carried out in stirring, after 30 minutes Temperature fall under room temperature, reacts under room temperature, reaction is complete to be diluted in frozen water, filter after regulating pH value neutrality, dry after rinsing with water, obtain formula (
) compound,
formula II compound N-acetyl-Cys formula (
) compound.
Formula as described in 8. as arbitrary in claim 1-6 (
) application of compound in preparation treatment anti-inflammatory drugs.
Formula as described in 9. as arbitrary in claim 1-6 (
) application of compound in preparation treatment airway inflammation medicine.
Formula as described in 10. as arbitrary in claim 1-6 (
) application of compound in preparation treatment eye inflammation medicine.
11. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation treatment skin inflammation medicine.
12. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation treatment inflammatory bowel medicine.
13. as arbitrary in claim 1-6 as described in formula (
) application of compound in preparation autoimmune disease medicine.
14. 1 kinds of pharmaceutical compositions, is characterized in that containing any one or a few the compound described in the formula as claimed in claim 1 (I) as activeconstituents and one or more pharmaceutical excipients.
15. pharmaceutical compositions as claimed in claim 14, is characterized in that described composition is the pharmaceutical composition being applicable to Formulations for systemic administration or topical.
16. pharmaceutical compositions as claimed in claim 14, the composition being applicable to Formulations for systemic administration described in it is characterized in that is the pharmaceutical composition of oral administration or drug administration by injection.
17. pharmaceutical compositions as claimed in claim 15, is characterized in that the pharmaceutical composition of described topical is inhalation, nasal formulations, external preparation, orally administering preparation, ophthalmic preparation and liposome or microcapsule formulation.
18. pharmaceutical compositions as claimed in claim 16, is characterized in that described composition is inhalation, nasal formulations and external preparation.
19. pharmaceutical compositions as claimed in claim 17, is characterized in that described inhalation is the one of aerosol, Foradil Aerolizer formoterol fumarate, sprays.
20. pharmaceutical compositions as claimed in claim 19, when it is characterized in that described pharmaceutical composition is aerosol, described pharmaceutical excipient comprises the pharmaceutically useful propellent and one or more low volatility component that are applicable to aerosol.
21. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is one or more in fluorohydrocarbon compounds.
22. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is one in HFA 134a and 1,1,1.2,3,3,3-heptafluoro-propane or its combination.
23. pharmaceutical compositions as claimed in claim 20, is characterized in that described propellent is HFA134a.
24. pharmaceutical compositions as claimed in claim 20, is characterized in that low volatility component is one or more in solvent, latent solvent, suspending agent, stablizer, correctives, sanitas.
25. pharmaceutical compositions as claimed in claim 24, is characterized in that described latent solvent is ethanol.
26. pharmaceutical compositions as claimed in claim 24, is characterized in that described solvent is glycerine.
27. as pharmaceutical composition as described in arbitrary in claim 24,25, and when it is characterized in that making aerosol, filling a prescription is: active component content is 1-8mg/ml; Ethanol weight percent content as latent solvent is 5-20%, and the propellent of surplus.
28. pharmaceutical compositions as claimed in claim 19, when it is characterized in that making Foradil Aerolizer formoterol fumarate, described powder inhalation is made up of dried powder, and described excipient substance comprises carrier and additives.
29. pharmaceutical compositions as claimed in claim 28, described carrier is one or more in carbohydrate carrier, amino acid.
30. pharmaceutical compositions as claimed in claim 29, described amino acid comprises glycine, α-amino-isovaleric acid, and described carbohydrate comprises monose, disaccharides and/or its derived carbohydrate.
31. pharmaceutical compositions as claimed in claim 30, described monose comprises N.F,USP MANNITOL, fructose, glucose, described disaccharides comprises maltose, trehalose, cellobiose, lactose, sucrose, and described derived carbohydrate comprises eight cellulose acetate two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid marine alga sugar esters.
32. pharmaceutical compositions as claimed in claim 31, as carrier in described derived carbohydrate is eight acetic acid-D-cellobiose esters.
33. pharmaceutical compositions as claimed in claim 29, is characterized in that the preferred lactose of described carrier.
34. pharmaceutical compositions as claimed in claim 33, is characterized in that described lactose is alpha-lactose monohydrate, β-lactose hydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose.
35. pharmaceutical compositions as claimed in claim 33, is characterized in that the preferred crystallizing and drying lactose of described lactose.
36. pharmaceutical composition as claimed in claim 28, the additives described in its feature contain one or more in tensio-active agent, lubricant, static inhibitor.
37. pharmaceutical compositions as claimed in claim 36, the preferred poloxamer of tensio-active agent described in its feature, the weight ratio of activeconstituents and poloxamer is 1:0.01 ~ 5.
38. pharmaceutical compositions as claimed in claim 36, it is characterized in that described lubricant is one or more in Magnesium Stearate, micropowder silica gel, talcum powder, consumption is 0.01% ~ 1% of carrier micropowder weight.
39. pharmaceutical compositions as claimed in claim 28, is characterized in that the summation of described activeconstituents and the weight ratio of carrier are 1:10 ~ 1000.
40. pharmaceutical compositions as claimed in claim 28, is characterized in that the summation of described activeconstituents and the weight ratio of carrier are 1:10 ~ 200.
41. as arbitrary in claim 19 as described in pharmaceutical composition, it is characterized in that when being prepared into Foradil Aerolizer formoterol fumarate can the packaged of single or multiple dosage, and adopt the mode packing of capsule, each capsule contains the above-mentioned powder inhalation of 5-40mg.
42. pharmaceutical compositions as claimed in claim 41, is characterized in that each capsule contains the above-mentioned powder inhalation of 10-30mg.
43. pharmaceutical compositions as claimed in claim 15, is characterized in that the pharmaceutical composition of described topical is for local cavity preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110184121.2A CN102850426B (en) | 2011-07-01 | 2011-07-01 | A kind of 21 is the glucocorticosteroid of N-acetylcystein ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110184121.2A CN102850426B (en) | 2011-07-01 | 2011-07-01 | A kind of 21 is the glucocorticosteroid of N-acetylcystein ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102850426A CN102850426A (en) | 2013-01-02 |
| CN102850426B true CN102850426B (en) | 2015-12-02 |
Family
ID=47397452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110184121.2A Active CN102850426B (en) | 2011-07-01 | 2011-07-01 | A kind of 21 is the glucocorticosteroid of N-acetylcystein ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102850426B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851734B (en) * | 2019-11-27 | 2024-02-06 | 重庆华邦胜凯制药有限公司 | Preparation method of betamethasone dipropionate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1527838A (en) * | 2001-04-30 | 2004-09-08 | Anti-inflammatory 17. beta-carbothioate ester derivatives of androstane with a cyclic ester group in position 17. alpha |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003210871A1 (en) * | 2002-02-09 | 2003-09-04 | Wilbur Milhous | Mixed steroidal 1,2,4,5-tetraoxane compounds and methods of making and using thereof |
| AU2003261424A1 (en) * | 2002-08-06 | 2004-02-23 | Nitromed, Inc. | Nitrosated and/or nitrosylated ursodeoxycholic acid compounds, compositions and methods of use |
-
2011
- 2011-07-01 CN CN201110184121.2A patent/CN102850426B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1527838A (en) * | 2001-04-30 | 2004-09-08 | Anti-inflammatory 17. beta-carbothioate ester derivatives of androstane with a cyclic ester group in position 17. alpha |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102850426A (en) | 2013-01-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101516333A (en) | Aqueous dronabinol formulations | |
| WO2021198115A1 (en) | Treatment | |
| JP2016515640A (en) | Composition comprising at least two dry powders obtained by spray drying to improve the stability of the formulation | |
| WO2021110064A1 (en) | New multi-functional oligopeptides | |
| CN102178956B (en) | Preparation, medical application and composition of 20S-protopanaxadiol beta-cyclodextrin inclusion compound | |
| CN101347436B (en) | Uses of methylprednisolone and derivatives thereof in preparing medicament for treating allergic rhinitis | |
| CN109662949A (en) | A kind of fludrocortisone acetate oral disnitegration tablet and preparation method thereof | |
| AU2005281735A1 (en) | Ciclesonide and syk inhibitor combination and methods of use thereof | |
| KR20170093114A (en) | Composition comprising at least one dry powder obtained by spray drying to increase the stability of the formulation | |
| CN115124532B (en) | Rhein and matrine co-crystals and their preparation methods and their compositions and uses | |
| CN102850426B (en) | A kind of 21 is the glucocorticosteroid of N-acetylcystein ester | |
| WO2020143744A1 (en) | New formulations containing leukotriene receptor antagonists | |
| CN107982240B (en) | Potassium sodium dehydroandroan drographolide succinate enteric coated granules capable of being accurately dissolved out and preparation method thereof | |
| WO2023213019A1 (en) | Dry powder inhalant for treating idiopathic pulmonary fibrosis and method for preparing same | |
| CN102477058B (en) | New 16,17-dihydroxy intermediate for preparing budesonide | |
| CN101659687A (en) | Novel anti-inflammatory androstane compound | |
| CN101659689B (en) | Methylprednisolone derivative | |
| CN102079769A (en) | Cyclopropyl pregnene compound and application thereof | |
| CN104208045A (en) | Compound inhalation preparation containing penicillin antibiotic and glucocorticoid | |
| CN117338717B (en) | A baicalein external preparation and its application in treating atopic dermatitis | |
| CN101397330B (en) | Novel nitrogen-containing medicament with anti-inflammatory activity | |
| Chen et al. | Preparation and pulmonary delivery of astragaloside IV dry powder inhaler for the treatment of silicosis fibrosis | |
| WO2025120213A1 (en) | Tranexamic acid compositions | |
| CN102477065B (en) | Novel 16, 17-ketal intermediate for preparing budesonide | |
| CN102250185B (en) | Glucocorticoid with NMDA ester positioned on site 21 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |