FI112917B - Menetelmä paratyroidihormonin biologisesti aktiivisia fragmentteja sisältävän farmaseuttisen koostumuksen valmistamiseksi - Google Patents
Menetelmä paratyroidihormonin biologisesti aktiivisia fragmentteja sisältävän farmaseuttisen koostumuksen valmistamiseksi Download PDFInfo
- Publication number
- FI112917B FI112917B FI951465A FI951465A FI112917B FI 112917 B FI112917 B FI 112917B FI 951465 A FI951465 A FI 951465A FI 951465 A FI951465 A FI 951465A FI 112917 B FI112917 B FI 112917B
- Authority
- FI
- Finland
- Prior art keywords
- pth
- fragment
- parathyroid hormone
- biologically active
- fragments
- Prior art date
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 116
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract description 111
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 110
- 229960001319 parathyroid hormone Drugs 0.000 title claims abstract description 110
- 239000012634 fragment Substances 0.000 title claims abstract description 68
- 238000000034 method Methods 0.000 title claims description 23
- 230000008569 process Effects 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000000843 powder Substances 0.000 claims abstract description 29
- 239000003380 propellant Substances 0.000 claims abstract description 12
- 210000004898 n-terminal fragment Anatomy 0.000 claims abstract description 9
- 210000004072 lung Anatomy 0.000 claims description 21
- 230000002685 pulmonary effect Effects 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 239000000443 aerosol Substances 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 239000007789 gas Substances 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
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 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
- 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 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- -1 HAS Chemical compound 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 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
- 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
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical group F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000001814 pectin Substances 0.000 claims description 2
- 235000010987 pectin Nutrition 0.000 claims description 2
- 229920001277 pectin Polymers 0.000 claims description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 2
- 229960005055 sodium ascorbate Drugs 0.000 claims description 2
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 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 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 2
- 239000012062 aqueous buffer Substances 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 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 claims 1
- 210000002966 serum Anatomy 0.000 abstract description 23
- 239000000203 mixture Substances 0.000 abstract description 20
- 238000009472 formulation Methods 0.000 abstract description 10
- 239000006185 dispersion Substances 0.000 abstract description 5
- 238000012384 transportation and delivery Methods 0.000 abstract description 5
- 239000006193 liquid solution Substances 0.000 abstract description 3
- 239000006194 liquid suspension Substances 0.000 abstract description 3
- 238000002663 nebulization Methods 0.000 abstract description 3
- 230000000541 pulsatile effect Effects 0.000 abstract description 2
- 230000000241 respiratory effect Effects 0.000 abstract description 2
- 102100036893 Parathyroid hormone Human genes 0.000 abstract 5
- 229940071648 metered dose inhaler Drugs 0.000 abstract 1
- 238000012385 systemic delivery Methods 0.000 abstract 1
- 235000001014 amino acid Nutrition 0.000 description 18
- 150000001413 amino acids Chemical class 0.000 description 17
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 description 10
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 description 10
- 102000058004 human PTH Human genes 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 208000001132 Osteoporosis Diseases 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000003623 enhancer Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 229930003316 Vitamin D Natural products 0.000 description 3
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 210000003437 trachea Anatomy 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 150000003710 vitamin D derivatives Chemical class 0.000 description 3
- 229940046008 vitamin d Drugs 0.000 description 3
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102100023915 Insulin Human genes 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
- 239000000654 additive Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-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
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 1
- UYCPJVYQYARFGB-YDHLFZDLSA-N Asn-Phe-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O UYCPJVYQYARFGB-YDHLFZDLSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 102000053602 DNA Human genes 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- POMXSEDNUXYPGK-IHRRRGAJSA-N Leu-Met-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N POMXSEDNUXYPGK-IHRRRGAJSA-N 0.000 description 1
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 description 1
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000006877 Pituitary Hormones Human genes 0.000 description 1
- 108010047386 Pituitary Hormones Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- NIOYDASGXWLHEZ-CIUDSAMLSA-N Ser-Met-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOYDASGXWLHEZ-CIUDSAMLSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA 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
- AIISTODACBDQLW-WDSOQIARSA-N Trp-Leu-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 AIISTODACBDQLW-WDSOQIARSA-N 0.000 description 1
- NJCQVAKYBOCUCS-UHFFFAOYSA-N [C].F Chemical compound [C].F NJCQVAKYBOCUCS-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229940069978 calcium supplement Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000003128 head Anatomy 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
- 230000013632 homeostatic process Effects 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 238000007443 liposuction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000005265 lung cell Anatomy 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
- 239000000463 material Substances 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 125000001360 methionine group Chemical class N[C@@H](CCSC)C(=O)* 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 231100000017 mucous membrane irritation Toxicity 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- IDOWTHOLJBTAFI-UHFFFAOYSA-N phenmedipham Chemical compound COC(=O)NC1=CC=CC(OC(=O)NC=2C=C(C)C=CC=2)=C1 IDOWTHOLJBTAFI-UHFFFAOYSA-N 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
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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
-
- 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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Dispersion Chemistry (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pens And Brushes (AREA)
- Resistance Heating (AREA)
- Mechanical Pencils And Projecting And Retracting Systems Therefor, And Multi-System Writing Instruments (AREA)
- Steroid Compounds (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
112917
Menetelmä paratyroidihormonin biologisesti aktiivisia fragmentteja sisältävän farmaseuttisen koostumuksen valmistamiseksi
Keksinnön tausta 5 1. Keksinnön ala Tämä keksintö koskee menetelmää farmaseuttisen koostumuksen valmistamiseksi, joka sisältää paratyroidihormonin (PTH) biologisesti aktiivista N-terminaalista fragmenttia ja joka on tarkoitettu keuhkoihin annos-10 teltavaksi. Yleisesti tässä kuvataan menetelmiä ja koostumuksia paratyroidihormonin systeemiseen antoon nisäkäsisän-nälle ja erityisemmin aktiivisten paratyroidihormonin fragmenttien antoa keuhkoihin sykkeisten konsentraation profiilien tuottamiseksi seerumiin.
15 Ihmisen paratyroidihormoni (PTH) on 84 aminohapon proteiini, joka on osallisena kalsium- ja fosfori-homeostasiassa sekä luun kasvun ja tiheyden säätelyssä. PTH: n N-terminaalisissa fragmenteissa, erityisesti aminohapoista 1-34 ja 1-38 koostuvissa, on säilyneenä intaktin 20 proteiinin täysi biologinen aktiivisuus. Äskettäin havaittiin, että PTH:n ja PTH-fragmenttien käyttö yhdessä D- • vitamiinin tai ravinnon kalsiumin kanssa oli tehokasta os- : teoporoosin hoidossa, kun niitä annettiin jaksottaisella, edullisesti päivittäisellä, perustalla.
• 25 Tähän saakka PTH:n ja PTH-fragmenttien anto on yleensä toteutettu subkutaanisesti ts. injektiolla. Tarve injisoida PTH:ta (tai mitä tahansa muuta lääkettä) päivittäin ei kuitenkaan ole toivottavaa. Useimmille poti-, , laille on vastenmielistä injisoida lääkkeitä itseensä 30 ja tarve käydä antoa varten klinikalla tai lääkärin vastaanotolla on hankalaa ja rasittavaa. Vaikka muita : * antomuotoja on ehdotettu, kuten esim. vapautusta suun kautta mahaan, transdermaalista vapautusta ja nenänie-* t luabsorptiota, mikään näistä vapautusreiteistä ei ole 35 osoittautunut tehokkaaksi ja kussakin niistä on tiet- tyjä haittoja. Vapautus suun kautta antaa tulokseksi 2 112917 polypeptidilääkkeiden hyvin alhaisen biologisen hyöty-osuuden, tavallisesti alle 1 %, johtuen pilkkoutumisesta mahasuolikanavassa. Lisäksi mahasuolikanavan epiteelipeite on läpäisemätön useimmille polypeptideille. Vapautuksessa 5 nenänieluun ja transdermaalisesti vältetään entsyy-mipilkonnan ongelmat, mutta ne vaativat tavallisesti läpäisyn tehostajia systeemisen absorption aikaansaamiseksi. Tällaisten läpäisyn tehostajien myötäkin on biologinen hyötyosuus tavallisesti hyvin alhainen ja 10 läpäisyn tehostajat voivat usein aiheuttaa ei-toivottavaa ärsytystä. Nenänieluannon tapauksessa läpäisyn tehostajat voivat usein vahingoittaa nenän epiteeliä ja pitkäaikainen käyttö on yhdistetty nenäpeitteen hyperplasiaan.
Polypeptidilääkkeiden vapautusta keuhkoihin tai 15 hengitysteitse on myös ehdotettu. Suhteellisen suuret proteiinit, kuten esim. kasvutekijät ja sytokiinit, jotka ovat tyypillisesti suurempia kuin 150 aminohappoa, absorboidaan usein helposti nisäkäskeuhkon keuhkorakkula-alueen solupeitteen läpi. Edullisesti tällainen absorptio 20 voidaan saada aikaan ilman läpäisyn tehostajien käyttöä.
Pienempien, tavallisesti alle 100 aminohapon pituisten, : ; : proteiinien absorbtio keuhkoissa on paljon vähemmän ; ; ; ennustettavissa. Nisäkäskeuhko ei absorboi monia pienempiä natiiveja polypeptidejä, mutta tiettyjen esimerkki-: 25 tapausten, kuten esim. insuliinin (51 aminohappoa) ja : , kalsitoniinin (32 aminohappoa) , on havaittu keuhkoihin vapautettuna absorboituvan systeemisesti. Vaikka isäntä “ absorboi proteiinilääkkeen systeemisesti keuhkon kautta, lääkkeen farmakologinen kinetiikka ei ole ennustettavissa.
> ' 30 Lääkkeen biologisen hyötyosuuden sekä määrä että ajoitus 1,,’ ovat siten ennustamattomia.
Tällä hetkellä uskotaan, että PTH annetaan poti-. y laalle tehokkaimmin sykkeisellä tavalla. Se tarkoittaa, että PTH-konsentraatioiden seerumissa tulisi nousta 35 nopeasti annon jälkeen ja pudota nopeasti sen jälkeen kun huippukohta on saavutettu, mikä tavallisesti aiheuttaa 3 112917 piikin konsentraatioprofiiliin seerumissa. Mille tahansa PTH-vapautuksen reitille on siten eduksi tuottaa sellainen konsentraatioprofiili seerumiin.
Näistä syistä olisi toivottavaa tuottaa käyttöön 5 potilaille soveltuvia vaihtoehtoisia paratyroidihormonin vapautusmenetelmiä. Sellaisten menetelmien tulisi välttää injektiota ihon alle, rajoittaa ihon ja kehon limakalvojen ärsytystä ja tuottaa edellä puheena ollut toivottava syk-keinen vapautusprofiili. Sellaisten menetelmien tulisi 10 edelleen ylläpitää korkeita PTH:n biologisia hyötyosuuksia, olla mukautuvia potilaan itsensä annettavaksi ja olla taloudellisia .
2. Tausta-alan kuvaus US-patenttijulkaisut numerot 4 833 125 ja 4 698 328 15 kuvaavat paratyroidihormonin aktiivisten fragmenttien annon yhdessä D-vitamiinin tai ravinnon kalsiumtäydennyksen kanssa. Ehdotetut antoreitit pitävät sisällään paren-teraalisen annon injektiolla, nopean infuusion, nenänieluabsorption, dermaalisen absorbtion, tai annon suun 20 kautta. Katso myös Neer ym. (1987) Osteoporosis 53:829 -835. US-patenttijulkaisu numero 5 011 678 kuvaa amfo-: : j fiilisten steroidien käytön läpäisyn tehostajana proteiinien ja polypeptidien vapautuksessa nenään tai
< t I
keuhkoputkiin ja keuhkoihin (bronchopulmonary), listaten , I 25 paratyroidihormonin yhdeksi "todellisesta joukosta" proteiineja, joita voitaisiin vapauttaa tehostajan kanssa. )!.' Paratyroidihormoni (täyspitkä) eritetään luonnollisesti • ’ lisäkilpirauhasesta sarjana piikkejä sykkeisesti, mikä on analogista aivolisäkkeen hormonien kanssa (Harms ym. (1987) 30 Int. Symp. on Osteoporosis, Aalborg, Abstract 232).
- Täyspitkä hormoni pilkotaan verenkierrossa nopeasti useiksi : fragmenteiksi, jotka ovat seerumin vallitsevia muotoja. On ; esitetty hypoteesi, että paratyroidihormonin katkonainen tai sykkeinen eritystäpä on välttämätön sen luuta ’ 35 parantavien ominaisuuksien ylläpitämiseksi (Hesch ym.
d (1988) Calcif. Tissue Int. 42:341 - 344 ja Habener ym.
4 112917 (1971) Proc. Natl. Acad. Sci. USA 68:2986 - 2991). Patton ja Platz (1992) Adv. Drug Deliver. Rev. 8:179 - 196.
kuvaavat menetelmiä proteiinien ja polypeptidien vapauttamiseen höyryhengityksellä syvältä keuhkojen kautta.
5 Yhteenveto keksinnöstä
Keksinnön mukaiselle menetelmälle farmaseuttisen koostumuksen valmistamiseksi, joka sisältää paratyroidi-hormonin (PTH) biologisesti aktiivista N-terminaalista fragmenttia ja joka on tarkoitettu keuhkoihin annos-10 teltavaksi, on tunnusomaista se, mitä patenttivaatimuksessa 1 esitetään.
Tämän keksinnön mukaisesti valmisteut koostumukset paratyroidihormonin (PTH) systeemiseen antoon nisäkäs-isännälle, erityisesti ihmispotilaalle, jolla on vaivana 15 osteoporoosi tai jolla on sen riski, ylläpitävät annon jälkeen edullista PTH:n sykkeistä konsentraatioprofiilia isännän seerumissa. Erityisesti tämän keksinnön mukaisella menetelmällä saadut koostumukset tähtäävät PTH:n biologisesti aktiivisen N-terminaalisen fragmentin vapautukseen keuh-20 koihin tai hengitysteihin, missä fragmentin vapautuminen keuhkojen keuhkorakkula-alueen kautta johtaa nopeaan PTH-i konsentraation huippuun isännän seerumissa, mitä seuraa ; h; konsentraation nopea aleneminen. Intaktin PTH-proteiinin . , vapautus keuhkoihin samoissa olosuhteissa johtaa yllättäen ,g 25 suhteellisen vakioon PTH:n konsentraatioon seerumissa pitkäksi ajanjaksoksi. Taitoa saada aikaan toivottava sykkei-nen konsentraatioprofiili seerumiin PTH-fragmenttien vapautuksessa keuhkoihin, vastakohtana intaktin PTH:n vapautukselle, ei olisi voitu ennustaa minkään asteisella ' 30 varmuudella ennen tässä raportoitua työtä.
: Esimerkkinä olevan toteutusmuodon mukaisesti tämän ; keksinnön mukainen menetelmä käsittää ennalta valitun PTH- . fragmenttimäärän dispergoinnin sellaiseen kaasutilavuuteen, että saadaan tuotettua aerosolimuotoinen bolus. PTH-35 fragmentti koostuu tavallisesti PTH-molekyylin 34:stä tai 38:sta N-terminaalisesta aminohaposta (mutta voi olla minkä 5 112917 tahansa kokoinen N-terminaalinen fragmentti, joka osoittaa toivottua farmakokineettistä profiilia, ollen tavallisesti 50 aminohappoa tai vähemmän), ja dispersio voidaan tuottaa saattamalla fragmenttia kuivana jauheena korkean nopeuden 5 kaasuvirtaan, höyryttämällä fragmentin nestemäinen liuos tai suspensio, tai päästämällä PTH-fragmentin sisältävä ponneaine suuttimen läpi. Potilas höyryhengittää sitten aerosolisoidun boluksen sisään suun kautta ja keuhkojen keuhkorakkula-alueelle. Toistamalla dispergointi- ja 10 höyryhengitysvaiheet riittävän monta kertaa voidaan potilaaseen saattaa toivottu kokonaisannostus PTH-fragmenttia.
Tämän keksinnön mukaisesti saatavat farmaseuttiset koostumukset sisältävät kuivajauheformulaatiot, joissa PTH-fragmentti on läsnä jauheena, jonka keskimääräinen hiukkas-15 koko on alueella 0,5 - 5 pm farmaseuttisesti soveliaassa kuivassa täytejauheessa, jossa PTH:ta on mukana 1 - 10 %. Höyryttämiseen sovelias farmaseuttinen koostumus käsittää PTH:n biologisesti aktiivisen fragmentin vesi-puskurissa pH:ssa 4-6 pitoisuutena, joka on alueella 1-20 mg/ml. 20 Ponneainedispergointiin soveliaat farmaseuttiset koostumukset käsittävät PTH-jauheen, jonka keskimääräinen hiukkasko-ko on alueella 0,5-5 pm, aerosoliponneaineen mukana.
PTH-fragmenttien edullisen sykkeisen farmakoki-, neettisen seerumiprofiilin lisäksi tämän keksinnön mukai- . 25 sella menetelmällä saatavat koostumukset tuottavat korkean tason soveltuvuuden potilaille. PTH:n anto ei vaadi injek- tiota ja potilas voi antaa sitä itselleen päivittäin, ta vallisesti ilman komplikaatioita, kuten sellaisia, jotka ovat yhteydessä transdermaaliseen ja nenänsisäiseen vapau-30 tukseen. Tämän keksinnön mukaisella menetelmällä saatavat koostumukset pitävät myös yllä PTH:n biologisen hyötyosuu-; den korkeaa tasoa ja ne ovat taloudellisia.
Lyhyt kuvaus piirustuksista
Kuvio 1 on käyrä, joka kuvaa ajan funktiona PTH34:n : 35 profiilia seerumissa annettuna suonensisäisesti ja 6 112917 henkitorveen rotille, kuten jäljempänä kokeellisessa osassa on yksityiskohtaisesti kuvattu.
Kuvio 2 on käyrä, joka kuvaa PTH84:n profiilia seerumissa annettuna suoneen ja henkitorveen rotille, kuten 5 jäljempänä kokeellisessa osassa on yksityiskohtaisesti kuvattu .
Erityisten toteutusmuotojen kuvaus
Paratyroidihormoni (PTH) vapautetaan nisäkäs-isäntään höyryhengityksellä isännän keuhkojen keuhko-10 rakkula-alueelle. Syvällä nisäkäskeuhkossa solupeite on äärimmäisen ohut (0,1 pm) ja sen on havaittu olevan luonnostaan läpäisevä sekä täyspitkälle PTH:lie että tietyille PTH:n biologisesti aktiivisille N-terminaalisille fragmenteille, kuten alla on kuvattu. Yllättäen kuitenkin 15 ainoastaan PTH-fragmenttien (eikä täyspitkän PTH:n) tällaisen vapautuksen keuhkoihin tai hengitysteihin on havaittu tuottavan toivotun sykkeisen PTH:n konsentraatioprofiilin seerumiin, minkä uskotaan tehostavan PTH: n biologista aktiivisuutta, erityisesti hoidettaessa 20 osteoporoosia.
Tämän keksinnön mukaisesti saatava koostumus huolehtii siten PTH:n biologisesti aktiivisten N-terminaalisten fragmenttien vapautuksesta keuhkoihin tai hengitysteihin potilaan höyryhengittäessä koostumusta suun 25 kautta, missä tällaiset fragmentit ovat kooltaan pienempiä kuin täysikokoinen luonnollinen ihmisen PTH (ihmisen PTH on * 84 aminohappoa) ja mikä johtaa seerumissa sykkeiseen * konsentraatioprofiiliin, jolle on tunnusmerkillistä nopea nousu huippuun ja tätä seuraava nopea lasku. PTH-fragmentit I 30 ovat edullisesti ihmisen PTH:n fragmentteja (tai rekombinanttitekniikoilla tuotettuja polypeptidejä, joilla . on ihmisen PTH:n sekvenssi), jotka tyypillisesti sisältävät aina 50:een saakka aminohappoja PTH-molekyylin N-päästä, koostuen edullisemmin ihmisen PTH:n aminohapoista 1-34 tai 35 aminohapoista 1-38, kuten jäljempänä taulukossa 1 on esitetty.
7 112917 Käyttökelpoiset PTH:n biologisesti aktiiviset fragmentit sisältävät myös kemiallisesti muunnetut paratyroidihormonin fragmentit, jotka säilyttävät para-tyroidihormoniin liittyvän aktiivisuuden. Välttämätön 5 aktiivisuus on luunmuodostuksen stimulointi. Muunnokset, joita voidaan harkita, pitävät sisällään: (1) PTH-fragmentit, joissa on karboksyylin aminohappopidennyksiä ihmisen PTH-molekyylin paikan 34 toiselle puolelle (mutta tavallisesti ei paikan 50 toiselle 10 puolelle) tai aminoterminaalisia pidennyksiä, tai muita toivottavia ominaisuuksia tuottavia aminohapposub- stituutioita, jotka tuottavat muita toivottuja ominaisuuksia, sellaisia kuten alfa-karboksyylin amidi karboksyylipäässä. Toivottava muunnos tehostaisi aktii-15 visuutta in vivo.
(2) PTH-fragmentit pidennettyinä sisältämään aminohapot 1-38, mikä tehostaisi reseptoriin sitoutumista ja siten aktiivisuutta moolia kohti.
(3) PTH-fragmentit, jotka on kemiallisesti muokattu 20 niin, että se tehostaa absorbtiota keuhkojen keuhkorakkula- alueen kautta.
(4) Fysiologisesti soveliaat PTH-fragmenttien suolat ja esterit.
*
Nisäkkäästä saatavissa oleva PTH-fragmentti on 25 yleensä edullinen verrattuna muun tyyppisiin paraty roidihormonin fragmentteihin, kuten johdannaisiin. Ihmisen : paratyroidihormonin ensimmäisistä 34:stä aminohappo- * tähteestä koostuvan PTH-fragmentin (tästä eteenpäin lyhennettynä "PTH34") käyttö on erityisen edullista : 30 käytettäväksi ihmisillä. Muita edullisia PTH-fragmentteja ; ovat sellaiset, jotka osoittavat joitakin tai kaikkia seuraavista toivottavista ominaisuuksista: lisääntynyt teho välttämättömän aktiivisuuden osalta, annon lisääntynyt helppous, lisääntynyt selektiivisyys mahdollisten sivu-35 vaikutusten vähentämiseksi ja alentunut antigeenisyys ihmisissä haitallisen immuunivasteen välttämiseksi. PTH- 8 112917 fragmenttien molekyylit, joilla on taulukon 1 mukaiset sekvenssit 1-34 tai 1-38, ovat erityisen edullisia: Taulukko 1 1 6 5 Η,Ν-ε·Γ-V«l-ε·ί-Glu-II»-Gin-L»u-Met-Hi»-
10 IB
Aen-Leu-Gly-Ly·-Hi»-Leu-A»n-Ger-Met-Glu- 20 25
Arg-Vei-Glu-Trp —— Leu-Aro-Ly·-Ly·-Leu-Gin — 30 35
1 0 Atp-Vei-Hi»-A«n-Phe-Vei-Ale-Leu-Gly-COOH
Edulliset PTH34- ja PTH38-fragmentit voidaan saada kaupallisesti sellaisilta toimittajilta kuten Peninsula Laboratories, Inc., Belmont, CA; Sigma Chemical Co., St. Louis, MO; Bachem California, Torrance, CA; ja muilta. 15 Vaihtoehtoisesti PTH-fragmentit voidaan tuottaa rekombi- nanttitekniikoilla ekspressoimalla viljellyissä soluissa rekombinantti-DNA-molekyylejä, jotka koodittavat PTH-mo-lekyylin haluttua fragmenttia. Soveliaita rekombinantti-ekspressiosysteemejä ja -menetelmiä on kuvattu hyvin kir-20 jallisuudessa. Katso esim. Manniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York, 1982.
' . DNA-molekyylit, jotka ekspressoidaan, voivat itse olla synteettisiä tai peräisin luonnollisesta lähteestä. Synteettisiä polynukleotideja voidaan syntetisoida hyvin 25 tunnetuilla tekniikoilla, esim. yksijuosteisia DNA-frag- mentteja voidaan valmistaa fosforaminiittimenetelmällä, : jonka ensimmäisenä kuvasivat Beaucage ja Carruthers (1981) * Tett. Lett. 22:1859 - 1862. Kaksijuosteinen fragmentti voidaan sitten saada syntetisoimalla komplementaarinen : 30 juoste ja antamalla juosteiden liittyä yhteen sopivissa olosuhteissa, tai lisäämällä komplementaarinen juoste käyttämällä DNA-polymeraasia yhdessä sopivan aloittajasek-venssin kanssa. Synteettisten DNA-sekvenssien valmistus on toteutettavissa kätevästi käyttämällä automaattista lait-r 35 teistoa, jollainen on saatavissa sellaisilta toimittajilta kuten Applied Biosystems, Inc., Foster City, California.
9 112917 PTH-fragmentit formuloidaan farmaseuttisesti soveliaisiin koostumuksiin, jotka ovat soveliaita vapautettavaksi keuhkoihin tai hengitysteitse nisäkäsisäntään, tavallisesti ihmisisäntään, jolla on osteoporoosin riski tai 5 joka potee sitä. Erityisiin formulaatioihin kuuluvat kuivat jauheet, sumutukseen sopivat nestemäiset liuokset tai suspensiot, sekä ponneaineformulaatiot, jotka ovat soveliaita käytettäväksi mitatun annoksen höyryhengityslait-teissa (MDI:t) (metered dose inhalers). Tällaisten formu-10 laatioiden valmistus on kuvattu hyvin patenttikirjallisuu-dessa, tieteellisessä ja lääketieteellisessä kirjallisuudessa, ja seuraavat kuvaukset on tarkoitettu ainoastaan esimerkeiksi.
Kuivajauheformulaatiot käsittävät tavallisesti PTH-15 fragmentin kuivassa, tavallisesti lyofilisoidussa muodossa hiukkaskoon ollessa edullisella alueella keuhkojen keuhkorakkula-alueelle saattamiseksi, tyypillisesti 0,5 - 5 pm.
PTH-fragmenttien hengitettäviä jauheita edullisen koko-jakauman puitteissa voidaan tuottaa useilla erilaisilla ta-20 vanomaisilla tekniikoilla, sellaisilla kuten suihku-jauhatus (jet-milling), sumutuskuivauksella (spray-drying), liuotinsaostuksella ja muilla samankaltaisilla. Kuivat jauheet voidaan sitten antaa potilaalle tavanomaisilla kuivan jauheen höyryhengityslaitteilla (DPI:t), joissa käytetään 25 potilaan sisäänhengitystä laitteen kautta jauheen disper-gointiin, tai ilma-avusteisilla laitteilla, joissa käyte-; tään ulkoista voiman lähdettä jauheen dispergoimiseksi ae- • rosolipilveen. Erityisen käyttökelpoinen kuivan jauheen dispergoija on kuvattu samaan aikaan vireillä olevassa pa-: 30 tenttihakemuksessa sarjanumeroltaan 07/910 048, joka on : siirretty tämän keksinnön siirron saajalle.
Kuivajauhelaitteet vaativat tavallisesti jauhe-massan, joka on välillä noin 1 - 10 mg yhden aerosolisoidun annoksen ("henkonen" ["puff"]) tuottamiseksi. Koska tar-35 vittava PTH-fragmentin annos on tavallisesti paljon pienempi kuin tämä määrä, kuten jäljempänä tarkastellaan, 10 112917 PTH-jauhe yhdistetään tavallisesti farmaseuttisesti soveliaan kuivan täytejauheen kanssa, PTH:ta ollessa mukana tavallisesti noin 1 - 10 painoprosenttia. Edullisiin kuiviin täytejauheisiin kuuluvat sakkaroosi, laktoosi, 5 trehaloosi, ihmisen seerumin albumiini (HSA) ja glysiini. Muihin soveliaisiin kuiviin täytejauheisiin kuuluvat sellobioosi, dekstraanit, maltotrioosi, pektiini, natrium-sitraatti, natriumaskorbaatti, mannitoli ja muut näiden kaltaiset. Sopivia puskureita ja suoloja voidaan tyy-10 pillisesti käyttää stabiloimaan PTH-fragmentit liuoksessa ennen hiukkasten muodostusta. Sopiviin puskureihin kuuluvat fosfaatti, sitraatti, asetaatti ja tris-HCl, tyypillisesti konsentraatioissa noin 5 - 50 mM. Sopiviin suoloihin kuuluvat natriumkloridi, natriumkarbonaatti, kalsiumkloridi 15 ja muut näiden kaltaiset. Muut lisäaineet, kuten esim. kelatoivat aineet, peptidaasi-inhibiittorit ja näiden kaltaiset, jotka edistäisivät PTH-fragmentin biologista aktiivisuutta kun se kerran on liuennut keuhkoissa, olisivat soveliaita. Esimerkiksi etyleenidiamiinitet-20 raetikkahappo (ETDA) voisi olla hyödyllinen divalenttien kationeiden kelaattorina, jotka kationit ovat peptidaasien kofaktoreita.
[ Sumutussysteemeissä käytettävissä PTH-fragmenttien nesteformulaatioissa voidaan käyttää lievästi happamia 25 puskureita (pH 4-6) PTH-konsentraatioiden ollessa noin 1 -20 mg/ml. Sopiviin puskureihin kuuluvat asetaatti, , askorbaatti ja sitraatti konsentraatioissa 5-50 mM. Nämä ' puskurit voivat toimia antioksidantteina, tai muita fysiologisesti soveliaita antioksidantteja voidaan lisätä : 30 suojaamaan PTH-fragmentissa olevia vapaita metioniineja hapettumiselta. Muita komponentteja voidaan lisätä tehostamaan tai ylläpitämään kemiallista stabiilisuutta, mukaan lukien kelatoivia aineita, proteaasi-inhi-biittoreita, isotonisia muuntajia, inerttejä kaasuja ja 35 muita näiden kaltaisia. Edullinen sumutintyyppi tällaisten nestemäisten formulaatioiden vapauttamiseen on kuvattu 11 112917 samaan aikaan vireillä olevassa patenttihakemuksessa sarjanumeroltaan 07/910 048.
MDI:issa käytettäväksi tämän keksinnön mukaiset PTH-fragmentit liuotetaan tai suspensoidaan sopivaan aero-5 soliponneaineeseen, kuten esim. klooritluorihiileen (CFC) tai vetytluorihiileen (HFC). Sopiviin CFC:ihin kuuluvat trikloorimonofluorimetaani (ponneaine 11), diklooritet-rafluorimetaani (ponneaine 114) ja diklooridifluorimetaani (ponneaine 12). Sopiviin HFCiihin kuuluvat tetrafluo-10 rietaani (HFC-134a) ja heptafluoripropaani (HFC-227).
Aerosoliponneaineisiin inkorporointia varten tässä kuvatut PTH-fragmentit prosessoidaan edullisesti hengitettäviksi hiukkasiksi kuten kuivajauheformulaatioille on kuvattu. Partikkelit suspensoidaan sitten ponneaineeseen, 15 tyypillisesti niiden ollessa päällystettyjä pinta- aktiivisella aineella niiden dispergoitumisen tehostamiseksi. Sopiviin pinta-aktiivisiin aineisiin kuuluvat öljyhappo, sorbitaanitrioleaatti sekä useat eri pitkäketjuiset diglyseridit ja fosfolipidit.
20 Sellaiset aerosoliponneaineformulaatiot voivat edelleen sisältää alemman alkoholin, sellaisen kuin etanoli : ; (aina 30:een painoprosenttiin asti) ja muita lisäaineita : kemiallisen stabiilisuuden ja fysiologisen soveltuvuuden * ylläpitämiseksi tai tehostamiseksi.
• 25 Tässä kuvattujen PTH-fragmenttien anto keuhkoihin tai hengitysteitse on hyödyksi osteoporoosin hoidossa, jossa PTH-fragmentti annetaan yhdessä D-vitamiinin, kalsi-tosiinin ja/tai ravinnon kalsiumtäydennysten kanssa. Sellaiset hoitomenetelmät on kuvattu hyvin US-patent-30 tijulkaisuissa nrot 4 698 328 ja 4 833 125.
PTH-fragmentin koko aerosoliannos osteoporoosin hoidossa on tyypillisesti alueella noin 100 - 2 000 pg päivässä, ollen tavallisesti alueella noin 250 - 1 000 pg päivässä. Sellaiset annokset johtavat systeemisen saata-35 vuuden kokonaismäärään (ts. vereen vapautettuun määrään), joka on alueella noin 50 - 500 pg päivässä, tavallisesti 12 112917 100 - 250 pg päivässä. Täsmälliset annokset vaihtelevat tietenkin riippuen käytetyn nimenomaisen PTH-fragmentin tai analogin aktiivisuudesta ja muista tunnetuista farma-kokineettisistä tekijöistä. Tavallisesti PTH-fragmentin 5 kokonaisannos vapautetaan useina erillisinä aerosoli- soituina annoksina, joita tyypillisesti on ainakin kaksi ja usein kolmesta kymmeneen, joissa kukin aerosolisoitu bolus sisältää 50 - 500 pg PTH-fragmenttia.
On havaittu, että PTH-fragmenttien vapautus 10 keuhkoihin tämän keksinnön mukaisesti saatavana koostumuksena tuottaa toivottavan sykkeisen kon-sentraatioprofiilin seerumiin. Sykkeinen seerumin PTH-fragmentin konsentraatio-profiili saavuttaa tyypillisesti huippunsa 30 minuutin kuluessa annosta, konsentraatioiden 15 seerumissa laskiessa nopeasti, tyypillisesti alle 50 %:iin maksimista 30 minuutin sisällä huipusta ja alle 25 %:iin 60 minuutin sisällä huipusta.
Kuivajauheformulaation tapauksessa lisätään riittävä määrä kuivaa täytejauhetta niin, että edellä 20 mainitulla alueella oleva PTH-fragmentin kokonaisannos saavutetaan yhdellä tai useammalla potilaan höyry-; hengittämällä boluksella. Tyypillisesti PTH-fragmenttia on : läsnä noin 1 - 25 painoprosenttia jauheesta aerosoli- soitujen bolusten sisältäessä 1 - 10 mg jauhetta.
; 25 Sumuttimissa käytettäväksi soveliaissa nestemäisissä , formulaatioissa on tyypillisesti PTH-fragmentin konsent- raatio alueella noin 1-20 mg/ml, boluksen vapauttamiseen tarvittavan höyrystetyn nesteen kokonaismäärän ollessa alueella noin 0,1 - 1 ml. Aerosoliponneaineformulaatiot 30 annetaan MDI:llä PTH-fragmenttia ollessa noin 0,5 - 5 mg aerosoliannosta kohti. MDI-laitteiden tehottomuuden vuoksi vain pieni osa, tyypillisesti alueella 5 - 20 %, lääkkeestä saavuttaa keuhkot. Riittävä määrä PTH-fragmenttia voidaan siten vapauttaa sisään kahdesta viiteen 35 aerosolisoidusta boluksesta, joissa kussakin boluksessa on noin 1 mg PTH-fragmenttia.
13 112917
Seuraavat esimerkit esitetään havainnollistamisen vuoksi, ei rajoitukseksi.
Kokeellinen osa
Materiaalit ja menetelmät 5 Rekombinanttituote ihmisen paratyroidihormoni (PTH84) saatiin Peninsula Laboratories, Inc:sta, Belmont, California (erä nro 800929). Ihmisen paratyroidihormonin rekombinanttifragmentti (aminohapot 1-34) (PTH34) saa tiin Sigma Chemical Co:sta, St. Louis, Missouri (erä nro 10 098F48052).
Rotat (noin 300 - 320 g) saatiin Simonsone Labsis-ta, Gilroy, CA.
PTH84 ja PTH34 annettiin rotille suonensisäisesti (IV) tai henkitorveen (IT) suspensoituna 100 yl;aan 20 mM 15 sitraattipuskuria, pH 5. Annokset olivat 5 yg PTH84:n IV-annossa, 100 yg PTH84:n IT-annossa, 25 yg PTH34:n IV-annossa ja 100 yg PTH34:n IT-annossa. IT-anto toteutettiin tekemällä yhden tuuman aukaisu kaulan keskialueelle ja paljastamalla henkitorvi. Polypeptidisuspensiot injisoitiin 20 henkitorveen käyttämällä tuberkuliiniruiskua 30 gaugen neulalla noin yhden minuutin kuluessa. Rotan pää pidettiin • pystyasennossa henkitorvensisäisen injektion ajan ja yhden ; lisäminuutin ajan sen jälkeen.
Rotan seerumista määritettiin PTH34 jaksottaisin : 25 väliajoin PTH34-annon jälkeen käyttäen Nichols Instrument INS PTH -määrityskittiä, joka mittaa PTH34:n ilman mitään ristireaktiota PTH28-54:n, PTH44-68:n ja PTH53-84:n kanssa. Näytteitä laimennettiin kuten välttämätöntä mitattavien konsentraatioiden saamiseksi.
30 Rotan seerumista määritettiin PTH84 Nichols
Instrument Alegro -määrityskitillä ihmisen PTH:ta varten, joka mittaa PTH84:n ilman mitään ristireaktiivisuutta PTH34:n, PTH39-68:n, PTH44-68:n, PTH53-84:n ja PTH39-84:n kanssa. Näytteitä laimennettiin kuten välttämätöntä 35 mitattavien konsentraatioiden saamiseksi.
14 112917
Tulokset PTH34:n ja PTH84:n seerumiprofiilit rotilla IV- ja IT-antojen jälkeen on esitetty vastaavasti kuvioissa 1 ja 2. PTH34:n absoluuttinen biologinen hyötyosuus, joka 5 ilmaisee vereen kulkeutuneen hormonin prosenttiosuuden annetusta kokonaismäärästä, oli noin 40 %. PTH34:n absorptioprofiili osoitti huippua 15 minuutin kohdalla, aktiivisuuden aletessa nopeasti sen jälkeen. Tämä on samankaltainen subkutaanisen injektion jälkeen nähdyn 10 profiilin kanssa. Vastakohtana tälle, PTH84 osoitti samanlaisena henkitorven sisäisenä annoksena hyvin erilaista absorptioprofiilia. Huipun sijasta ilmeni seerumitasoissa tasanne, joka ei alentunut merkittävästi kokeen 90 minuutin aikana. PTH84:n biologinen hyötyosuus 90 15 minuutin kohdalla oli noin 23 % (mitattuna katkaistusta alueesta käyrän alapuolelta aina 90 minuuttiin saakka), mutta hidas pitkittynyt vapautuksen absorptioprofiili viittaa siihen, että seerumitasot olisivat säilyneet pidempiä aikoja.
20 Vaikka edellä oleva keksintö on kuvattu yksityis kohtaisesti selvyyden ja ymmärtämisen vuoksi, on ilmeistä, : että tiettyjä muunnoksia voidaan toteuttaa liitteenä : olevien patenttivaatimusten suoja-alan puitteissa.
15 112917
SEQUENCE LISTING
(1) GENERAL INFORMATION: (i) APPLICANT: Patton, John S.
5 (ii) TITLE OF INVENTION: Pulmonary Delivery of Active Fragments of Parathyroid Hormone (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS: 10 (A) ADDRESSEE: Townsend and Townsend Khourie and Crew (B) STREET: One Market Plaza, Steuart Tower, Suite 2000 (C) CITY: San Francisco (D) STATE: California
(E) COUNTRY: USA
(F) ZIP: 94105 (V) COMPUTER READABLE FORM: ib (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentin Release /1.0, Version /1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: US 07/953,397 20 (B) FILING DATE: 29-SEP-1992 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Heslin, James M.
(B) REGISTRATION NUMBER: 29,541 (C) REFERENCE/DOCKET NUMBER: 15225-3 25 (IX) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 415-326-2400 (B) TELEFAX: 415-326-2422 16 112917 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: 5 (A) LENGTH: 38 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 10 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:
Ser Val Ser Glu lie Gin Leu Met His Asn Leu Gly Lys His Leu Asn 15 10 15 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gin Asp Val ΠΐΞ 20 25 30
Asn Phe Val Ala Leu Gly 20 35
Claims (6)
112917
1. Menetelmä farmaseuttisen koostumuksen valmistamiseksi, joka sisältää paratyroidihormonin (PTH) biolo-5 gisesti aktiivista N-terminaalista fragmenttia ja joka on tarkoitettu keuhkoihin annosteltavaksi, tunnettu siitä, että i) hankitaan mainittu PTH:n biologisesti aktiivinen N-terminaalinen fragmentti ja joko 10 ii(a) varmistetaan, että mainittu PTH:n biologi sesti aktiivinen N-terminaalinen fragmentti on kuivan jauheen muodossa, jonka keskimääräinen hiukkaskoko on alueella 0,5-5 pm, jotta se voidaan annostella keuhkojen keuhkorakkuloiden alueelle, ja joko 15 ii(al) yhdistetään mainittu fragmentti far maseuttisesti soveliaan kuivan täytejauheen kanssa, jolloin PTH:n pitoisuus on 1 - 25 paino-%, tai ii(a2) liuotetaan tai suspensoidaan saatu kui-vajauhe sopivaan aerosoliponneaineeseen tai vaihtoehtoi-20 sesti ii (b) liuotetaan tai suspensoidaan mainittu frag-j mentti vesipitoiseen puskuriin pH:ssa 4-6 loppu- : pitoisuuteen 1-20 mg/ml.
2. Patenttivaatimuksen 1 mukainen menetelmä, : 25 tunnettu siitä, että täytejauhe on valittu ryh mästä, jonka muodostavat sakkaroosi, laktoosi, trehaloosi, HAS, glysiini, sellobioosi, dekstraani, maltotrioosi, pektiini, natriumsitraatti, natriumaskorbaatti ja mannitoli. '30 3. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että kuivajauhe on aerosolina : kaasussa.
4. Patenttivaatimuksen 3 mukainen menetelmä, tunnettu siitä, että aerosolin tilavuus on 35 10 - 750 ml. 112917
5. Minkä tahansa patenttivaatimuksen 1-4 mukainen menetelmä, tunnettu siitä, että aerosoli-ponneaine on kloorifluorihiili tai vetytluorihiili.
6. Patenttivaatimuksen 1 mukainen menetelmä, 5 tunnettu siitä, että puskuri on valittu ryhmästä, jonka muodostavat asetaatti, askorbaatti ja sitraat-ti, jolloin kunkin pitoisuus on 5 - 50 mM. 112917
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95339792A | 1992-09-29 | 1992-09-29 | |
| US95339792 | 1992-09-29 | ||
| US9309270 | 1993-09-29 | ||
| PCT/US1993/009270 WO1994007514A1 (en) | 1992-09-29 | 1993-09-29 | Pulmonary delivery of active fragments of parathyroid hormone |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI951465A0 FI951465A0 (fi) | 1995-03-28 |
| FI951465L FI951465L (fi) | 1995-05-10 |
| FI112917B true FI112917B (fi) | 2004-02-13 |
Family
ID=25493936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI951465A FI112917B (fi) | 1992-09-29 | 1995-03-28 | Menetelmä paratyroidihormonin biologisesti aktiivisia fragmentteja sisältävän farmaseuttisen koostumuksen valmistamiseksi |
Country Status (18)
| Country | Link |
|---|---|
| US (6) | US5607915A (fi) |
| EP (1) | EP0679088B1 (fi) |
| JP (1) | JP3717925B2 (fi) |
| KR (1) | KR100291620B1 (fi) |
| AT (1) | ATE220327T1 (fi) |
| AU (1) | AU688283B2 (fi) |
| BR (1) | BR9307141A (fi) |
| CA (1) | CA2145418A1 (fi) |
| CZ (1) | CZ286632B6 (fi) |
| DE (1) | DE69332105T2 (fi) |
| DK (1) | DK0679088T3 (fi) |
| ES (1) | ES2179831T3 (fi) |
| FI (1) | FI112917B (fi) |
| NO (1) | NO322244B1 (fi) |
| NZ (1) | NZ257212A (fi) |
| PT (1) | PT679088E (fi) |
| RU (1) | RU2142815C1 (fi) |
| WO (1) | WO1994007514A1 (fi) |
Families Citing this family (224)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5814603A (en) * | 1992-06-12 | 1998-09-29 | Affymax Technologies N.V. | Compounds with PTH activity |
| US6231851B1 (en) * | 1994-05-18 | 2001-05-15 | Inhale Therapeutic Systems | Methods and compositions for the dry powder formulation of interferons |
| US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
| WO1994007514A1 (en) | 1992-09-29 | 1994-04-14 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
| US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
| US5506203C1 (en) * | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| US20010003739A1 (en) * | 1993-06-24 | 2001-06-14 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| IS1796B (is) * | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
| US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US20030113273A1 (en) * | 1996-06-17 | 2003-06-19 | Patton John S. | Methods and compositions for pulmonary delivery of insulin |
| US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
| CZ295827B6 (cs) | 1994-03-07 | 2005-11-16 | Nektar Therapeutics | Způsob aerosolizace dávky inzulinu, inzulinový přípravek a jeho použití |
| US5955425A (en) * | 1996-08-02 | 1999-09-21 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
| US6110892A (en) | 1994-06-20 | 2000-08-29 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
| US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
| US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
| US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
| EE9700138A (et) | 1994-12-22 | 1997-12-15 | Astra Aktiebolag | Aerosoolravimvormid |
| CA2206657C (en) * | 1994-12-22 | 2009-05-19 | Astra Aktiebolag | Therapeutic preparation for inhalation containing parathyroid hormone, pth |
| SE9404468D0 (sv) * | 1994-12-22 | 1994-12-22 | Astra Ab | Powder formulations |
| US5513630A (en) * | 1995-03-08 | 1996-05-07 | Century; Theodore J. | Powder dispenser |
| US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
| US6652837B1 (en) | 1996-05-24 | 2003-11-25 | Massachusetts Institute Of Technology | Preparation of novel particles for inhalation |
| US20020052310A1 (en) | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
| US5874064A (en) * | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
| USRE37053E1 (en) | 1996-05-24 | 2001-02-13 | Massachusetts Institute Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
| US5855913A (en) * | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
| US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
| US6458574B1 (en) | 1996-09-12 | 2002-10-01 | Transkaryotic Therapies, Inc. | Treatment of a α-galactosidase a deficiency |
| US6083725A (en) * | 1996-09-13 | 2000-07-04 | Transkaryotic Therapies, Inc. | Tranfected human cells expressing human α-galactosidase A protein |
| US5976574A (en) * | 1996-12-31 | 1999-11-02 | Inhale Therapeutic Systems | Processes for spray drying hydrophobic drugs in organic solvent suspensions |
| US20030203036A1 (en) * | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
| US6517860B1 (en) * | 1996-12-31 | 2003-02-11 | Quadrant Holdings Cambridge, Ltd. | Methods and compositions for improved bioavailability of bioactive agents for mucosal delivery |
| US6126919A (en) * | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
| EP0986395A4 (en) * | 1997-05-14 | 2004-12-01 | Aventis Pharm Prod Inc | PEPTIDE ANALOGS OF THE PARATHYROID HORMONE |
| ATE364374T1 (de) * | 1997-08-11 | 2007-07-15 | Pfizer Prod Inc | Feste pharmazeutische dispersionen mit erhöhter bioverfügbarkeit |
| US7052678B2 (en) | 1997-09-15 | 2006-05-30 | Massachusetts Institute Of Technology | Particles for inhalation having sustained release properties |
| US20060165606A1 (en) * | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| US6433040B1 (en) * | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
| US6946117B1 (en) | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
| US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| EP2042161A1 (en) * | 1997-10-01 | 2009-04-01 | Novadel Pharma Inc. | Propellant-free spray composition comprising anti-emetic agent |
| US20050287075A1 (en) * | 1997-10-01 | 2005-12-29 | Dugger Harry A Iii | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
| US20030095926A1 (en) * | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the gastrointestinal tract or urinary tract |
| US20050163719A1 (en) * | 1997-10-01 | 2005-07-28 | Dugger Harry A.Iii | Buccal, polar and non-polar spray containing diazepam |
| US20040141923A1 (en) * | 1997-10-01 | 2004-07-22 | Dugger Harry A. | Buccal, polar and non-polar spray containing alprazolam |
| US20030077229A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs |
| US20050281752A1 (en) * | 1997-10-01 | 2005-12-22 | Dugger Harry A Iii | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
| US20030077228A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating endocrine disorders |
| US7632517B2 (en) * | 1997-10-01 | 2009-12-15 | Novadel Pharma Inc. | Buccal, polar and non-polar spray containing zolpidem |
| US20030082107A1 (en) * | 1997-10-01 | 2003-05-01 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating an infectious disease or cancer |
| US20030190286A1 (en) * | 1997-10-01 | 2003-10-09 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating allergies or asthma |
| US20030095925A1 (en) * | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating metabolic disorders |
| US20040136915A1 (en) * | 1997-10-01 | 2004-07-15 | Dugger Harry A. | Buccal, polar and non-polar spray containing atropine |
| US20030077227A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system |
| US20030185761A1 (en) * | 1997-10-01 | 2003-10-02 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
| US20040136913A1 (en) * | 1997-10-01 | 2004-07-15 | Dugger Harry A. | Buccal, polar and non-polar spray containing sumatriptan |
| US20050180923A1 (en) * | 1997-10-01 | 2005-08-18 | Dugger Harry A.Iii | Buccal, polar and non-polar spray containing testosterone |
| US20090162300A1 (en) * | 1997-10-01 | 2009-06-25 | Dugger Iii Harry A | Buccal, polar and non-polar spray containing alprazolam |
| US20050002867A1 (en) * | 1997-10-01 | 2005-01-06 | Novadel Pharma Inc. | Buccal, polar and non-polar sprays containing propofol |
| US20030095927A1 (en) * | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating muscular and skeletal disorders |
| US20040136914A1 (en) * | 1997-10-01 | 2004-07-15 | Dugger Harry A. | Buccal, polar and non-polar spray containing ondansetron |
| MY120063A (en) | 1997-12-09 | 2005-08-30 | Lilly Co Eli | Stabilized teriparatide solutions |
| US6770623B1 (en) * | 1997-12-09 | 2004-08-03 | Eli Lilly And Company | Stabilized teriparatide solutions |
| EP0922467A3 (en) * | 1997-12-12 | 2000-05-24 | Takeda Chemical Industries, Ltd. | Iontophoretic drug delivery |
| SE9801495D0 (sv) * | 1998-04-28 | 1998-04-28 | Astra Ab | Protein formulationa |
| IL139307A0 (en) | 1998-05-19 | 2001-11-25 | Res Dev Foundation | Triterpene compositions and methods for use thereof |
| US6593133B1 (en) | 1998-07-06 | 2003-07-15 | Nsgene A/S | Neurotrophic factors |
| US6956021B1 (en) * | 1998-08-25 | 2005-10-18 | Advanced Inhalation Research, Inc. | Stable spray-dried protein formulations |
| EP1666054A1 (en) | 1998-08-28 | 2006-06-07 | Eli Lilly & Company | Method for administering insulinotropic peptides |
| US6234167B1 (en) * | 1998-10-14 | 2001-05-22 | Chrysalis Technologies, Incorporated | Aerosol generator and methods of making and using an aerosol generator |
| US20020006901A1 (en) * | 1999-02-05 | 2002-01-17 | Aldo T. Iacono | Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease |
| US20080108086A1 (en) * | 1999-06-02 | 2008-05-08 | Cantor Thomas L | Parathyroid hormone antagonists and uses thereof |
| WO2004028444A2 (en) * | 1999-06-02 | 2004-04-08 | Scantibodies Laboratory, Inc. | Parathyroid hormone antagonists and uses thereof |
| US6586008B1 (en) * | 1999-08-25 | 2003-07-01 | Advanced Inhalation Research, Inc. | Use of simple amino acids to form porous particles during spray drying |
| US7252840B1 (en) | 1999-08-25 | 2007-08-07 | Advanced Inhalation Research, Inc. | Use of simple amino acids to form porous particles |
| US6749835B1 (en) | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
| WO2001013891A2 (en) * | 1999-08-25 | 2001-03-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
| US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
| US20010036481A1 (en) * | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
| US6596261B1 (en) * | 2000-01-25 | 2003-07-22 | Aeropharm Technology Incorporated | Method of administering a medicinal aerosol formulation |
| JP4711520B2 (ja) * | 2000-03-21 | 2011-06-29 | 日本ケミカルリサーチ株式会社 | 生理活性ペプチド含有粉末 |
| MY136453A (en) * | 2000-04-27 | 2008-10-31 | Philip Morris Usa Inc | "improved method and apparatus for generating an aerosol" |
| US6883516B2 (en) | 2000-04-27 | 2005-04-26 | Chrysalis Technologies Incorporated | Method for generating an aerosol with a predetermined and/or substantially monodispersed particle size distribution |
| BR0110499A (pt) | 2000-05-02 | 2003-04-01 | Hoffmann La Roche | Retinóides gama seletivos |
| US8404217B2 (en) * | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
| US7871598B1 (en) * | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| TWI290473B (en) | 2000-05-10 | 2007-12-01 | Alliance Pharma | Phospholipid-based powders for drug delivery |
| NZ522839A (en) * | 2000-06-27 | 2004-11-26 | Genelabs Tech Inc | Novel compounds possessing antibacterial, antifungal or antitumor activity |
| US7575761B2 (en) * | 2000-06-30 | 2009-08-18 | Novartis Pharma Ag | Spray drying process control of drying kinetics |
| AU2001280934A1 (en) * | 2000-07-28 | 2002-02-13 | Alliance Pharmaceutical Corp. | Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds |
| US6573092B1 (en) * | 2000-10-10 | 2003-06-03 | Genvec, Inc. | Method of preparing a eukaryotic viral vector |
| DE60138641D1 (de) | 2000-10-27 | 2009-06-18 | Baxter Healthcare Sa | Herstellung von mikrokügelchen |
| US20060148732A1 (en) * | 2000-11-17 | 2006-07-06 | Gutterman Jordan U | Inhibition of NF-kappaB by triterpene compositions |
| US6799572B2 (en) * | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
| US6701921B2 (en) | 2000-12-22 | 2004-03-09 | Chrysalis Technologies Incorporated | Aerosol generator having heater in multilayered composite and method of use thereof |
| US7077130B2 (en) | 2000-12-22 | 2006-07-18 | Chrysalis Technologies Incorporated | Disposable inhaler system |
| US6501052B2 (en) | 2000-12-22 | 2002-12-31 | Chrysalis Technologies Incorporated | Aerosol generator having multiple heating zones and methods of use thereof |
| US6681998B2 (en) | 2000-12-22 | 2004-01-27 | Chrysalis Technologies Incorporated | Aerosol generator having inductive heater and method of use thereof |
| US6491233B2 (en) | 2000-12-22 | 2002-12-10 | Chrysalis Technologies Incorporated | Vapor driven aerosol generator and method of use thereof |
| WO2002062755A2 (en) * | 2000-12-27 | 2002-08-15 | Genelabs Technologies, Inc. | Polyamide analogs as dna minor groove binders |
| US20020141946A1 (en) * | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
| CA2433335C (en) * | 2000-12-29 | 2010-04-20 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
| US7442370B2 (en) | 2001-02-01 | 2008-10-28 | Biogen Idec Ma Inc. | Polymer conjugates of mutated neublastin |
| US7276580B2 (en) | 2001-03-12 | 2007-10-02 | Biogen Idec Ma Inc. | Neurotrophic factors |
| GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
| DK1418890T3 (da) * | 2001-08-16 | 2008-08-11 | Baxter Int | Drivmiddel-baserede mikropartikelformuleringer |
| EP1944016A1 (en) | 2001-08-16 | 2008-07-16 | Baxter International Inc. | Propellant-based microparticle formulatons |
| PT1420827E (pt) | 2001-08-17 | 2009-12-15 | Novartis Ag | 5-cnac como agente de administração oral de fragmentos da hormona paratiróide |
| US6568390B2 (en) | 2001-09-21 | 2003-05-27 | Chrysalis Technologies Incorporated | Dual capillary fluid vaporizing device |
| US6640050B2 (en) | 2001-09-21 | 2003-10-28 | Chrysalis Technologies Incorporated | Fluid vaporizing device having controlled temperature profile heater/capillary tube |
| AU2002352836B2 (en) | 2001-11-20 | 2005-09-29 | Alkermes, Inc. | Improved particulate compositions for pulmonary delivery |
| WO2003043603A1 (en) * | 2001-11-20 | 2003-05-30 | Advanced Inhalation Research, Inc. | Particulate compositions for improving solubility of poorly soluble agents |
| US6804458B2 (en) * | 2001-12-06 | 2004-10-12 | Chrysalis Technologies Incorporated | Aerosol generator having heater arranged to vaporize fluid in fluid passage between bonded layers of laminate |
| US6681769B2 (en) | 2001-12-06 | 2004-01-27 | Crysalis Technologies Incorporated | Aerosol generator having a multiple path heater arrangement and method of use thereof |
| ES2364636T3 (es) * | 2001-12-19 | 2011-09-08 | Novartis Ag | Administración pulmonar de aminoglucósidos. |
| US6701922B2 (en) | 2001-12-20 | 2004-03-09 | Chrysalis Technologies Incorporated | Mouthpiece entrainment airflow control for aerosol generators |
| WO2003057212A1 (en) * | 2001-12-26 | 2003-07-17 | Genelabs Technologies, Inc. | Polyamide derivatives possessing antibacterial, antifungal or antitumor activity |
| US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
| US20040071686A1 (en) * | 2002-04-25 | 2004-04-15 | Treco Douglas A. | Treatment of alpha-galactosidase A deficiency |
| US9339459B2 (en) | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
| AR040661A1 (es) * | 2002-07-26 | 2005-04-13 | Theravance Inc | Diclorhidrato cristalino de n-{2-[-((r)-2-hidroxi-2-feniletilamino)fenil]etil}-(r)-2hidroxi-2-(3-formamido-4-hidroxifenil)etilamina, agonista del receptor adrenergico beta 2 |
| CN1694689A (zh) * | 2002-09-30 | 2005-11-09 | 阿库斯菲尔公司 | 供吸入的缓释多孔微粒 |
| JP4571776B2 (ja) * | 2002-11-05 | 2010-10-27 | Ｊｘ日鉱日石エネルギー株式会社 | 潤滑油組成物 |
| EP1575562B1 (en) * | 2002-11-26 | 2016-10-05 | Seacoast Neurosciene, Inc. | Buoyant polymer particles delivering therapeutic agents |
| ES2545619T3 (es) | 2003-01-31 | 2015-09-14 | The Mount Sinai School Of Medicine Of New York University | Terapia de combinación para tratar trastornos de deficiencia de proteínas |
| NZ574121A (en) | 2003-04-18 | 2011-06-30 | Biogen Idec Inc | Polyethylene glycol-conjugated gylcosylated neublastin and uses thereof for treatment of pain |
| US7367334B2 (en) | 2003-08-27 | 2008-05-06 | Philip Morris Usa Inc. | Fluid vaporizing device having controlled temperature profile heater/capillary tube |
| WO2005032523A1 (en) * | 2003-09-30 | 2005-04-14 | Acusphere, Inc. | Injectable, oral, or topical sustained release pharmaceutical formulations |
| EP1718277A1 (en) * | 2004-02-10 | 2006-11-08 | Advanced Inhalation Research, Inc. | Particles for inhalation rapid release properties |
| ES2326670T3 (es) | 2004-03-30 | 2009-10-16 | Nsgene A/S | Uso terapeutico del factor de crecimiento nsg33. |
| US20060039985A1 (en) * | 2004-04-27 | 2006-02-23 | Bennett David B | Methotrexate compositions |
| US20070213272A1 (en) * | 2004-07-14 | 2007-09-13 | Katsuhiko Sato | Transmucosal Administration Agent Containing Pth |
| KR101309770B1 (ko) | 2004-07-19 | 2013-09-30 | 바이오콘 리미티드 | 인슐린―올리고머 접합체，제형 및 이들의 용도 |
| US20090136552A1 (en) * | 2004-07-30 | 2009-05-28 | Mette Gronborg | Growth factors nsg28, nsg30, and nsg32 |
| WO2006023782A2 (en) | 2004-08-19 | 2006-03-02 | Biogen Ideca Ma Inc. | Refolding transforming growth factor beta family proteins |
| EP2335713A3 (en) * | 2004-08-19 | 2011-11-02 | Biogen Idec MA Inc. | Neublastin variants |
| US8268791B2 (en) * | 2004-08-25 | 2012-09-18 | Aegis Therapeutics, Llc. | Alkylglycoside compositions for drug administration |
| US20060046962A1 (en) | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
| US9114069B2 (en) * | 2004-08-25 | 2015-08-25 | Aegis Therapeutics, Llc | Antibacterial compositions for drug administration |
| US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
| US20060046969A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Antibacterial compositions for drug administration |
| US20140162965A1 (en) | 2004-08-25 | 2014-06-12 | Aegis Therapeutics, Inc. | Compositions for oral drug administration |
| US8642564B2 (en) * | 2004-08-25 | 2014-02-04 | Aegis Therapeutics, Llc | Compositions for drug administration |
| US9895444B2 (en) | 2004-08-25 | 2018-02-20 | Aegis Therapeutics, Llc | Compositions for drug administration |
| AR056327A1 (es) * | 2005-04-25 | 2007-10-03 | Genelabs Tech Inc | Compuestos de nucleosidos para el tratamiento de infecciones virales |
| WO2006125141A2 (en) | 2005-05-17 | 2006-11-23 | Amicus Therapeutics, Inc. | A method for the treatment of pompe disease using 1-deoxynojirimycin derivatives |
| US20070031342A1 (en) * | 2005-06-22 | 2007-02-08 | Nektar Therapeutics | Sustained release microparticles for pulmonary delivery |
| US20100119525A1 (en) * | 2005-08-01 | 2010-05-13 | Mount Sinai Schoool Of Medicine Of New York University | Method for extending longevity using npc1l1 antagonists |
| AU2006315132A1 (en) * | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| WO2007070556A2 (en) * | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | N-(6-membered aromatic ring)-amido anti-viral compounds |
| US20070178166A1 (en) * | 2005-12-15 | 2007-08-02 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration |
| US20070148211A1 (en) * | 2005-12-15 | 2007-06-28 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for oral administration |
| WO2007095288A2 (en) * | 2006-02-13 | 2007-08-23 | Nektar Therapeutics | Methionine-containing protein or peptide compositions and methods of making and using |
| TWI501774B (zh) | 2006-02-27 | 2015-10-01 | Biogen Idec Inc | 神經性病症之治療 |
| WO2007103182A2 (en) * | 2006-03-01 | 2007-09-13 | Biogen Idec Ma Inc. | Compostions and methods for administering gdnf ligand family proteins |
| CA2649288C (en) | 2006-04-19 | 2015-11-24 | Novartis Ag | 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting csf-1r signaling |
| CA2649895C (en) * | 2006-04-19 | 2013-03-26 | Novadel Pharma Inc. | Stable hydroalcoholic oral spray formulations and methods |
| US8226949B2 (en) | 2006-06-23 | 2012-07-24 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
| US7825267B2 (en) * | 2006-09-08 | 2010-11-02 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Synthesis of FR901464 and analogs with antitumor activity |
| USRE49444E1 (en) | 2006-10-03 | 2023-03-07 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
| CN102274492B (zh) | 2006-10-03 | 2014-11-26 | 半径健康公司 | 骨合成代谢蛋白质的药物递送方法 |
| EP1961765A1 (en) * | 2006-12-08 | 2008-08-27 | Zealand Pharma A/S | Truncated PTH peptides with a cyclic conformation |
| CA2673049C (en) * | 2006-12-22 | 2016-02-23 | Novadel Pharma Inc. | Stable anti-nausea oral spray formulations and methods |
| EP2120875B1 (en) | 2007-02-11 | 2018-07-11 | Map Pharmaceuticals Inc. | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
| JP5583005B2 (ja) * | 2007-05-01 | 2014-09-03 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | 血管新生を増大させるための組成物および方法 |
| KR20100022974A (ko) * | 2007-05-10 | 2010-03-03 | 노바델 파마 인코포레이티드 | 항불면증 조성물 및 제조 방법 |
| BRPI0812159A2 (pt) | 2007-05-21 | 2017-05-02 | Novartis Ag | inibidores de csf-1r, composições e métodos de uso |
| US8415390B2 (en) | 2008-05-30 | 2013-04-09 | Microdose Therapeutx, Inc. | Methods and compositions for administration of oxybutynin |
| US9119777B2 (en) | 2008-05-30 | 2015-09-01 | Microdose Therapeutx, Inc. | Methods and compositions for administration of oxybutynin |
| EP2205634A2 (en) * | 2007-08-08 | 2010-07-14 | Biogen Idec MA, Inc. | Anti-neublastin antibodies and uses thereof |
| US7985325B2 (en) * | 2007-10-30 | 2011-07-26 | Novellus Systems, Inc. | Closed contact electroplating cup assembly |
| US9011840B2 (en) | 2008-03-14 | 2015-04-21 | The Board Of Trustees Of The University Of Illinois | Activated mesenchymal stem cells for wound healing and impaired tissue regeneration |
| US20110044958A1 (en) * | 2008-03-14 | 2011-02-24 | The Board Of Trustees Of The University Of Illinois | Activated mesenchymal stem cells for the prevention and repair of inflammatory states |
| AU2009228093B2 (en) | 2008-03-28 | 2014-08-07 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| WO2010039872A1 (en) * | 2008-10-01 | 2010-04-08 | The Board Of Trustees Of The University Of Illinois | Pulse parathyroid hormone for treatment of the hematopoietic syndrome, stromal cell loss, and vascular injury resulting from acute exposure to lethal radiation |
| US8440631B2 (en) | 2008-12-22 | 2013-05-14 | Aegis Therapeutics, Llc | Compositions for drug administration |
| WO2010102066A1 (en) | 2009-03-05 | 2010-09-10 | Bend Research, Inc. | Dextran polymer powder for inhalation administration of pharmaceuticals |
| PT3130396T (pt) | 2009-03-27 | 2021-05-12 | Bend Res Inc | Processo de secagem por pulverização |
| JP5645918B2 (ja) | 2009-04-09 | 2014-12-24 | アミカス セラピューティックス インコーポレイテッド | リソソーム蓄積障害の予防および／または治療方法 |
| EP2995306B1 (en) | 2009-10-19 | 2018-12-19 | Amicus Therapeutics, Inc. | Novel compositions for preventing and/or treating lysosomal storage disorders |
| EP2490532B1 (en) | 2009-10-19 | 2016-11-23 | Amicus Therapeutics, Inc. | Novel compositions for preventing and/or treating degenerative disorders of the central nervous system |
| WO2011066505A2 (en) * | 2009-11-30 | 2011-06-03 | Pathak Holdings Llc | Methods and compositions for filling fleshy fruits and vegetables |
| EP2509996A1 (en) | 2009-12-07 | 2012-10-17 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| JP2013532144A (ja) | 2010-06-14 | 2013-08-15 | ハー・ルンドベック・アクチエゼルスカベット | ＳｏｒＬＡとＧＤＮＦファミリーリガンド受容体の間の相互作用の調節 |
| ES2594556T3 (es) | 2010-07-30 | 2016-12-21 | Daito Chemix Corporation | Derivado de naftaleno |
| EP2611529B1 (en) | 2010-09-03 | 2019-01-23 | Bend Research, Inc. | Spray-drying method |
| US8815294B2 (en) | 2010-09-03 | 2014-08-26 | Bend Research, Inc. | Pharmaceutical compositions of dextran polymer derivatives and a carrier material |
| WO2012031133A2 (en) | 2010-09-03 | 2012-03-08 | Bench Research, Inc. | Spray-drying apparatus and methods of using the same |
| US9248584B2 (en) | 2010-09-24 | 2016-02-02 | Bend Research, Inc. | High-temperature spray drying process and apparatus |
| WO2012092484A2 (en) | 2010-12-29 | 2012-07-05 | Inhibitex, Inc. | Substituted purine nucleosides, phosphoroamidate and phosphorodiamidate derivatives for treatment of viral infections |
| EP2661254B1 (en) | 2011-01-05 | 2017-08-02 | Hospira, Inc. | Spray drying vancomycin |
| WO2012094451A1 (en) | 2011-01-06 | 2012-07-12 | Beta Pharma Canada Inc. | Novel ureas for the treatment and prevention of cancer |
| US9060938B2 (en) | 2011-05-10 | 2015-06-23 | Bend Research, Inc. | Pharmaceutical compositions of active agents and cationic dextran polymer derivatives |
| EP2720699B1 (en) | 2011-06-14 | 2018-05-16 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine |
| US20130096170A1 (en) | 2011-10-14 | 2013-04-18 | Hospira, Inc. | Methods of treating pediatric patients using dexmedetomidine |
| US8242158B1 (en) | 2012-01-04 | 2012-08-14 | Hospira, Inc. | Dexmedetomidine premix formulation |
| NZ630612A (en) | 2012-03-27 | 2016-11-25 | Amicus Therapeutics Inc | Novel compounds for preventing and/or treating lysosomal storage disorders and/or degenerative disorders of the central nervous system |
| US9771377B2 (en) | 2012-12-21 | 2017-09-26 | University of Pittsburgh—of the Commonwealth System of Higher Education | Synthesis of FR901464 and analogs with antitumor activity |
| DK2959903T3 (en) | 2013-02-20 | 2019-01-21 | Univ Kyoto | Medicine for the treatment of eye disease |
| CN104043104B (zh) | 2013-03-15 | 2018-07-10 | 浙江创新生物有限公司 | 含盐酸万古霉素的喷雾干粉及其工业化制备方法 |
| ES2708577T3 (es) | 2013-09-04 | 2019-04-10 | Univ Kyoto | Composición medicinal que mejora la resistencia a la leptina |
| EA201691603A1 (ru) | 2014-02-12 | 2016-11-30 | Амикус Терапьютикс, Инк. | Производные сахаров, содержащие серосодержащие фрагменты, способы их получения и способы их применения для лечения mps iiic |
| US9675627B2 (en) | 2014-04-14 | 2017-06-13 | Amicus Therapeutics, Inc. | Dosing regimens for treating and/or preventing cerebral amyloidoses |
| CA2962719A1 (en) | 2014-10-31 | 2016-05-06 | Bend Research Inc. | Process for forming active domains dispersed in a matrix |
| US10179128B2 (en) | 2015-08-31 | 2019-01-15 | Amicus Therapeutics, Inc. | Regimens for treating and preventing lysosomal disorders and degenerative disorders of the central nervous system |
| NL2017294B1 (en) | 2016-08-05 | 2018-02-14 | Univ Erasmus Med Ct Rotterdam | Natural cryptic exon removal by pairs of antisense oligonucleotides. |
| US11839604B2 (en) | 2016-12-31 | 2023-12-12 | Bioxcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| WO2018200618A1 (en) | 2017-04-25 | 2018-11-01 | Amicus Therapeutics, Inc. | Novel compositions for preventing and/or treating degenerative disorders of the central nervous system and/or lysosomal storage disorders |
| US10996208B2 (en) | 2017-04-28 | 2021-05-04 | Radius Health, Inc. | Abaloparatide formulations and methods of testing, storing, modifying, and using same |
| CN109528717B (zh) | 2017-09-21 | 2021-08-17 | 中国科学院分子细胞科学卓越创新中心 | 治疗或预防肥胖或其相关疾病的化合物及其应用 |
| CN110156674A (zh) | 2018-02-13 | 2019-08-23 | 中国科学院上海有机化学研究所 | 一种作为吲哚胺-2,3-双加氧酶抑制剂的螺环化合物 |
| PT3813802T (pt) | 2018-06-27 | 2025-01-15 | Arx Llc | Formulações de películas contendo dexmedetomidina e métodos de produção das mesmas |
| CN109053854B (zh) | 2018-09-29 | 2021-05-14 | 深圳清博汇能医药科技有限公司 | 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 |
| US11160791B2 (en) | 2018-11-01 | 2021-11-02 | Medefil, Inc. | Dexmedetomidine injection premix formulation in ready to use (RTU) bags |
| BR112022000992A2 (pt) | 2019-07-19 | 2022-06-14 | Arx Llc | Regimes de tratamento de dexmedetomidina não sedantes |
| CN119528915A (zh) | 2021-09-14 | 2025-02-28 | 中国科学院上海有机化学研究所 | 抑制细胞程序性死亡的化合物及其制备方法 |
| JP2025505820A (ja) | 2022-02-18 | 2025-02-28 | ベイジン フィトベント ファーマシューティカル テクノロジー カンパニー，リミテッド | サルササポゲニン構造に基づく誘導体およびその医薬組成物の使用 |
| US11806334B1 (en) | 2023-01-12 | 2023-11-07 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
Family Cites Families (273)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE471490C (de) | 1931-08-12 | Karl Zeyen | Vorrichtung zum Zerstaeuben mehlfoermiger Stoffe | |
| US979993A (en) | 1910-03-24 | 1910-12-27 | Joseph Francis O'byrne | Projectile. |
| US1855591A (en) | 1926-02-03 | 1932-04-26 | Wallerstein Co Inc | Invertase preparation and method of making the same |
| US2457036A (en) | 1946-04-10 | 1948-12-21 | Albert A Epstein | Coffee concentrate and the process of producing it |
| US3362405A (en) | 1964-04-06 | 1968-01-09 | Hamilton O. Hazel | Method and apparatus for admixing gas with solid particles |
| GB1122284A (en) | 1965-03-19 | 1968-08-07 | Fisons Pharmaceuticals Ltd | Inhalation device |
| GB1182779A (en) | 1966-09-17 | 1970-03-04 | Fisons Pharmaceuticals Ltd | Inhalation Device |
| US3557717A (en) | 1968-05-17 | 1971-01-26 | Gen Mills Inc | Process for making candy floss |
| US3619294A (en) | 1968-07-15 | 1971-11-09 | Penick & Ford Ltd | Method of combining crystalline sugar with impregnating agents and products produced thereby |
| DE1812574A1 (de) | 1968-12-04 | 1970-06-11 | Riedel De Haen Ag | Verfahren zur Herstellung biozider Granulate |
| US3632357A (en) | 1969-07-29 | 1972-01-04 | Standard Brands Inc | Method of producing hard candy |
| US3655442A (en) | 1969-08-27 | 1972-04-11 | California & Hawaiian Sugar | Method of making sugar and sugar products |
| US3937668A (en) | 1970-07-15 | 1976-02-10 | Ilse Zolle | Method for incorporating substances into protein microspheres |
| GB1265615A (fi) | 1970-09-10 | 1972-03-01 | ||
| US3745682A (en) | 1971-09-28 | 1973-07-17 | Pneu Dart Inc | Gun for propelling a drug or medicine projectile |
| DE2246013A1 (de) | 1972-09-20 | 1974-03-28 | Boehringer Mannheim Gmbh | Verfahren zur herstellung von poroesen tabletten |
| DE2415159A1 (de) | 1974-03-29 | 1975-10-09 | Hoechst Ag | Alkalialkansulfonathaltige spruehprodukte und verfahren zu ihrer herstellung |
| US3948263A (en) | 1974-08-14 | 1976-04-06 | Minnesota Mining And Manufacturing Company | Ballistic animal implant |
| JPS5134879A (en) | 1974-09-19 | 1976-03-24 | Eisai Co Ltd | Bishochukuryushinoseizoho |
| US3964483A (en) | 1975-01-13 | 1976-06-22 | Syntex Puerto Rico, Inc. | Inhalation device |
| US4005711A (en) | 1975-01-13 | 1977-02-01 | Syntex Puerto Rico, Inc. | Inhalation device |
| FR2299011A1 (fr) | 1975-01-29 | 1976-08-27 | Obert Jean Claude | Generateur d'aerosols de part |
| US4102999A (en) | 1975-02-10 | 1978-07-25 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Process for producing stable macromomycin powder |
| GB1533012A (en) | 1976-12-20 | 1978-11-22 | Lloyd C | Confectionery machines |
| NL7704348A (nl) | 1977-04-21 | 1978-10-24 | Philips Nv | Werkwijze voor het bereiden van een geattenueer- de transmissible gastroenteritis(tge)-virusstam voor toepassing in levende vaccins. |
| US4180593A (en) | 1977-04-29 | 1979-12-25 | Cohan Allan N | Process for producing round spherical free flowing blown bead food products of controlled bulk density |
| US4127502A (en) | 1977-06-10 | 1978-11-28 | Eastman Kodak Company | Stabilizers for reconstituted, lyophilized samples |
| US4211769A (en) | 1977-08-24 | 1980-07-08 | Takeda Chemical Industries, Ltd. | Preparations for vaginal administration |
| US4244949A (en) | 1978-04-06 | 1981-01-13 | The Population Council, Inc. | Manufacture of long term contraceptive implant |
| US4158544A (en) | 1978-07-17 | 1979-06-19 | Beckman Instruments, Inc. | Process for preparing a biological composition for use as a reference control in diagnostic analysis |
| US4253468A (en) | 1978-08-14 | 1981-03-03 | Steven Lehmbeck | Nebulizer attachment |
| US4588744A (en) | 1978-09-19 | 1986-05-13 | Mchugh John E | Method of forming an aqueous solution of 3-3-Bis(p-hydroxyphenyl)-phthalide |
| GB2037735B (en) | 1978-12-21 | 1983-11-09 | Standard Telephones Cables Ltd | Glass composition |
| DE3061384D1 (en) | 1979-02-21 | 1983-01-27 | Ici Plc | A process for the extraction of poly-3-hydroxy-butyric acid from microbial cells |
| US4452239A (en) | 1980-03-25 | 1984-06-05 | Hilal Malem | Medical nebulizing apparatus |
| US4326524A (en) | 1980-09-30 | 1982-04-27 | Minnesota Mining And Manufacturing Company | Solid dose ballistic projectile |
| US4327076A (en) | 1980-11-17 | 1982-04-27 | Life Savers, Inc. | Compressed chewable antacid tablet and method for forming same |
| US4371557A (en) | 1981-01-21 | 1983-02-01 | General Foods Corporation | Maintenance of protein quality in foods containing reducing sugars |
| US5366734A (en) | 1981-02-16 | 1994-11-22 | Zeneca Limited | Continuous release pharmaceutical compositions |
| US4327077A (en) | 1981-05-29 | 1982-04-27 | Life Savers, Inc. | Compressed chewable antacid tablet and method for forming same |
| US4484577A (en) | 1981-07-23 | 1984-11-27 | Key Pharmaceuticals, Inc. | Drug delivery method and inhalation device therefor |
| DE3268533D1 (en) | 1981-07-24 | 1986-02-27 | Fisons Plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
| US5260306A (en) | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
| GB2105189B (en) | 1981-07-24 | 1985-03-20 | Fisons Plc | Inhalation drugs |
| KR890000664B1 (ko) | 1981-10-19 | 1989-03-22 | 바리 안소니 뉴우샘 | 미분된 베클로메타손 디프로피오네이트 일수화물의 제조방법 |
| US4713249A (en) | 1981-11-12 | 1987-12-15 | Schroeder Ulf | Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof |
| JPS58164683A (ja) | 1982-03-25 | 1983-09-29 | Takeda Chem Ind Ltd | 安定化された固体組成物 |
| US4659696A (en) | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
| US4457916A (en) | 1982-08-31 | 1984-07-03 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same |
| US4591552A (en) | 1982-09-29 | 1986-05-27 | New York Blood Center, Inc. | Detection of hepatitis B surface antigen (or antibody to same) with labeled synthetic peptide |
| JPS59163313A (ja) | 1983-03-09 | 1984-09-14 | Teijin Ltd | 経鼻投与用ペプチドホルモン類組成物 |
| US4883762A (en) | 1983-06-06 | 1989-11-28 | Ciba Corning Diagnostics Corp. | Stabilized isoenzyme control products |
| JPS6035263A (ja) | 1983-08-05 | 1985-02-23 | Wako Pure Chem Ind Ltd | 不溶性担体に固定化された免疫活性物質の安定化法及び該物質を構成単位として含む生理活性物質測定用試薬 |
| FR2550204B1 (fr) * | 1983-08-05 | 1987-11-13 | Toyo Jozo Kk | Derives peptidiques de (nle8,nle1b, tyr34)-h-pth |
| US4865871A (en) | 1983-08-23 | 1989-09-12 | Board Of Regents The University Of Texas System | Method for cryopreparing biological tissue |
| GB8323094D0 (en) | 1983-08-26 | 1983-09-28 | Franks F | Preservation of cells |
| EP0139286B1 (en) | 1983-10-14 | 1991-08-21 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
| US4534343A (en) | 1984-01-27 | 1985-08-13 | Trutek Research, Inc. | Metered dose inhaler |
| US4758583A (en) | 1984-03-19 | 1988-07-19 | The Rockefeller University | Method and agents for inhibiting protein aging |
| US4617272A (en) | 1984-04-25 | 1986-10-14 | Economics Laboratory, Inc. | Enzyme drying process |
| US4620847A (en) | 1984-06-01 | 1986-11-04 | Vsesojuzny Nauchno-Issledovatelsky Institut Meditsinskikh Polimerov | Device for administering powdered substances |
| JPS60258195A (ja) | 1984-06-05 | 1985-12-20 | Ss Pharmaceut Co Ltd | α．α―トレハロース脂肪酸ジエステル誘導体 |
| JPS60258125A (ja) | 1984-06-06 | 1985-12-20 | Hayashibara Biochem Lab Inc | 蛋白性生理活性物質を含有する水溶性乾燥物 |
| US4721709A (en) | 1984-07-26 | 1988-01-26 | Pyare Seth | Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions |
| IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
| DE3445010A1 (de) | 1984-12-10 | 1986-06-19 | Boehringer Mannheim Gmbh | Kontroll- bzw. eichserum fuer die lipid-diagnostik |
| GB8500698D0 (en) | 1985-01-11 | 1985-02-13 | Unilever Plc | Preparation of reagents |
| FR2575923B1 (fr) | 1985-01-15 | 1988-02-05 | Jouveinal Sa | Composition laxative a base de lactulose, et son procede de fabrication |
| US4830858A (en) | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
| US4942544A (en) | 1985-02-19 | 1990-07-17 | Kenneth B. McIntosh | Medication clock |
| GB8508173D0 (en) | 1985-03-28 | 1985-05-01 | Standard Telephones Cables Ltd | Controlled delivery device |
| IL78342A (en) * | 1985-04-04 | 1991-06-10 | Gen Hospital Corp | Pharmaceutical composition for treatment of osteoporosis in humans comprising a parathyroid hormone or a fragment thereof |
| WO1986006959A1 (en) | 1985-05-22 | 1986-12-04 | Liposome Technology, Inc. | Liposome inhalation method and system |
| ATE68524T1 (de) | 1985-07-09 | 1991-11-15 | Quadrant Bioresources Ltd | Beschuetzung von proteinen und aehnlichem. |
| US4847079A (en) | 1985-07-29 | 1989-07-11 | Schering Corporation | Biologically stable interferon compositions comprising thimerosal |
| NZ217645A (en) | 1985-09-25 | 1991-11-26 | Oncogen | Recombinant viruses expressing lav/htlv-iii related epitopes and vaccine formulations |
| US4680027A (en) | 1985-12-12 | 1987-07-14 | Injet Medical Products, Inc. | Needleless hypodermic injection device |
| JPS62174094A (ja) | 1985-12-16 | 1987-07-30 | Ss Pharmaceut Co Ltd | α．α―トレハロース誘導体 |
| JPH0710344B2 (ja) | 1985-12-26 | 1995-02-08 | 株式会社林原生物化学研究所 | 無水グリコシルフルクト−スによる含水物の脱水方法 |
| GB8604983D0 (en) | 1986-02-28 | 1986-04-09 | Biocompatibles Ltd | Protein preservation |
| SE453566B (sv) | 1986-03-07 | 1988-02-15 | Draco Ab | Anordning vid pulverinhalatorer |
| US5017372A (en) | 1986-04-14 | 1991-05-21 | Medicis Corporation | Method of producing antibody-fortified dry whey |
| US4739754A (en) | 1986-05-06 | 1988-04-26 | Shaner William T | Suction resistant inhalator |
| US5160745A (en) | 1986-05-16 | 1992-11-03 | The University Of Kentucky Research Foundation | Biodegradable microspheres as a carrier for macromolecules |
| US4762857A (en) | 1986-05-30 | 1988-08-09 | E. I. Du Pont De Nemours And Company | Trehalose as stabilizer and tableting excipient |
| US4832686A (en) | 1986-06-24 | 1989-05-23 | Anderson Mark E | Method for administering interleukin-2 |
| EP0257915B1 (en) | 1986-08-11 | 1993-03-10 | Innovata Biomed Limited | Pharmaceutical formulations comprising microcapsules |
| ES2032831T5 (es) | 1986-08-19 | 2001-02-16 | Genentech Inc | Dispositivo y dispersion para suministro intrapulmonar de factores de crecimiento polipeptidos y citoquinas. |
| DE3636669C2 (de) | 1986-10-28 | 2001-08-16 | Siemens Ag | Anordnung zur Zufuhr von Aerosol zu den Luftwegen und/oder Lungen eines Patienten |
| US5049388A (en) | 1986-11-06 | 1991-09-17 | Research Development Foundation | Small particle aerosol liposome and liposome-drug combinations for medical use |
| US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
| US4906463A (en) | 1986-12-22 | 1990-03-06 | Cygnus Research Corporation | Transdermal drug-delivery composition |
| US5089181A (en) | 1987-02-24 | 1992-02-18 | Vestar, Inc. | Method of dehydrating vesicle preparations for long term storage |
| FR2611501B1 (fr) | 1987-03-04 | 1991-12-06 | Corbiere Jerome | Nouvelles compositions pharmaceutiques pour la voie buccale a base d'acetylsalielylate de lysine et leur procede d'obtention |
| CA1337268C (en) | 1987-03-09 | 1995-10-10 | Edmund P. Bass | Canine distemper virus vaccine |
| US5387431A (en) | 1991-10-25 | 1995-02-07 | Fuisz Technologies Ltd. | Saccharide-based matrix |
| US4855326A (en) | 1987-04-20 | 1989-08-08 | Fuisz Pharmaceutical Ltd. | Rapidly dissoluble medicinal dosage unit and method of manufacture |
| JP2656944B2 (ja) | 1987-04-30 | 1997-09-24 | クーパー ラボラトリーズ | タンパク質性治療剤のエアロゾール化 |
| US4861627A (en) | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
| US4790824A (en) | 1987-06-19 | 1988-12-13 | Bioject, Inc. | Non-invasive hypodermic injection device |
| US5571499A (en) | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
| GB8715238D0 (en) | 1987-06-29 | 1987-08-05 | Quadrant Bioresources Ltd | Food process |
| US5240712A (en) | 1987-07-17 | 1993-08-31 | The Boots Company Plc | Therapeutic agents |
| JPH02111A (ja) * | 1987-08-03 | 1990-01-05 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド製剤 |
| US5059587A (en) * | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
| EP0303746B2 (en) | 1987-08-21 | 1998-12-02 | Mallinckrodt Group Inc. | Stabilization of growth promoting hormones |
| CA1327161C (en) | 1987-09-01 | 1994-02-22 | Mitsugu Kobayashi | Lyophilized pharmaceutical composition of neocarzinostatin derivative |
| GB8723846D0 (en) | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
| EP0325936A3 (en) | 1988-01-16 | 1990-01-17 | Ono Pharmaceutical Co., Ltd. | Aminoguanidine derivatives and inhibitory agents on maillard reaction containing them as active ingredients |
| GB8801338D0 (en) | 1988-01-21 | 1988-02-17 | Quadrant Bioresources Ltd | Preservation of viruses |
| GB8802174D0 (en) | 1988-02-01 | 1988-03-02 | Quadrant Bioresources Ltd | Method of drying macromolecules |
| US5096885A (en) | 1988-04-15 | 1992-03-17 | Genentech, Inc. | Human growth hormone formulation |
| DE3815221C2 (de) | 1988-05-04 | 1995-06-29 | Gradinger F Hermes Pharma | Verwendung einer Retinol- und/oder Retinsäureester enthaltenden pharmazeutischen Zubereitung zur Inhalation zur Einwirkung auf die Schleimhäute des Tracheo-Bronchialtraktes einschließlich der Lungenalveolen |
| US5045446A (en) | 1988-08-26 | 1991-09-03 | Cryopharm Corporation | Lyophilization of cells |
| US5049664A (en) | 1988-08-26 | 1991-09-17 | Sawai Pharmaceutical Co., Ltd. | Trehalose derivatives |
| US5342625A (en) | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
| EP0360340A1 (en) | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
| US4984158A (en) | 1988-10-14 | 1991-01-08 | Hillsman Dean | Metered dose inhaler biofeedback training and evaluation system |
| GB8824897D0 (en) | 1988-10-24 | 1988-11-30 | Ici Plc | Biocatalysts |
| GB8826429D0 (en) | 1988-11-11 | 1988-12-14 | Univ Leeds Ind Service Ltd | Enzyme stabilisation systems |
| US5225183A (en) | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| US4906476A (en) | 1988-12-14 | 1990-03-06 | Liposome Technology, Inc. | Novel liposome composition for sustained release of steroidal drugs in lungs |
| US5043165A (en) | 1988-12-14 | 1991-08-27 | Liposome Technology, Inc. | Novel liposome composition for sustained release of steroidal drugs |
| US5006343A (en) | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
| US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
| GB8903593D0 (en) | 1989-02-16 | 1989-04-05 | Pafra Ltd | Storage of materials |
| US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
| WO1990011756A1 (en) | 1989-04-12 | 1990-10-18 | Aberdeen University | Slow release vitreous systems |
| US5270048A (en) | 1989-04-21 | 1993-12-14 | Borden (Uk) Limited | Controlled delivery devices |
| GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
| ATE99546T1 (de) | 1989-05-01 | 1994-01-15 | Alkermes Inc | Verfahren zur herstellung von kleinen partikeln von biologisch aktiven molekuelen. |
| DE69012458T3 (de) | 1989-05-31 | 2000-01-20 | Fisons Plc, Ipswich | Medikament und Inhalationsvorrichtung dafür. |
| FI84698C (fi) | 1989-06-16 | 1992-01-10 | Huhtamaeki Oy | Anordning foer finfoerdelning av agglomerat av en enkeldos av ett laekemedelpreparat i pulverform. |
| GB8917470D0 (en) | 1989-07-31 | 1989-09-13 | Quadrant Bioresources Ltd | Composition and method |
| US5238920A (en) * | 1989-08-22 | 1993-08-24 | Abbott Laboratories | Pulmonary surfactant protein fragments |
| US5240846A (en) | 1989-08-22 | 1993-08-31 | The Regents Of The University Of Michigan | Gene therapy vector for cystic fibrosis |
| US5013557A (en) | 1989-10-03 | 1991-05-07 | Warner-Lambert Company | Taste masking compositions comprising spray dried microcapsules containing sucralfate and methods for preparing same |
| IT1237118B (it) | 1989-10-27 | 1993-05-18 | Miat Spa | Inalatore multidose per farmaci in polvere. |
| US5707644A (en) | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
| GB2237510B (en) | 1989-11-04 | 1993-09-15 | Danbiosyst Uk | Small particle drug compositions for nasal administration |
| US5312335A (en) | 1989-11-09 | 1994-05-17 | Bioject Inc. | Needleless hypodermic injection device |
| JPH03161441A (ja) | 1989-11-20 | 1991-07-11 | Senjiyu Seiyaku Kk | メイラード反応阻害剤 |
| JP2854631B2 (ja) | 1989-11-21 | 1999-02-03 | 千寿製薬株式会社 | 糖尿病合併症および老化によって引き起こされる疾患の予防・治療剤 |
| CA2030718C (en) | 1989-11-28 | 1998-05-12 | Jacob Berger | Tricyclic compounds |
| US5376386A (en) | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
| GB9001635D0 (en) | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
| US5113855A (en) | 1990-02-14 | 1992-05-19 | Newhouse Michael T | Powder inhaler |
| ATE129152T1 (de) | 1990-02-19 | 1995-11-15 | Senju Pharma Co | Zusammensetzungen von maillard-reaktion inhibitoren. |
| US5312909A (en) | 1990-03-28 | 1994-05-17 | Gist Brocades, N.V. | Recombinant DNA encoding neutral trehalase |
| JPH05963A (ja) | 1990-04-13 | 1993-01-08 | Toray Ind Inc | ポリペプチド類組成物 |
| US5112596A (en) | 1990-04-23 | 1992-05-12 | Alkermes, Inc. | Method for increasing blood-brain barrier permeability by administering a bradykinin agonist of blood-brain barrier permeability |
| AU7908791A (en) | 1990-05-08 | 1991-11-27 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
| GB9010742D0 (en) | 1990-05-14 | 1990-07-04 | Quadrant Bioresources Ltd | Stabilization of biological macromolecular substances |
| US5621094A (en) | 1990-05-14 | 1997-04-15 | Quadrant Holdings Cambridge Limited | Method of preserving agarose gel structure during dehydration by adding a non-reducing glycoside of a straight-chain sugar alcohol |
| GB9012663D0 (en) | 1990-06-07 | 1990-08-01 | Erba Carlo Spa | Galenic formulations containing cyclodextrins |
| IT1246350B (it) | 1990-07-11 | 1994-11-17 | Eurand Int | Metodo per ottenere una rapida sospensione in acqua di farmaci insolubili |
| WO1992002133A1 (en) | 1990-08-10 | 1992-02-20 | Analytical Control Systems, Inc. | Improved diagnostic and therapeutic compositions |
| US5230884A (en) * | 1990-09-11 | 1993-07-27 | University Of Wales College Of Cardiff | Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations |
| AU650045B2 (en) | 1990-09-12 | 1994-06-09 | Lifecell Corporation | Method and apparatus for cryopreparation dry stabilization and rehydration of biological suspensions |
| US5200399A (en) | 1990-09-14 | 1993-04-06 | Boyce Thompson Institute For Plant Research, Inc. | Method of protecting biological materials from destructive reactions in the dry state |
| GB9020544D0 (en) | 1990-09-20 | 1990-10-31 | Sandoz Ltd | Improvements in or relating to organic compounds |
| US5173298A (en) | 1990-09-27 | 1992-12-22 | Allergan, Inc. | Nonaqueous fluorinated drug delivery vehicle suspensions |
| DE4039656A1 (de) * | 1990-12-12 | 1992-06-17 | Bissendorf Peptide Gmbh | Arzneimittel, enthaltend das humane parathormon-fragment (1-37) in der form des amids oder ethylamids als aktiven wirkstoff |
| JPH06506455A (ja) | 1991-02-08 | 1994-07-21 | ケンブリッジ・ニューロサイエンス・インコーポレイテッド | 神経伝達物質放出調節剤としてのグアニジン置換体及びその誘導体ならびに神経伝達物質放出遮断物質を同定するための新規な方法 |
| US5182097A (en) | 1991-02-14 | 1993-01-26 | Virginia Commonwealth University | Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
| WO1992014449A1 (en) | 1991-02-20 | 1992-09-03 | Nova Pharmaceutical Corporation | Controlled release microparticulate delivery system for proteins |
| US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
| US6565841B1 (en) | 1991-03-15 | 2003-05-20 | Amgen, Inc. | Pulmonary administration of granulocyte colony stimulating factor |
| JP3507486B2 (ja) | 1991-03-15 | 2004-03-15 | アムジエン・インコーポレーテツド | 顆粒球コロニー刺激因子の肺内投与 |
| EP0504459B1 (de) | 1991-03-21 | 1996-06-05 | PAUL RITZAU PARI-WERK GmbH | Vernebler insbesondere zur Anwendung in Geräten für die Inhalationstherapie |
| US5993805A (en) | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
| GB9107628D0 (en) | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
| DE69228332T2 (de) | 1991-05-07 | 1999-09-16 | The Liposome Co.,Inc. | Liposomale Prostaglandinformulierungen |
| US6060069A (en) | 1991-05-20 | 2000-05-09 | Dura Pharmaceuticals, Inc. | Pulmonary delivery of pharmaceuticals |
| AU659645B2 (en) | 1991-06-26 | 1995-05-25 | Inhale Therapeutic Systems | Storage of materials |
| ATE189124T1 (de) | 1991-07-02 | 2000-02-15 | Inhale Inc | Verfahren und vorrichtung zum abgeben von medikamenten in aerosolform |
| JP3138870B2 (ja) | 1991-07-31 | 2001-02-26 | ファロス ブラター アーゲー | 特に製紙機械用ロールの円柱状または球状の面を研磨するためのグラインダー |
| TW221689B (fi) | 1991-08-27 | 1994-03-11 | Otsuka Pharma Co Ltd | |
| US6123924A (en) | 1991-09-25 | 2000-09-26 | Fisons Plc | Pressurized aerosol inhalation compositions |
| US6013638A (en) | 1991-10-02 | 2000-01-11 | The United States Of America As Represented By The Department Of Health And Human Services | Adenovirus comprising deletions on the E1A, E1B and E3 regions for transfer of genes to the lung |
| GB9123953D0 (en) | 1991-11-12 | 1992-01-02 | Minnesota Mining & Mfg | Inhalation device |
| EP0615438B1 (en) | 1991-12-05 | 1996-07-24 | Mallinckrodt Veterinary, Inc. | A carbohydrate glass matrix for the sustained release of a therapeutic agent |
| KR0131678B1 (ko) | 1991-12-09 | 1998-04-17 | 유미꾸라 레이이찌 | 파라티로이드 호르몬류의 안정화 조성물 |
| DE4140689B4 (de) | 1991-12-10 | 2007-11-22 | Boehringer Ingelheim Kg | Inhalationspulver und Verfahren zu ihrer Herstellung |
| CA2421976C (en) | 1991-12-12 | 2004-04-20 | Glaxo Group Limited | Medicaments |
| US5849700A (en) | 1991-12-20 | 1998-12-15 | Novo Nordisk A/S | Pharmaceutical formulation |
| CA2127877A1 (en) | 1992-01-21 | 1993-07-22 | Robert M. Platz | Improved process for preparing micronized polypeptide drugs |
| WO1993017663A1 (en) | 1992-03-10 | 1993-09-16 | Fisons Plc | Pharmaceutical inhalation compositions |
| CA2075521C (en) | 1992-05-05 | 1995-11-28 | Kuniaki Koyama | Stabilized live vaccine |
| IT1254359B (it) | 1992-05-11 | 1995-09-14 | Serono Cesare Ist Ricerca | Composizioni farmaceutiche contenenti il-6 |
| NL9200844A (nl) | 1992-05-13 | 1993-12-01 | De Wijdeven Gijsbertus G P Van | Inrichting en werkwijze voor het injecteren met een vaste stof. |
| US5215079A (en) | 1992-05-19 | 1993-06-01 | Armstrong Pharmaceuticals, Inc. | Single dose metered dose inhaler for delivery of vaccines and other drugs |
| GB9213874D0 (en) | 1992-06-30 | 1992-08-12 | Fisons Plc | Process to novel medicament form |
| US6231851B1 (en) | 1994-05-18 | 2001-05-15 | Inhale Therapeutic Systems | Methods and compositions for the dry powder formulation of interferons |
| US6673335B1 (en) | 1992-07-08 | 2004-01-06 | Nektar Therapeutics | Compositions and methods for the pulmonary delivery of aerosolized medicaments |
| US6509006B1 (en) | 1992-07-08 | 2003-01-21 | Inhale Therapeutic Systems, Inc. | Devices compositions and methods for the pulmonary delivery of aerosolized medicaments |
| US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
| US5239993A (en) | 1992-08-26 | 1993-08-31 | Glaxo Inc. | Dosage inhalator providing optimized compound inhalation trajectory |
| WO1994007514A1 (en) * | 1992-09-29 | 1994-04-14 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
| GB9221329D0 (en) | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
| US5380473A (en) | 1992-10-23 | 1995-01-10 | Fuisz Technologies Ltd. | Process for making shearform matrix |
| US5422384A (en) | 1992-11-25 | 1995-06-06 | Battelle Memorial Institute | Glass/polymer composites and methods of making |
| JP3168550B2 (ja) | 1992-12-02 | 2001-05-21 | 株式会社林原生物化学研究所 | 脱水剤およびそれを用いる含水物の脱水方法並びにその方法で得られる脱水物品 |
| SE9203743D0 (sv) | 1992-12-11 | 1992-12-11 | Astra Ab | Efficient use |
| US5453514A (en) | 1992-12-25 | 1995-09-26 | Yamanouchi Pharmaceutical Co., Ltd. | Pyrazole derivatives and compositions and methods of use as maillard reaction inhibitors |
| US5354934A (en) | 1993-02-04 | 1994-10-11 | Amgen Inc. | Pulmonary administration of erythropoietin |
| RU2143889C1 (ru) | 1993-02-23 | 2000-01-10 | Генентек, Инк. | Способ стабилизации полипептида, способы получения композиций полипептида и композиции |
| US5994314A (en) | 1993-04-07 | 1999-11-30 | Inhale Therapeutic Systems, Inc. | Compositions and methods for nucleic acid delivery to the lung |
| DK42093D0 (da) | 1993-04-07 | 1993-04-07 | Bukh Meditec | Administrationsmetode |
| US20020132787A1 (en) | 1993-04-07 | 2002-09-19 | Mohammed Eljamal | Compositions and methods for nucleic acid delivery to the lung |
| TW404844B (en) | 1993-04-08 | 2000-09-11 | Oxford Biosciences Ltd | Needleless syringe |
| TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| GB9313642D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
| GB9313650D0 (en) | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
| GB9314886D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Production of a biological control agent |
| AU4953393A (en) | 1993-08-24 | 1995-03-21 | Mogen International N.V. | Production of trehalose in plants |
| US5935927A (en) | 1994-02-03 | 1999-08-10 | The Picower Institute For Medical Research | Compositions and methods for stimulating amyloid removal in amyloidogenic diseases using advanced glycosylation endproducts |
| ATE268605T1 (de) | 1994-03-04 | 2004-06-15 | Genentech Inc | Pharmazeutische akzeptabel dnase zusammensetzung |
| US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
| US20030113273A1 (en) | 1996-06-17 | 2003-06-19 | Patton John S. | Methods and compositions for pulmonary delivery of insulin |
| CZ295827B6 (cs) | 1994-03-07 | 2005-11-16 | Nektar Therapeutics | Způsob aerosolizace dávky inzulinu, inzulinový přípravek a jeho použití |
| GB2288732B (en) | 1994-04-13 | 1998-04-29 | Quadrant Holdings Cambridge | Pharmaceutical compositions |
| US5955448A (en) | 1994-08-19 | 1999-09-21 | Quadrant Holdings Cambridge Limited | Method for stabilization of biological substances during drying and subsequent storage and compositions thereof |
| ZA953703B (en) | 1994-05-10 | 1996-01-10 | American Home Prod | Modified live BRSV vaccine |
| DK0762897T3 (da) | 1994-06-02 | 2003-07-21 | Elan Drug Delivery Ltd | Fremgangsmåde til forebyggelse af aggregering af proteiner/peptider ved rehydratisering eller optøning |
| US5567439A (en) | 1994-06-14 | 1996-10-22 | Fuisz Technologies Ltd. | Delivery of controlled-release systems(s) |
| US5591453A (en) | 1994-07-27 | 1997-01-07 | The Trustees Of The University Of Pennsylvania | Incorporation of biologically active molecules into bioactive glasses |
| US6142216A (en) | 1994-07-27 | 2000-11-07 | Bradford White Corporation | Indirect water heater |
| WO1996003978A1 (en) | 1994-08-04 | 1996-02-15 | Quadrant Holdings Cambridge Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
| US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
| US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
| JP3706136B2 (ja) | 1994-09-21 | 2005-10-12 | ネクター セラピューティクス | 乾燥粉末薬剤の分散装置及び方法 |
| US5547696A (en) | 1994-10-13 | 1996-08-20 | Novo Nordisk A/S | Pharmaceutical formulation |
| US5512547A (en) | 1994-10-13 | 1996-04-30 | Wisconsin Alumni Research Foundation | Pharmaceutical composition of botulinum neurotoxin and method of preparation |
| US5631225A (en) | 1994-10-13 | 1997-05-20 | Novo Nordisk A/S | Pharmaceutical formulation |
| US5654278A (en) | 1994-10-13 | 1997-08-05 | Novo Nordisk A/S | Composition and method comprising growth hormone and leucine |
| US5660854A (en) | 1994-11-28 | 1997-08-26 | Haynes; Duncan H | Drug releasing surgical implant or dressing material |
| JPH08157491A (ja) | 1994-11-30 | 1996-06-18 | Hayashibara Biochem Lab Inc | トレハロース誘導体の製造方法 |
| US5681746A (en) | 1994-12-30 | 1997-10-28 | Chiron Viagene, Inc. | Retroviral delivery of full length factor VIII |
| US5705482A (en) | 1995-01-13 | 1998-01-06 | Novo Nordisk A/S | Pharmaceutical formulation |
| WO1996027393A1 (en) | 1995-03-07 | 1996-09-12 | University Of Pittsburgh | A dry powder formulation for gene therapy |
| US6165463A (en) | 1997-10-16 | 2000-12-26 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
| KR19980703876A (ko) | 1995-04-14 | 1998-12-05 | 스티븐 엘. 허스트 | 분산성이 개선된 분말화된 약학적 조성물 |
| US6309671B1 (en) | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
| US6258341B1 (en) | 1995-04-14 | 2001-07-10 | Inhale Therapeutic Systems, Inc. | Stable glassy state powder formulations |
| US5780014A (en) | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
| US6019968A (en) | 1995-04-14 | 2000-02-01 | Inhale Therapeutic Systems, Inc. | Dispersible antibody compositions and methods for their preparation and use |
| US6190859B1 (en) | 1995-04-17 | 2001-02-20 | The United States Of America As Represented By The Secretary Of The Army | Method and kit for detection of dengue virus |
| GB9508691D0 (en) | 1995-04-28 | 1995-06-14 | Pafra Ltd | Stable compositions |
| US5904935A (en) | 1995-06-07 | 1999-05-18 | Alza Corporation | Peptide/protein suspending formulations |
| CN1245957C (zh) | 1995-06-07 | 2006-03-22 | 廓德伦特控股剑桥有限公司 | 将物质稳定掺入干燥泡沫玻璃基质中的方法以及由此制得的组合物 |
| US5611344A (en) | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
| NZ331865A (en) | 1996-03-18 | 1999-04-29 | Univ Wales Bangor Change Of Na | Apparatus with electrode arrays for carrying out chemical, physical or physico-chemical reactions |
| US5766520A (en) | 1996-07-15 | 1998-06-16 | Universal Preservation Technologies, Inc. | Preservation by foam formation |
| US6468782B1 (en) | 1996-12-05 | 2002-10-22 | Quadrant Healthcare (Uk) Limited | Methods of preserving prokaryotic cells and compositions obtained thereby |
| US5976574A (en) | 1996-12-31 | 1999-11-02 | Inhale Therapeutic Systems | Processes for spray drying hydrophobic drugs in organic solvent suspensions |
| US20030203036A1 (en) | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
| EP0991702B2 (en) | 1997-06-20 | 2017-07-19 | Coloplast A/S | A hydrophilic coating |
| US20030035778A1 (en) | 1997-07-14 | 2003-02-20 | Robert Platz | Methods and compositions for the dry powder formulation of interferon |
| US6423334B1 (en) | 1997-10-01 | 2002-07-23 | Elan Corporation, Plc | Composition and method for enhancing transport across gastrointestinal tract cell layers |
| US6655379B2 (en) | 1998-03-16 | 2003-12-02 | Nektar Therapeutics | Aerosolized active agent delivery |
| US6265384B1 (en) | 1999-01-26 | 2001-07-24 | Dale L. Pearlman | Methods and kits for removing, treating, or preventing lice with driable pediculostatic agents |
| US6630169B1 (en) | 1999-03-31 | 2003-10-07 | Nektar Therapeutics | Particulate delivery systems and methods of use |
| US6737066B1 (en) | 1999-05-06 | 2004-05-18 | The Immune Response Corporation | HIV immunogenic compositions and methods |
| MXPA02004193A (es) | 1999-10-29 | 2002-12-13 | Inhale Therapeutic Syst | Composiciones de polvo seco que tienen caracteristicas de dispersion mejoradas. |
| GB0011807D0 (en) | 2000-05-16 | 2000-07-05 | Quadrant Holdings Cambridge | Formulation for inhalation |
| AU2001281113B2 (en) | 2000-08-07 | 2006-07-20 | Nektar Therapeutics | Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation |
| CN1306195C (zh) * | 2000-09-07 | 2007-03-21 | Cmb工业公司 | 小长度套筒阀门 |
| JP3620479B2 (ja) | 2001-07-31 | 2005-02-16 | 株式会社島津製作所 | イオン蓄積装置におけるイオン選別の方法 |
| US6752893B2 (en) | 2001-09-28 | 2004-06-22 | Gentex Corporation | Rimless spectacles and method for making the same |
| EP1487407A4 (en) | 2002-03-12 | 2010-08-25 | Microdose Therapeutx Inc | SITE SPECIFICITY ADMINISTRATION OF MEDICAMENTS SIMULTANEOUSLY TAKEN BY INHALATION |
| WO2005067898A2 (en) | 2004-01-07 | 2005-07-28 | Nektar Therapeutics | Improved sustained release compositions for pulmonary administration of insulin |
-
1993
- 1993-09-29 WO PCT/US1993/009270 patent/WO1994007514A1/en active IP Right Grant
- 1993-09-29 BR BR9307141A patent/BR9307141A/pt not_active Application Discontinuation
- 1993-09-29 JP JP50928594A patent/JP3717925B2/ja not_active Expired - Fee Related
- 1993-09-29 EP EP93923742A patent/EP0679088B1/en not_active Expired - Lifetime
- 1993-09-29 KR KR1019950701209A patent/KR100291620B1/ko not_active Expired - Fee Related
- 1993-09-29 CZ CZ1995803A patent/CZ286632B6/cs not_active IP Right Cessation
- 1993-09-29 AT AT93923742T patent/ATE220327T1/de not_active IP Right Cessation
- 1993-09-29 DK DK93923742T patent/DK0679088T3/da active
- 1993-09-29 PT PT93923742T patent/PT679088E/pt unknown
- 1993-09-29 AU AU53496/94A patent/AU688283B2/en not_active Ceased
- 1993-09-29 ES ES93923742T patent/ES2179831T3/es not_active Expired - Lifetime
- 1993-09-29 NZ NZ257212A patent/NZ257212A/en not_active IP Right Cessation
- 1993-09-29 CA CA002145418A patent/CA2145418A1/en not_active Abandoned
- 1993-09-29 RU RU95112536A patent/RU2142815C1/ru not_active IP Right Cessation
- 1993-09-29 DE DE69332105T patent/DE69332105T2/de not_active Expired - Lifetime
-
1994
- 1994-04-25 US US08/232,849 patent/US5607915A/en not_active Expired - Lifetime
-
1995
- 1995-03-28 NO NO19951192A patent/NO322244B1/no not_active IP Right Cessation
- 1995-03-28 FI FI951465A patent/FI112917B/fi active
-
1996
- 1996-03-28 US US08/625,586 patent/US5814607A/en not_active Expired - Fee Related
-
1998
- 1998-08-03 US US09/128,401 patent/US6080721A/en not_active Expired - Fee Related
-
2000
- 2000-05-22 US US09/577,264 patent/US7456150B1/en not_active Expired - Fee Related
-
2002
- 2002-09-18 US US10/245,707 patent/US7300919B2/en not_active Expired - Fee Related
-
2007
- 2007-10-30 US US11/981,198 patent/US20080075782A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| FI951465L (fi) | 1995-05-10 |
| CA2145418A1 (en) | 1994-04-14 |
| NO322244B1 (no) | 2006-09-04 |
| US5607915A (en) | 1997-03-04 |
| US20080075782A1 (en) | 2008-03-27 |
| NZ257212A (en) | 1996-11-26 |
| NO951192D0 (no) | 1995-03-28 |
| CZ286632B6 (cs) | 2000-05-17 |
| ES2179831T3 (es) | 2003-02-01 |
| CZ80395A3 (en) | 1995-11-15 |
| JP3717925B2 (ja) | 2005-11-16 |
| ATE220327T1 (de) | 2002-07-15 |
| AU688283B2 (en) | 1998-03-12 |
| WO1994007514A1 (en) | 1994-04-14 |
| US7456150B1 (en) | 2008-11-25 |
| US5814607A (en) | 1998-09-29 |
| EP0679088A4 (en) | 1996-02-28 |
| KR100291620B1 (ko) | 2001-10-24 |
| NO951192L (no) | 1995-03-28 |
| BR9307141A (pt) | 1999-03-30 |
| FI951465A0 (fi) | 1995-03-28 |
| PT679088E (pt) | 2002-12-31 |
| US6080721A (en) | 2000-06-27 |
| DK0679088T3 (da) | 2002-10-28 |
| DE69332105T2 (de) | 2003-03-06 |
| RU2142815C1 (ru) | 1999-12-20 |
| JPH08504756A (ja) | 1996-05-21 |
| US7300919B2 (en) | 2007-11-27 |
| US20030171282A1 (en) | 2003-09-11 |
| EP0679088A1 (en) | 1995-11-02 |
| EP0679088B1 (en) | 2002-07-10 |
| AU5349694A (en) | 1994-04-26 |
| RU95112536A (ru) | 1996-12-20 |
| DE69332105D1 (de) | 2002-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI112917B (fi) | Menetelmä paratyroidihormonin biologisesti aktiivisia fragmentteja sisältävän farmaseuttisen koostumuksen valmistamiseksi | |
| JP3818852B2 (ja) | 肺への薬物送達 | |
| KR100620338B1 (ko) | 에어로졸형 활성 제제 전달 방법 | |
| CA2206657C (en) | Therapeutic preparation for inhalation containing parathyroid hormone, pth | |
| KR100419037B1 (ko) | 폐를통한인슐린의전달방법및그조성물 | |
| EP0951911A2 (en) | Method for administering aspb28-human insulin | |
| JP2003519664A (ja) | Ｇｌｐ−１誘導体の経上皮送達 | |
| WO1990009781A1 (en) | Therapeutic aerosol formulations | |
| JP2005521695A (ja) | 肺送達による成長ホルモンの投与方法 | |
| JP4721520B2 (ja) | エアロゾル噴射剤に溶解した薬剤 | |
| AU6189099A (en) | Insulin preparations for pulmonary delivery containing menthol | |
| US6635617B1 (en) | Insulin preparations for pulmonary delivery containing menthol | |
| WO2006006674A1 (ja) | Pthを含有する経粘膜投与剤 |