CN1304290A - 雷洛昔芬的肺和鼻传递给药 - Google Patents
雷洛昔芬的肺和鼻传递给药 Download PDFInfo
- Publication number
- CN1304290A CN1304290A CN99807011A CN99807011A CN1304290A CN 1304290 A CN1304290 A CN 1304290A CN 99807011 A CN99807011 A CN 99807011A CN 99807011 A CN99807011 A CN 99807011A CN 1304290 A CN1304290 A CN 1304290A
- Authority
- CN
- China
- Prior art keywords
- raloxifene
- preparation
- atomization quantity
- patient
- dry powder
- 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.)
- Pending
Links
- 229960004622 raloxifene Drugs 0.000 title claims abstract description 106
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 230000002685 pulmonary effect Effects 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims description 34
- 239000000843 powder Substances 0.000 claims description 28
- 210000004072 lung Anatomy 0.000 claims description 27
- 238000000889 atomisation Methods 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000003203 everyday effect Effects 0.000 claims description 10
- 229960002119 raloxifene hydrochloride Drugs 0.000 claims description 8
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 claims description 8
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 239000003380 propellant Substances 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000006193 liquid solution Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000003434 inspiratory effect Effects 0.000 claims 1
- 230000009245 menopause Effects 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000000241 respiratory effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 4
- 230000005540 biological transmission Effects 0.000 description 15
- 241000282693 Cercopithecidae Species 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 239000000443 aerosol Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000008021 deposition Effects 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 6
- 230000036765 blood level Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 241000282566 Macaca arctoides Species 0.000 description 4
- 238000004442 gravimetric analysis Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 230000036387 respiratory rate Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003684 drug solvent Substances 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229940071648 metered dose inhaler Drugs 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- 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
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- DBTMGCOVALSLOR-UHFFFAOYSA-N 32-alpha-galactosyl-3-alpha-galactosyl-galactose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(OC2C(C(CO)OC(O)C2O)O)OC(CO)C1O DBTMGCOVALSLOR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 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 description 1
- 244000208874 Althaea officinalis Species 0.000 description 1
- 235000006576 Althaea officinalis Nutrition 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 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 description 1
- 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 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 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 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 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 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- -1 atomized drying Substances 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method 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
- 238000002224 dissection Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 235000021022 fresh fruits Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- UKACHOXRXFQJFN-UHFFFAOYSA-N heptafluoropropane Chemical compound FC(F)C(F)(F)C(F)(F)F UKACHOXRXFQJFN-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000001035 marshmallow Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940100630 metacresol Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940126703 systemic medication Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside 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]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dispersion Chemistry (AREA)
- Rheumatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及经肺和鼻给予雷洛昔芬的制剂和方法。
Description
本申请要求1998年4月8日申请的美国临时申请号第60/081,102号的权益。
发明领域
本发明涉及雷洛昔芬(Raloxifene)的肺和鼻给药的方法及制剂。
发明背景
在美国专利第4,418,068号中描述了雷洛昔芬，并已知它对治疗绝经后综合症症状、尤其是骨质疏松症是有效的。甚至1997年末美国食品与药品管理局(FDA)批准雷洛昔芬盐酸盐作为预防性治疗骨质疏松症投入市场。
雷洛昔芬盐酸盐具有如下结构：
迄今，雷洛昔芬盐酸盐的给药通常是口服给予，即摄入片剂和胶囊剂。
决定药物最低有效剂量是临床试验的基本目的。特殊药物的给药途径和/或制剂对最小有效剂量的大小有明显影响。给予提供所需作用的药物最小剂量往往减少该药物引起的任何不必要的副作用到最小可能，而且还为药物生产商和消费者提供经济效益。
在大多数情况下，相对口服给药途径，药物的呼吸和/或鼻给药在药物接受者产生较低的药物血液水平。这样，呼吸道和/鼻给予的最小有效剂量通常高于口服给药。另外，吸入到肺或通过鼻给药不普遍，因为一些药品的吸入负性地改变接受者的呼吸参数。
发明概述
本发明涉及肺传递雷洛昔芬给患者的方法，包括：
让患者经嘴吸入雾化量雷洛昔芬到肺；和
任选重复所述吸入步骤足够次数直到雷洛昔芬的有效剂量传递给患者。
另外，本发明涉及对患者的雷洛昔芬鼻传递方法，包括：
让患者吸入雾化量雷洛昔芬吸入到鼻；和
任选重复所述吸入步骤足够次数直到雷洛昔芬的有效剂量传递给患者。
此外，本发明涉及一种药用制剂，该制剂任选在一种或多种防腐剂、表面活性剂或气体存在下，含有以1mg/mL-100mg/mL浓度溶解或悬浮在药物溶剂中的雷洛昔芬，所述制剂适合于雾化或喷雾。
而且，本发明涉及一种药用制剂，该制剂任选在乙醇存在下，在气雾剂喷射剂中包括质量平均等量空气动力学直径(mass medianequivalent aerodynamic diameter)0.5-100μg的雷洛昔芬干粉末，所述制剂适合在计量剂量的吸入器中使用。
本发明的方法提供意想不到的雷洛昔芬的高水平的生物利用度，使得可通过鼻和/或肺传递雷洛昔芬。
发明的详细描述
当提到“雷洛昔芬”时，当然该术语特别指雷洛昔芬盐酸盐，但是这样的术语也包括其它盐类和它们的溶剂化物。
术语“肺传递”和“呼吸传递”指通过嘴吸入到肺将雷洛昔芬系统传递给患者。
术语“鼻传递”指通过吸入到鼻将雷洛昔芬系统传递给患者。
术语“患者”指需要雷洛昔芬的哺乳动物、尤其是人类女性。尤其需要的是患有或可能患有骨质疏松症的人类绝经妇女。使用雷洛昔芬抑制骨质疏松症在美国专利第5,393,763、5,457,117、5,478,847、4,698,328号中有充分描述，各说明书通过引用结合到本文中。雷洛昔芬的其它用途(需要)和易受雷洛昔芬抑制的病理状态至少在以下美国专利中有论述：第5,389,670、5,391,557、5,393,763、5,441,966、5,446,053、5,447,941、5,451,589、5,457,113、5,447,116、5,464,845、5,478,847、5,502,074、5,510,370、5,534,526、5,552,416、5,571,808、5,593,987、5,610,168和5,698,572号，各说明书内容通过引用结合到本文中。
本文使用的术语“有效量”是指雷洛昔芬能抑制上述各种病理状态如骨质疏松症的剂量。
术语“抑制”和“抑制性”具有其通常的意思，包括抑制、治疗、停止、遏制、减慢或逆转病程，或减轻上述各种病理状态的严重程度。这样，这些方法包括医学治疗性(急性)和/或预防性(防止)适当给药。
术语“药用的”当用作形容词时，是指基本上对患者无毒性作用。
本发明涉及将雷洛昔芬通过肺和/或鼻传递给哺乳动物患者、尤其是人类患者的方法和适用于适用于上述肺和鼻传递的药用制剂。通过分散一定量的雷洛昔芬在一定容积的气体中产生雾化量而实施本发明的方法。这种分散作用可以通过以下方法产生：患者吸气产生；把雷洛昔芬干粉末引入高速气流；雾化或喷雾雷洛昔芬的液体溶液或悬浮液，或经喷嘴释放含有喷射剂的雷洛昔芬。患者通过嘴和/或鼻吸入所述雾化量到肺和/或鼻。重复分散和吸入步骤足够次数，可将所需要的雷洛昔芬总剂量(有效剂量)传递给患者。
雷洛昔芬可以通过所建立的方法生产，如在美国专利第4,418,068和第5,629,425号中详尽描述的方法，其内容通过引用结合到本文中。适用于呼吸和鼻传递给患者的雷洛昔芬具体制剂包括干粉末、适于雾化或喷雾的液体溶液剂或悬浮剂和适用于在计量剂量的吸入器(MDI’s)使用的喷射制剂。这类制剂的制备在专利、科学和医学文献以及下面的实施例中有很好描述。
呼吸制剂与鼻制剂两者的主要区别是雷洛昔芬的颗粒大小要求鼻传递不象呼吸传递那样受限制。事实上，呼吸制剂的可操作的颗粒大小范围属于鼻制剂可操作颗粒大小范围的一个亚组。所以通常可使用比较简单的设备如鼻泵喷雾器经鼻传递雷洛昔芬。
下面讨论适合于鼻和/或肺传递的制剂并不是以任何方式限制本发明的实践，因为它独立于任何具体类型的鼻和/或肺传递制剂/系统。
干粉制剂通常含有具有适宜的颗粒大小和或在适宜的颗粒大小范围内的干粉、通常为冷冻干粉型的雷洛昔芬。适宜肺沉积的最小颗粒大小典型地是0.5μm质量平均等量空气动力学直径(MMEAD)，但优选1μm MMEAD，最优选2μm MMEAD。适宜肺沉积的最大颗粒大小典型地是10μm MMEAD，但优选为8μm MMEAD，最优选4μmMMEAD。最优大约3μm MMEAD的颗粒大小。适宜沉积在鼻的最小颗粒大小典型地是0.5μm MMEAD，但优选3μm MMEAD，最优选5μm MMEAD。适宜沉积在鼻的最大颗粒大小典型地是100μmMMEAD，但优选50μm MMEAD，最优选20μm。用各种常规技术可生产在优选在大小范围内的可吸入雷洛昔芬粉末，所述常规技术如喷射磨粉、喷雾干燥、溶剂沉淀、超临界流体冷凝等。因为颗粒大小对鼻传递不太重要，从溶液中结晶就可满足要求。若不能满足要求，可通过喷射磨粉或球磨粉加强。
这些具有合适MMEAD的干粉可通过常规干粉吸入器(DPI’s)给预患者，所述吸入器依赖患者呼吸，当呼吸时将将所述干粉分散成雾化量。或者，所述干粉剂可通过空气助喷装置给予，该装置用外源动力将所述粉末分散成雾化量，例如活塞泵。
干粉装置通常要求粉末质量范围从约1mg到20mg，以产生单一气雾剂量(“一团雾，(puff)”)。如果所要求或需要的雷洛昔芬剂量抵于该剂量，就象如下讨论，通常就将所述雷洛昔芬粉末与药用干增量粉结合，以提供所要求的粉末总质量。优选的干增量粉包括蔗糖、乳糖、葡萄糖、甘露糖醇、甘氨酸、海藻糖、人体血浆白蛋白(HAS)和淀粉。其它合适干增量粉包括纤维二糖、右旋糖酐、麦芽三糖、胶质、柠檬酸钠和抗坏血酸钠等。
当用溶剂沉淀制备所述干粉剂时，通常在颗粒形成前用缓冲剂和盐来稳定在溶液中的雷洛昔芬。合适的缓冲剂包括但不限于抗坏血酸盐、磷酸盐、柠檬酸盐、醋酸盐和tris-盐酸，通常其浓度为约5mM到50mM。合适的盐包括：氯化钠、碳酸钠、氯化钙等。用于雾化器系统的雷洛昔芬液体制剂可使雷洛昔芬溶解或悬浮在药物溶剂如水、乙醇或它们的混合物中，所述雾化器系统如压缩空气雾化器、喷射雾化器、超声雾化器和压电雾化器通常所溶解/悬浮的雷洛昔芬最小浓度是约1mg/mL，但优选5mg/mL，最优选10mg/mL。通常溶解/悬浮的雷洛昔芬最大浓度是约100mg/mL，但优选60mg/mL，最优选20mg/mL。传递所述雾化量的雾化液体总体积一般范围是约0.1mL到5mL。
所用的药用溶剂也可以是弱酸缓冲液。适宜的缓冲剂如上所述。还可加入其它成分以提高或保持化学稳定性，包括防腐剂、表面活性剂、分散剂或气体。合适的防腐剂包括但不限于酚、对羟基苯甲酸甲酯，对羟基苯甲酸酯、间甲酚、乙基汞硫代水杨酸钠、Benzylakonimum chloride等。合适的表面活性剂包括但不限于油酸、脱水山梨糖醇三油酸酯、多乙氧基醚、卵磷脂、磷酯酰(phosphotidyl)胆碱和各种长链的甘油二脂以及磷脂。合适的分散剂包括但不限于乙二氨四乙酸等。合适的气体包括但不限于氮气、氦气、二氧化碳、空气等。
用于呼吸和/或鼻传递雷洛昔芬的喷雾器系统应用的制剂与用于雾化器的所述制剂相似。关于这类肺传递系统和本文描述的其它系统，参见例如Wolff,R.K.和Niven,R.W.“雾化药物的产生，”J.AerosolMed.,7:89,1994。鼻传递系统在“Transdermal SystemicMedication”,Y.W.Chien编辑，Elsevier Publishers,New York,1985和美国专利第4,778,810号中已有描述，其内容通过引用结合到本文中。
为在MDI’s中使用，可将雷洛昔芬溶解或悬浮在合适的气溶胶抛射剂中如含氯氟烃(CFC)或氢氟烃(HFC)。这类悬浮剂每气雾剂剂量含10mg到100mg雷洛昔芬。合适的CFC包括三氯一氟甲烷(抛射剂11)，二氯四氟甲烷(抛射剂114)和二氯二氟甲烷(抛射剂12)。合适的HFC包括四氟乙烷(HFC-134a)和七氟丙烷(HFC-227)。
为引入气溶胶抛射剂，优选地将雷洛昔芬加工成上述干粉制剂的颗粒大小。然后如上所述将该颗粒悬浮在抛射剂中，但是通常用表面活性剂包衣以提高/促进其分散。合适的表面活性剂如上对液体制剂所定义的表面活性剂。抛射制剂进一步包括低级醇如乙醇(高至30％重量)和其它添加剂，以保持或提高化学稳定性和生理可接受性。适用于抛射制剂的添加剂包括上述表面活性剂，如三梨醇、油酸和卵磷脂。关于这类添加剂的进一步资料，见G.W.Hallworth.“Theformulation and evaluation of pressurised metered inhalers,”DrugDelivery to the Lung,D.Ganderton and T.Jone(编辑),Ellis,Horword,Chichester,U.K.第87-18页。
雷洛昔芬必需的准确剂量根据受治疗者的年龄、体型大小、性别和一般情况、需要治疗的疾病的性质和严重性等而变化；因此，准确的有效剂量应由护理者(caregiver)决定。
然而，雷洛昔芬治疗骨质疏松症的总气雾剂量典型地是每天约2mg到16mg之间，通常是在每天约4mg到8mg之间。这样的剂量将导致每天约0.5mg到5mg、通常每天约1.5mg到2.5mg的总的系统有效性(即传递到血液的量)。当然，准确剂量将随已知的药代学因素和吸入系统的独特特性(见以下对MDI的具体讨论)而变化。通常雷洛昔芬的总剂量将以几个(典型为1到3个、最典型为1到2个)分开的雾化剂量传递，此时每个雾化量包含1mg到8mg的雷洛昔芬。
在适用于雾化器或喷雾器的干粉制剂或液体制剂的情况下，上述范围的雷洛昔芬总剂量可由患者吸入一个或多个雾化量实现。
由于MDI装置效率低，通常仅5％-20％的一小部分药物能到达肺。因此，以2-5个雾化量能传递雷洛昔芬有效剂量范围，每个雾化量包含雷洛昔芬约20mg。
下面的操作实施例进一步说明本发明的实践，但是不是要在任何方面限制发明范围，因此不应该如此解释。
工作实施例1
已发现短尾猴是用于研究雷洛昔芬在人体的代谢和沉积的良好药代学模型。药物通过猴的肺和鼻的气雾剂沉积与人相似。Schlesinger,R.B.,“吸入气雾剂在实验动物和人的沉积比较：综述”J.Toxicol.Environ Health,15:197,1985。另外，鼻部解剖和粘膜(mucociliary)清除率在猴和人是相似的(Wolff等，“恒河猴的鼻部清除率，”J.AerosolMedicine,6:111-119,1993。
6只成年短尾猴(3只雄性，3只雌性)用于本研究。在生活开始阶段雄性猴重量从5.3公斤到5.5公斤。在生活开始阶段雌性猴重量从3.8公斤到4.9公斤。每只动物通过在大腿内侧所纹的独特数字来辨认。
所有动物都单独饲养在不锈钢笼内。室内温度恒定控制在72°F，保持实际温度在72±8°F范围。设计环境系统以维持相对湿度为20％，最大为80％。以12小时的周期用0600-1800光进行光照。所有动物用Purina Certified Primate Chow第5048号每日饲养两次，实验日除外。实验日，所有动物仅在吸入暴露完成后提供灵长类饲料。除了在暴露期间外，动物可随意饮水。
在开始研究的生活阶段之前，在约3个月的时间内用pole-and-coller的方法，使猴习惯于抓获、处理和置于限制椅中。食物象花生、药用蜀葵和各种干鲜果作为训练奖品。使猴保持在椅子上的时间逐渐增加到8小时。到训练结束，所有的猴都能被迅速抓住，很容易地放在限制椅上，并允许进行肢体操作，包括在椅子上对其取血。
每只猴每周研究一次，持续5周。雷洛昔芬活性的目标浓度从第1周到第5周分别是0、3、10、0和30mg/m3。通过校正所用的多次效价(potency of the lot used)汇集的雷洛昔芬量决定其活性。每次暴露8小时，以15分钟间隔分成4小时区段。在4小时暴露之间的15分钟间隔期间，使猴饮用果汁和摄食苹果片。上述调节期间，使用这种方法使动物避免由于饥饿或渴变得表现躁动不安。希望暴露期间的15分钟间隔不影响雷洛昔芬的血浓度。
每次暴露前将猴置于限制椅上。两条乳胶薄片(0.03英寸厚)置于动物的颈部周围密封。按照J.Appl.Toxicol.,15:13,1995中描述的方法，将7-升圆顶帽置于动物头上。通过排气部件上的校准横向流量(transvector)经头部圆顶帽保持气体流速15升/分。使用Wright DustFeed Ⅱ雾化雷洛昔芬。设计产生的气雾剂通过一个气旋(Environ.Sci.Technol.,13:1387,1979)，以利用惯性特征消除大于2μm MMEAD的颗粒。气雾剂跟随进入头部圆顶帽供猴呼吸用。因为化合物(包括雷洛昔芬)分子量比大数蛋白质小，这些大小的颗粒将沉积在鼻和肺部，并将从这两个部位吸收。Bond,S.W.，药物的呼吸道传递，D.Ganderton和T.Jones(编辑),Ellis Horwood Publishers,Chichester,U.K.，第133-139页，1987。
每天在使猴暴露之前，建立起暴露系统和取出重量分析样品测定雷洛昔芬浓度。然后将猴放置在椅子上，用同样的气雾剂发生器装置产生气雾剂。在暴露于猴后，将其从椅子上移开，重新安装系统，取另一重量分析样品。平均从两个重量分析样品获得的浓度得到雷洛昔芬的暴露浓度。重量分析浓度用直接从圆顶帽收集所述气雾剂到25mm Gelman type A/E玻璃纤维过滤器测定。气流透过过滤器是1升/分，3mg/m3暴露的取样时间为1小时和10-30mg/m3暴露的取样时间为20分钟。对每一暴露浓度进行一次颗粒大小测定。用配置Gelman Type A/E玻璃纤维过滤器的Sierra Model 218K CascadeImpactor收集样品测定颗粒大小。通过Cascade Impactor的气流是3升/分，3、10和30mg/m3暴露的取样时间分别为1143、300、115分钟。
在雷洛昔芬暴露期间，在暴露开始后约在下列时间从股动脉或股静脉取血5mL：暴露前、1、2、4、8、11和14小时。将血收集在肝素化管中。为得到血浆，将每管以200xg于4℃或10℃离心15分钟。去除上部1mL血浆，其余血浆留置在试管中并保存于-70℃直到送去检测雷洛昔芬浓度。
用连接圆顶帽排气口的‘0’号大小的呼吸速率描记器监测呼吸类型(潮气量，呼吸频率，分钟通气量)。用Buxco Electronics Inc.生产的LS20软件在个人电脑上收集信号。至少收集10分钟暴露前资料才开始暴露，接着收集暴露8小时期间资料。暴露前资料收集为1分钟平均值，暴露资料收集为5分钟平均值。
雷洛昔芬/总雷洛昔芬的AUC比率在10和30mg/m3剂量组分别是0.56和0.82(见下表1)。在该吸入研究中的雷洛昔芬/总雷洛昔芬的AUC比率与对短尾猴口服给予雷洛昔芬的相似研究中的观测值明显不同，其中所述口服研究的观测值是0.02-0.04。结果，通过这种用药途经使雷洛昔芬的有效剂量进入患者血液，所需要的雷洛昔芬总量显著少于口服给药。我们观察到雷洛昔芬、雷洛昔芬总量、Cmax或AUC值没有显著的性别差异。另外，在任何暴露期间，没有出现潮气量或呼吸频率的明显变化。完成实施例1实验所收集的部分资料示于下表1中。
表1
| 暴露浓度(mg Ralox./m3空气) | Cmax(平均Ralox.,ng/mL) | Cmax(总平均Ralox.,ng/mL) | AUC |
| 3.3 | 7 | * | * |
| 9.7 | 17 | 10 | 0.56 |
| 26.9 | 47 | 84 | 0.82 |
*值太低不能准确测定
与口服传递相比，鼻和肺传递降低药物首先通过肝脏的代谢。来自鼻的血液经静脉系统到心脏，再分布到全身。沉积在肺的物质吸收到毛细血管，再进入心脏。相应地，相对于口服传递，在实施例1中应用的暴露的肺/鼻途径产生较高初始水平的吸收入血的非代谢雷洛昔芬。然而，由于来自心脏的20％血流进入肝脏，人们预测肝代谢将迅速降低雷洛昔芬的血水平到口服传递后的相似值。令人惊奇的是，上述对6只成年短尾猴肺/鼻传递雷洛昔芬，产生较高的雷洛昔芬血液水平，并持续数小时。经肺/鼻传递获得的血液水平显著高于以相同剂量口服给药后获得的血液水平。
这些结果证实本发明的方法提供意想不到的高水平雷洛昔芬生物利用度。这种高水平生物利用度能转化为患者/制造商的经济效益，并可提供相对更高剂量的制剂/传递方法有利的安全分布。
Claims (30)
1．肺传递雷洛昔芬给患者的方法，该方法包括：让所述患者由嘴吸入雾化量雷洛昔芬到肺；和任选重复所述吸入步骤足够次数直到将有效剂量雷洛昔芬传递给所述患者。
2．按照权利要求1的方法，其中所述雷洛昔芬为雷洛昔芬盐酸盐。
3．按照权利要求2的方法，其中所述患者是人类女性。
4．按照权利要求3的方法，其中所述雾化量通过将雷洛昔芬干粉任选在增量剂存在下引入气流中产生。
5．按照权利要求4的方法，其中所述气流是患者的呼吸吸入气流。
6．按照权利要求3的方法，其中所述雾化量是通过雾化或喷雾雷洛昔芬的液体溶液或悬浮液产生。
7．按照权利要求4的方法，其中所述雾化量含雷洛昔芬约1-8mg，每天总剂量是约2-16mg。
8．按照权利要求6的方法，其中所述雾化量含雷洛昔芬约1-8mg，每天总剂量是约2-16mg。
9．按照权利要求3的方法，其中所述雾化量通过释放含抛射剂的雷洛昔芬干粉产生。
10．按照权利要求9的方法，其中所述雾化量含雷洛昔芬约10-100mg。
11．鼻传递雷洛昔芬给患者的方法，该方法包括：让所述患者吸入雾化量雷洛昔芬到鼻；和任选重复所述吸入步骤足够次数直到将有效剂量雷洛昔芬传递给所述患者。
12．按照权利要求11的方法，其中所述雷洛昔芬为雷洛昔芬盐酸盐。
13．按照权利要求12的方法，其中所述患者是人类绝经或绝经后妇女。
14．按照权利13的方法，其中所述雾化量通过将雷洛昔芬干粉任选在增量剂存在下引入气流中产生。
15．按照权利14的方法，其中所述气流是患者呼吸的吸气气流。
16．按照权利13的方法，其中所述雾化量是通过雾化或喷雾雷洛昔芬的液体溶液或悬浮液产生。
17．按照权利要求14的方法，其中所述雾化量含雷洛昔芬约1-8mg，每天总剂量是约2-16mg。
18．按照权利要求16的方法，其中所述雾化量含雷洛昔芬约1-8mg，每天总剂量是约2-16mg。
19．按照权利要求13的方法，其中所述雾化量是通过释放含抛射剂的雷洛昔芬干粉产生。
20．按照权利要求19的方法，其中所述雾化量含雷洛昔芬约10-100mg。
21．一种药物制剂，它任选在一种或多种防腐剂、表面活性剂或气体存在下含有溶解或悬浮在药用溶剂中的雷洛昔芬，雷洛昔芬浓度为1-100mg/mL，所述制剂适用于雾化或喷雾。
22．按照权利要求21的制剂，其中所述雷洛昔芬为雷洛昔芬盐酸盐。
23．按照权利要求22的制剂，其中所述雷洛昔芬存在浓度范围为5-60mg/mL。
24．按照权利要求23的制剂，其中所述浓度范围为10-20mg/mL。
25．一种药用制剂，它任选存在乙醇中在气溶胶抛射剂中含有作为干粉存在的雷洛昔芬，其中所述干粉的质量平均等量空气动力学直径0.5-100μm，所述制剂适用于计量剂量的吸入仪(MDI)。
26．按照权利要求26的制剂，其中所述雷洛昔芬为雷洛昔芬盐酸盐。
27．按照权利要求27的制剂，其中所述雷洛昔芬的平均颗粒大小范围为1-8μm。
28．按照权利要求28的制剂，其中所述平均颗粒大小范围为2-4μm。
29．按照权利要求27的制剂，其中所述雷洛昔芬的平均颗粒大小范围为3-50μm。
30．按照权利要求30的制剂，其中所述平均颗粒大小范围为5-20μm。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8110298P | 1998-04-08 | 1998-04-08 | |
| US60/081,102 | 1998-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1304290A true CN1304290A (zh) | 2001-07-18 |
Family
ID=22162102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99807011A Pending CN1304290A (zh) | 1998-04-08 | 1999-03-31 | 雷洛昔芬的肺和鼻传递给药 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US6080762A (zh) |
| EP (1) | EP1067839A1 (zh) |
| JP (1) | JP2002510603A (zh) |
| KR (1) | KR20010042531A (zh) |
| CN (1) | CN1304290A (zh) |
| AU (1) | AU749751B2 (zh) |
| BR (1) | BR9909492A (zh) |
| CA (1) | CA2327670A1 (zh) |
| EA (1) | EA003328B1 (zh) |
| HR (1) | HRP20000666A2 (zh) |
| HU (1) | HUP0101737A3 (zh) |
| ID (1) | ID27606A (zh) |
| IL (1) | IL138687A0 (zh) |
| NO (1) | NO20005045L (zh) |
| NZ (1) | NZ507151A (zh) |
| PL (1) | PL343438A1 (zh) |
| TR (1) | TR200002855T2 (zh) |
| WO (1) | WO1999051096A1 (zh) |
| ZA (1) | ZA200005154B (zh) |
Families Citing this family (59)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7052678B2 (en) | 1997-09-15 | 2006-05-30 | Massachusetts Institute Of Technology | Particles for inhalation having sustained release properties |
| US6956021B1 (en) * | 1998-08-25 | 2005-10-18 | Advanced Inhalation Research, Inc. | Stable spray-dried protein formulations |
| EP1185248B1 (en) | 1999-06-09 | 2012-05-02 | Robert E. Sievers | Supercritical fluid-assisted nebulization and bubble drying |
| US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
| US20010036481A1 (en) * | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
| US6749835B1 (en) | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
| JP2003507410A (ja) * | 1999-08-25 | 2003-02-25 | アドバンスト インハレーション リサーチ，インコーポレイテッド | 乾燥粉末製剤からの放出調節 |
| US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
| AU7993500A (en) * | 1999-11-15 | 2001-05-30 | New Millennium Pharmaceutical Research, Inc. | Intranasal administration of raloxifene and tamoxifen |
| US20020141946A1 (en) * | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
| ATE375786T1 (de) * | 2001-08-16 | 2007-11-15 | Cmp Therapeutics Ltd | Chitin-mikropartikel und ihre medizinische verwendung |
| ES2415654T3 (es) * | 2001-11-20 | 2013-07-26 | Civitas Therapeutics, Inc. | Composiciones particuladas mejoradas para suministro pulmonar |
| US20030215462A1 (en) * | 2001-12-21 | 2003-11-20 | Wacher Vincent J. | Use of UGT inhibitors to increase bioavailability |
| DE60318938T2 (de) | 2002-03-20 | 2009-01-22 | Mannkind Corp., Valencia | Inhalationsgerät |
| US7677411B2 (en) * | 2002-05-10 | 2010-03-16 | Oriel Therapeutics, Inc. | Apparatus, systems and related methods for processing, dispensing and/or evaluatingl dry powders |
| US6889690B2 (en) * | 2002-05-10 | 2005-05-10 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister devices, and associated methods of dispensing dry powder substances and fabricating blister packages |
| EP1534366B1 (en) * | 2002-06-27 | 2014-01-08 | Oriel Therapeutics, Inc. | Dry powder dose filling systems and related methods |
| KR100779484B1 (ko) * | 2002-10-04 | 2007-11-26 | 주식회사 만도 | 전자식유압브레이크의 마스터실린더 |
| US7534348B2 (en) * | 2003-09-12 | 2009-05-19 | Fenwal, Inc. | Flow-through removal device and system using such device |
| US7451761B2 (en) * | 2003-10-27 | 2008-11-18 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister package indexing and opening mechanisms, and associated methods of dispensing dry powder substances |
| US7377277B2 (en) * | 2003-10-27 | 2008-05-27 | Oriel Therapeutics, Inc. | Blister packages with frames and associated methods of fabricating dry powder drug containment systems |
| ES2385934T3 (es) | 2004-08-20 | 2012-08-03 | Mannkind Corporation | Catálisis de la síntesis de dicetopiperazina. |
| EP2314298B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Microparticles comprising diketopiperazine salts for drug delivery |
| EP2308469A1 (en) * | 2005-05-18 | 2011-04-13 | Pulmatrix, Inc. | Formulations for alteration of biophysical properties of mucosal lining |
| KR20160022404A (ko) | 2005-09-14 | 2016-02-29 | 맨카인드 코포레이션 | 활성제에 대한 결정질 미립자 표면의 친화력의 증가를 기반으로 하는 약물 제제화의 방법 |
| MX2008010721A (es) | 2006-02-22 | 2008-09-01 | Mannkind Corp | Un metodo para mejorar las propiedades farmaceuticas de microparticulas que contienen dicetopiperazina y un agente activo. |
| US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
| EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
| MX2010014240A (es) | 2008-06-20 | 2011-03-25 | Mankind Corp | Un metodo y aparato interactivo para perfilar en tiempo real esfuerzos de inhalacion. |
| TWI614024B (zh) | 2008-08-11 | 2018-02-11 | 曼凱公司 | 超快起作用胰島素之用途 |
| WO2010033207A1 (en) | 2008-09-19 | 2010-03-25 | Nektar Therapeutics | Polymer conjugates of therapeutic peptides |
| EP2344200A2 (en) * | 2008-09-19 | 2011-07-20 | Nektar Therapeutics | Modified therapeutics peptides, methods of their preparation and use |
| US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
| CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
| EP2246050A1 (en) * | 2009-04-27 | 2010-11-03 | IMR - International Medical Research - Partner GmbH | Combination therapy comprising mechanical vibration for the treatment of a disease of the musculoskeletal or nervous system |
| US8551528B2 (en) | 2009-06-12 | 2013-10-08 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
| EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
| BR112012033060A2 (pt) | 2010-06-21 | 2018-02-27 | Mannkind Corp | métodos de sistema de liberação de fármaco em pó seco |
| EP2464346A1 (en) | 2010-08-30 | 2012-06-20 | Pulmatrix, Inc. | Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder |
| JP5877201B2 (ja) | 2010-08-30 | 2016-03-02 | パルマトリックス，インコーポレイテッド | 肺疾患を治療するための乾燥粉末製剤および方法 |
| CN103228273B (zh) | 2010-09-29 | 2017-04-05 | 普马特里克斯营业公司 | 吸入用单价金属阳离子干粉剂 |
| DK2621488T3 (en) | 2010-09-29 | 2019-03-04 | Pulmatrix Operating Co Inc | CATIONIC DRY POWDER |
| KR101940832B1 (ko) | 2011-04-01 | 2019-01-21 | 맨카인드 코포레이션 | 의약 카트리지용 블리스터 패키지 |
| WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
| EP2776053A1 (en) | 2011-10-24 | 2014-09-17 | MannKind Corporation | Methods and compositions for treating pain |
| CA2865972C (en) | 2012-02-29 | 2022-01-04 | Pulmatrix, Inc. | Inhalable dry powders |
| SG11201500218VA (en) | 2012-07-12 | 2015-03-30 | Mannkind Corp | Dry powder drug delivery systems and methods |
| EP2911690A1 (en) | 2012-10-26 | 2015-09-02 | MannKind Corporation | Inhalable influenza vaccine compositions and methods |
| EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
| CA2907566C (en) | 2013-04-01 | 2023-08-22 | Pulmatrix, Inc. | Tiotropium dry powders |
| BR122019026637B1 (pt) | 2013-07-18 | 2023-09-26 | Mannkind Corporation | Formulações farmacêuticas de pó seco e método para a fabricação de uma formulação de pó seco |
| CA2920488C (en) | 2013-08-05 | 2022-04-26 | Mannkind Corporation | Insufflation apparatus and methods |
| WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
| US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
| WO2018071452A1 (en) | 2016-10-11 | 2018-04-19 | Growblox Life Sciences L.L.C. | Cannabinoid-containing complex mixtures for the treatment of neurodegenerative diseases |
| US10857107B2 (en) | 2017-02-01 | 2020-12-08 | Gbs Global Biopharma, Inc. | Cannabinoid-containing complex mixtures for the treatment of mast cell-associated or basophil-mediated inflammatory disorders |
| EP3630063A2 (en) | 2017-05-22 | 2020-04-08 | GBS Global Biopharma, Inc. | Myrcene-containing complex mixtures targeting trpv1 |
| WO2019226833A1 (en) | 2018-05-22 | 2019-11-28 | Gbs Global Biopharma, Inc. | Cannabinoids and/or terpenes for use in trpv1 modulation |
| EP3990925A1 (en) | 2019-06-28 | 2022-05-04 | GBS Global Biopharma, Inc. | Treatment of pain using allosteric modulator of trpv1 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| US5441965A (en) * | 1993-12-21 | 1995-08-15 | Eli Lilly And Company | Methods of inhibiting thrombin |
| US5478847A (en) * | 1994-03-02 | 1995-12-26 | Eli Lilly And Company | Methods of use for inhibiting bone loss and lowering serum cholesterol |
| US5484798A (en) * | 1994-09-20 | 1996-01-16 | Eli Lilly And Company | Benzothiopene compounds, compositions, and method of inhibiting restenosis |
| CA2214072C (en) * | 1996-08-29 | 2006-11-14 | Eli Lilly And Company | Benzo [b] thiophene compounds, intermediates, processes, compositions, and methods |
-
1999
- 1999-03-31 NZ NZ507151A patent/NZ507151A/xx unknown
- 1999-03-31 EP EP99916270A patent/EP1067839A1/en not_active Withdrawn
- 1999-03-31 AU AU34625/99A patent/AU749751B2/en not_active Ceased
- 1999-03-31 JP JP2000541877A patent/JP2002510603A/ja not_active Withdrawn
- 1999-03-31 WO PCT/US1999/007184 patent/WO1999051096A1/en not_active Application Discontinuation
- 1999-03-31 PL PL99343438A patent/PL343438A1/xx unknown
- 1999-03-31 CN CN99807011A patent/CN1304290A/zh active Pending
- 1999-03-31 HU HU0101737A patent/HUP0101737A3/hu unknown
- 1999-03-31 KR KR1020007011173A patent/KR20010042531A/ko not_active Application Discontinuation
- 1999-03-31 IL IL13868799A patent/IL138687A0/xx unknown
- 1999-03-31 BR BR9909492-4A patent/BR9909492A/pt not_active IP Right Cessation
- 1999-03-31 TR TR2000/02855T patent/TR200002855T2/xx unknown
- 1999-03-31 CA CA002327670A patent/CA2327670A1/en not_active Abandoned
- 1999-03-31 ID IDW20002122A patent/ID27606A/id unknown
- 1999-03-31 EA EA200001037A patent/EA003328B1/ru not_active IP Right Cessation
- 1999-04-08 US US09/288,446 patent/US6080762A/en not_active Expired - Fee Related
-
2000
- 2000-09-26 ZA ZA200005154A patent/ZA200005154B/xx unknown
- 2000-10-06 NO NO20005045A patent/NO20005045L/no not_active Application Discontinuation
- 2000-10-09 HR HR20000666A patent/HRP20000666A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO20005045L (no) | 2000-12-05 |
| EA003328B1 (ru) | 2003-04-24 |
| ID27606A (id) | 2001-04-12 |
| BR9909492A (pt) | 2000-12-12 |
| JP2002510603A (ja) | 2002-04-09 |
| KR20010042531A (ko) | 2001-05-25 |
| AU749751B2 (en) | 2002-07-04 |
| CA2327670A1 (en) | 1999-10-14 |
| HRP20000666A2 (en) | 2001-08-31 |
| WO1999051096A1 (en) | 1999-10-14 |
| IL138687A0 (en) | 2001-10-31 |
| PL343438A1 (en) | 2001-08-13 |
| US6080762A (en) | 2000-06-27 |
| EA200001037A1 (ru) | 2001-04-23 |
| AU3462599A (en) | 1999-10-25 |
| HUP0101737A2 (hu) | 2002-05-29 |
| EP1067839A1 (en) | 2001-01-17 |
| NZ507151A (en) | 2002-11-26 |
| ZA200005154B (en) | 2002-06-10 |
| HUP0101737A3 (en) | 2002-06-28 |
| TR200002855T2 (tr) | 2000-12-21 |
| NO20005045D0 (no) | 2000-10-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1304290A (zh) | 雷洛昔芬的肺和鼻传递给药 | |
| AU2009225363B2 (en) | Formulations for decreasing infectivity of pulmonary disease | |
| KR100277622B1 (ko) | 흡입용 초미립자 분말 및 그의 제조방법 | |
| US8858917B2 (en) | Methods for limiting spread of pulmonary infections | |
| KR100652532B1 (ko) | 유동 저항이 조절된 에어로졸화 활성 약물의 송달 | |
| WO2021252577A1 (en) | Pharmaceutical formulation containing umeclidinium bromide and vilanterol trifenatate | |
| JPH10509431A (ja) | 表面活性物質の分泌不足に関連する肺疾患の治療法 | |
| Magramane et al. | Formulation and characterization of pulmonary drug delivery systems | |
| US20050220720A1 (en) | Formulations limiting spread of pulmonary infections | |
| JP5437543B2 (ja) | 喘息検出用製剤 | |
| CN111110634A (zh) | 一种磷酸氯喹吸入气雾剂及其制备方法 | |
| CN117860712A (zh) | 一种吸入用氨糖组合物及其制备方法和其应用 | |
| CN117205186A (zh) | 一种雷芬那辛吸入喷雾剂及其制备方法 | |
| CN115835885A (zh) | 包含奥达特罗和布地奈德的药物组合物的制备 | |
| MXPA00009704A (en) | Pulmonary and nasal delivery of raloxifene | |
| AU2012202618A1 (en) | Formulations for decreasing infectivity of pulmonary disease | |
| CZ20003544A3 (cs) | Pulmonární a nasální podávání raloxifenu |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |