US20230390206A1 - Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces - Google Patents
Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces Download PDFInfo
- Publication number
- US20230390206A1 US20230390206A1 US18/235,592 US202318235592A US2023390206A1 US 20230390206 A1 US20230390206 A1 US 20230390206A1 US 202318235592 A US202318235592 A US 202318235592A US 2023390206 A1 US2023390206 A1 US 2023390206A1
- Authority
- US
- United States
- Prior art keywords
- active agent
- microparticles
- microparticle
- fdkp
- adsorption
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000011859 microparticle Substances 0.000 title claims abstract description 158
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000001965 increasing effect Effects 0.000 title claims description 14
- 239000013543 active substance Substances 0.000 title abstract description 144
- 239000013583 drug formulation Substances 0.000 title description 6
- BBNKIRVUCQNAQR-FETIZUMASA-N (e)-4-[4-[(2s,5s)-5-[4-[[(e)-3-carboxyprop-2-enoyl]amino]butyl]-3,6-dioxopiperazin-2-yl]butylamino]-4-oxobut-2-enoic acid Chemical compound OC(=O)\C=C\C(=O)NCCCC[C@@H]1NC(=O)[C@H](CCCCNC(=O)\C=C\C(O)=O)NC1=O BBNKIRVUCQNAQR-FETIZUMASA-N 0.000 claims description 81
- 229940094417 fumaryl diketopiperazine Drugs 0.000 claims description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 16
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 14
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 10
- 239000012530 fluid Substances 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 8
- 239000002550 vasoactive agent Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 abstract description 45
- 230000001737 promoting effect Effects 0.000 abstract description 10
- 230000002349 favourable effect Effects 0.000 abstract description 6
- 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 41
- 239000002245 particle Substances 0.000 description 41
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 36
- 229930105110 Cyclosporin A Natural products 0.000 description 36
- 108010036949 Cyclosporine Proteins 0.000 description 36
- 229960001265 ciclosporin Drugs 0.000 description 36
- 238000011068 loading method Methods 0.000 description 33
- 150000003839 salts Chemical group 0.000 description 33
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 26
- 108090000765 processed proteins & peptides Proteins 0.000 description 26
- 230000000694 effects Effects 0.000 description 25
- 230000000065 osmolyte Effects 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 108090000623 proteins and genes Proteins 0.000 description 24
- 108090000445 Parathyroid hormone Proteins 0.000 description 23
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 22
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 22
- 102000003982 Parathyroid hormone Human genes 0.000 description 22
- 230000003993 interaction Effects 0.000 description 22
- 229960001319 parathyroid hormone Drugs 0.000 description 22
- 239000000199 parathyroid hormone Substances 0.000 description 22
- 102000004877 Insulin Human genes 0.000 description 21
- 108090001061 Insulin Proteins 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 229940125396 insulin Drugs 0.000 description 20
- 239000003607 modifier Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 150000001298 alcohols Chemical class 0.000 description 19
- 102000004196 processed proteins & peptides Human genes 0.000 description 19
- 239000000126 substance Substances 0.000 description 18
- 230000002209 hydrophobic effect Effects 0.000 description 15
- 101800001586 Ghrelin Proteins 0.000 description 14
- 102400000442 Ghrelin-28 Human genes 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- BGHSOEHUOOAYMY-JTZMCQEISA-N ghrelin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)CN)C1=CC=CC=C1 BGHSOEHUOOAYMY-JTZMCQEISA-N 0.000 description 13
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000427 antigen Substances 0.000 description 10
- 102000036639 antigens Human genes 0.000 description 10
- 108091007433 antigens Proteins 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000012296 anti-solvent Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- -1 but not limited to Chemical compound 0.000 description 7
- 230000009881 electrostatic interaction Effects 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 230000002685 pulmonary effect Effects 0.000 description 7
- 238000012377 drug delivery Methods 0.000 description 6
- 229940051250 hexylene glycol Drugs 0.000 description 6
- 229920002521 macromolecule Polymers 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 5
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 5
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 5
- 238000001694 spray drying Methods 0.000 description 5
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 3
- 230000003196 chaotropic effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 230000001627 detrimental effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000000053 physical method Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- IPJDHSYCSQAODE-UHFFFAOYSA-N 5-chloromethylfluorescein diacetate Chemical compound O1C(=O)C2=CC(CCl)=CC=C2C21C1=CC=C(OC(C)=O)C=C1OC1=CC(OC(=O)C)=CC=C21 IPJDHSYCSQAODE-UHFFFAOYSA-N 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102100038803 Somatotropin Human genes 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000009878 intermolecular interaction Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000006174 pH buffer Substances 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000013223 sprague-dawley female rat Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- KWPACVJPAFGBEQ-IKGGRYGDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]pyrrolidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)CCl)C1=CC=CC=C1 KWPACVJPAFGBEQ-IKGGRYGDSA-N 0.000 description 1
- NTUPOKHATNSWCY-PMPSAXMXSA-N (2s)-2-[[(2s)-1-[(2r)-2-amino-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-PMPSAXMXSA-N 0.000 description 1
- NUYHTXOPSQBZKC-UHFFFAOYSA-N 3,6-bis(4-aminobutyl)piperazine-2,5-dione Chemical compound NCCCCC1NC(=O)C(CCCCN)NC1=O NUYHTXOPSQBZKC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101001095088 Homo sapiens Melanoma antigen preferentially expressed in tumors Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 108010029660 Intrinsically Disordered Proteins Proteins 0.000 description 1
- 102100037020 Melanoma antigen preferentially expressed in tumors Human genes 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100037686 Protein SSX2 Human genes 0.000 description 1
- 101710149284 Protein SSX2 Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- CJNCVBHTDXKTMJ-CYDGBPFRSA-N Ser-Asp-Lys-Pro Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(O)=O CJNCVBHTDXKTMJ-CYDGBPFRSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229960004717 insulin aspart Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- BGEHHDVYQRNMJB-UHFFFAOYSA-N morpholine;sulfuric acid Chemical class OS([O-])(=O)=O.C1COCC[NH2+]1 BGEHHDVYQRNMJB-UHFFFAOYSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000025402 neoplasm of esophagus Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 229940124272 protein stabilizer Drugs 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- 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
-
- 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
- A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
-
- 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
- A61K38/26—Glucagons
-
- 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
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- 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
- A61K38/28—Insulins
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
-
- 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
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- 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
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- This invention relates to drug formulations and is particularly related to methods. More specifically, binding or adsorbing active agents onto the surface of crystalline microparticles is disclosed.
- a broad range of drug formulation systems have been developed to address the problem of optimal drug delivery and are based on incorporation of drug into a matrix that acts as a carrier.
- Factors considered in drug formulation include requirements that the system be non-toxic and non-reactive with the drug to be delivered, economical to manufacture, formed of readily available components, and consistent with respect to final composition and physical characteristics, including stability and release rate. It is also preferable that the drug delivery system is formed of materials easily removed from the body by normal physiologic processes.
- microparticles are coated with an active agent by modifying the system comprising the microparticles and the dissolved active agent such that the active agent has a greater affinity for the microparticle surface than for remaining in solution.
- the present invention seeks to further promote the adsorption of an active agent to the microparticle surface by modifying/utilizing the properties of the active agent under a number of conditions in solution.
- a method for promoting binding of an active agent to a preformed crystalline microparticle in suspension comprising the steps of: i) modifying the chemical potential of the active agent wherein the modifying allows for an energetically favorable interaction between the active agent and microparticle independent of removal of solvent; and ii) adsorbing the active agent onto the surface of the microparticle.
- modifying the chemical potential comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent, individually or in combination.
- Modifying the chemical potential of the active agent comprises altering solution conditions. Altering solution conditions comprises adding an active agent modifier to the solution.
- the active agent modifier is selected from the group consisting of salts, surfactants, ions, osmolytes, alcohols, chaotropes, kosmotropes, acids, bases, and organic solvents.
- the salt is sodium chloride.
- the method further comprises the step of dissolving the active agent in the fluid phase of a suspension of microparticles and changing the pH of the fluid phase.
- the step of dissolving the active agent in a fluid phase refers to the dissolving of a solid.
- the step of dissolving the active agent refers to the addition of a concentrated solution of the active agent.
- the active agent modifier improves the structural stability of the active agent.
- the active agent is a protein, peptide, polypeptide, small molecule, or nucleic acid molecule.
- the active agent is selected from the group consisting of insulin, ghrelin, growth hormone, and parathyroid hormone (PTH).
- the active agent can comprise an antibody or antibody fragment.
- the antibody can recognize a disease-associated antigen including, without limitation, a tumor-associated antigen or an infectious pathogen-related antigen.
- the small molecule is an ionizable molecule or a hydrophobic molecule such as, but not limited to, cyclosporin A.
- modifying the chemical potential of the active agent comprises modulating one or more energetically favorable interactions such as, but not limited to, electrostatic interactions, hydrophobic interactions, and/or hydrogen bonding interactions between the active agent and the microparticle surface.
- the microparticle comprises a diketopiperazine such as, but not limited to, fumaryl diketopiperazine.
- the method further comprises a step for removing or exchanging the solvent.
- Solvent refers to the fluid medium in which the active agent and microparticle are “bathed.” It should not be interpreted to require that all components are in solution. Indeed in many instances it may be used to refer to the liquid medium in which the microparticles are suspended.
- the powder can be, for example, filtered but not dried.
- the process of modifying the chemical potential of the active agent allows for interaction between the active agent and a microparticle.
- modifying the chemical potential of the active agent comprises adding an active agent modifier to the solution.
- an active agent modifier can be selected from the group consisting of salts, surfactants, ions, osmolytes, alcohols, chaotropes, kosmotropes, acid, base, and organic solvents.
- the modifier decreases the solubility of the active agent molecule, promotes association between the active agent and a microparticle such as a diketopiperazine particle, and/or improves the structural stability of the active agent molecule.
- FIGS. 1 A- 1 C depict the effects of chaotropes and kosmotropes on loading curves for active agents onto fumaryl diketopiperazine (FDKP) microparticles as a function of pH and 100 mM chaotropic/kosmotropic agent according to the teachings of the present invention.
- FIG. 1 A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of chaotropes and kosmotropes at pH 3.0-5.0.
- FIG. 1 A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of chaotropes and kosmotropes at pH 3.0-5.0.
- FIG. 1 B depicts the loading of 0.25 mg/mL glucagon-like peptide 1 (GLP-1) onto 5 mg/mL FDKP microparticles in the presence of chaotropes and kosmotropes at pH 2.0-4.0.
- FIG. 1 C depicts the loading of 0.25 mg/mL parathyroid hormone (PTH) onto 5 mg/mL FDKP microparticles in the presence of the strong chaotropes, NaSCN and NaClO4, between pH 4.0-5.0.
- GLP-1 glucagon-like peptide 1
- PTH parathyroid hormone
- FIGS. 2 A- 2 C depict the effects of osmolytes on loading curves for active agents onto FDKP microparticles as a function of pH and osmolytes (100 mM) according to the teachings of the present invention.
- FIG. 2 A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of osmolytes at pH 3.0-5.0.
- FIG. 2 B depicts the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles in the presence of osmolytes between pH 2.0-4.0.
- FIG. 2 C depicts the loading of 0.10 mg/mL ghrelin peptide onto 5 mg/mL FDKP microparticles in the presence of strong osmolytes at pH 4.0-5.0.
- FIGS. 3 A- 3 D depict the effects of alcohols on loading curves for active agents onto FDKP microparticles as a function of pH and alcohols according to the teachings of the present invention.
- FIG. 3 A depicts the loading of 0.10 mg/mL ghrelin onto 5 mg/mL FDKP microparticles in the presence of hexafluoroisopropanol (HFIP) at 5%, 10%, 15%, and 20% v/v between pH 2.0-4.0.
- FIG. 3 B depicts the loading of 0.10 mg/mL ghrelin onto 5 mg/mL FDKP microparticles in the presence of trifluoroethanol (TFE) at 5%, 10%, 15%, and 20% v/v between pH 2.0-4.0.
- FIGS. 3 C and 3 D depict the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles at pH 2.0-5.0 in the presence of HFIP and TFE, respectively.
- FIGS. 4 A- 4 D depict the effects of salt on loading curves for active agents onto FDKP microparticles as a function of pH and NaCl concentration according to the teachings of the present invention.
- FIG. 4 A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH 2.0-5.0.
- FIG. 4 B depicts the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH 2.0-5.0.
- FIG. 4 A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH 2.0-5.0.
- FIG. 4 B depicts the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH
- FIG. 4 C depicts the loading of 0.25 mg/mL PTH peptide onto 5 mg/mL FDKP microparticles in the presence of 0-1000 mM NaCl at pH 2.0-5.0.
- FIG. 4 D depicts the secondary structural analysis of PTH at various salt concentrations (20° C.).
- the far-UV CD of 4.3 mg/mL PTH at pH 5.8 illustrates that as the concentration of NaCl increases the secondary structure of the peptide adopts a more helical conformation.
- FIGS. 5 A- 5 B depict the adsorption of hydrophobic molecules onto microparticles according to the teachings of the present invention.
- FIG. 5 A depicts the binding of cyclosporin A to FDKP microparticles with increasing anti-solvent (water) at 60%, 80% and 90% concentration.
- FIG. 5 B depicts the percent of theoretical maximum load achieved for cyclosporin A at varying mass ratios of cyclosporin A/FDKP microparticles in the presence of 90% anti-solvent.
- FIG. 6 depicts the pharmacokinetics of single intravenous injection (IV) and pulmonary insufffaltion (IS) in rats using various mass ratios of cyclosporin A/FDKP microparticles at 90% anti-solvent according to the teachings of the present invention.
- Described herein are methods useful for stabilizing pharmaceutical active agents in combination with crystalline microparticles.
- the resulting compositions provide stable active agents coated onto the crystalline microparticle surfaces.
- active agent The substance to be coated or adsorbed onto the crystalline microparticle is referred to herein as active agent.
- classes of active agent include pharmaceutical compositions, synthetic compounds, and organic macromolecules that have therapeutic, prophylactic, and/or diagnostic utility.
- active agents can be coated or adsorbed onto the surface of crystalline microparticles including, but not limited to, organic macromolecules, nucleic acids, synthetic organic compounds, polypeptides, peptides, proteins, polysaccharides and other sugars, and lipids.
- Peptides, proteins, and polypeptides are all chains of amino acids linked by peptide bonds. Peptides are generally considered to be less than 30 amino acid residues but may include more. Proteins are polymers that can contain more than 30 amino acid residues.
- the term polypeptide as is know in the art and as used herein, can refer to a peptide, a protein, or any other chain of amino acids of any length containing multiple peptide bonds, though generally containing at least 10 amino acids.
- the active agents used in the coating formulation can fall under a variety of biological activity classes, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antivirals, antigens, and antibodies.
- active agents examples include, in a non-limiting manner: growth hormone, antibodies and fragments thereof alkynes, cyclosporins (e.g. cyclosporin A), PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone, CMFDA (5-chloromethylfluorescein diacetate), Texas Red, clopiogrel, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), ghrelin, parathyroid hormone (PTH), insulin and insulin analogs (e.g., aspart insulin and insulin) and antibodies and fragments thereof, including, but not limited to: humanized or chimeric antibodies; F(ab), F(ab)2, or single-chain antibody alone or fused to other polypeptides; therapeutic or diagnostic monoclonal antibodies to cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell
- Non-limiting examples of antibodies to tumor antigens include anti-SSX-241-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME (preferentially expressed antigen of melanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen), anti-tyrosinase (melanoma tumor associated antigen), and anti-MOPC-21 (myeloma plasma—cell protein).
- anti-SSX-241-49 synovial sarcoma, X breakpoint 2
- anti-NY-ESO-1 esophageal tumor associated antigen
- anti-PRAME preferentially expressed antigen of melanoma
- anti-PSMA prostate-specific membrane antigen
- anti-Melan-A melanoma tumor associated antigen
- anti-tyrosinase melanoma tumor
- microparticle refers to a particle with a diameter of
- microspheres refers to microparticles with uniform spherical shape.
- Crystalline microparticles as used herein refers to microparticles that have the internal structure, though not necessarily the external form, of a crystal and have a regular arrangement of atoms in a space lattice.
- Ionizable crystalline surfaces refer to crystalline microparticles that have the additional capacity to carry an electrical charge.
- the microparticle can be a single regularly shaped crystal.
- the microparticle is irregularly shaped, is porous, has dissolved active agent-accessible interior surfaces, or comprises multiple crystals, in any combination. Such characteristics will generally increase surface area and thereby loading capacity. Such characteristics can also contribute to advantageous aerodynamic properties, important if the active agent is to be delivered by inhalation of a dry powder comprising the microparticles.
- the chemical substance composing the crystalline microparticle is reversibly reactive with the active agent to be delivered, non-toxic, as well as non-metabolized by rodents and humans.
- the active agent to be delivered, non-toxic, as well as non-metabolized by rodents and humans.
- some levels of toxicity are tolerable, depending, for example, on the severity of the condition to be treated or the amount of the substance to which a patient is exposed.
- the substance be completely metabolically inert.
- the crystalline structure of preferred microparticles is not substantially disrupted in the process of coating or binding with active agent.
- the composition of the crystalline microparticle determines what type of chemical interactions can be manipulated to drive adsorption of an active agent to the microparticle surface.
- microparticles as such have surfaces, the properties of which can be manipulated in the coating process as disclosed in copending U.S. patent application Ser. No. 11/532,063 (Attorney Docket No. 51300-00025), filed on the same date as the instant application, and U.S. Provisional Application Ser. No. 60/717,524 filed on Sep. 14, 2005, each of which is hereby incorporated by reference in its entirety.
- Representative materials from which crystalline microparticles can be formed include, but are not limited to, aromatic amino acids, or compounds with limited solubility in a defined pH range such as diketopiperazines and morpholine sulfates.
- microparticles as contemplated in the present invention are diketopiperazine (DKP) microparticles. As discussed herein, DKP microparticles are employed to facilitate the adsorption of the active agent.
- DKP diketopiperazine
- DKP diketopiperazine
- FDKP fumaryl diketopiperazine
- E 3-,6-bis[4-(N-carboxy-2-propenyl)amidobutyl]-2,5-diketopiperazine
- diketomorpholines and diketodioxanes forms microparticles with desirable size distributions and pH ranges as well as good payload tolerance.
- a wide range of stable, reproducible characteristics can be generated with appropriate manipulations of the substituent groups.
- These patents disclosed precipitation of the DKP in the presence of the active agent to form microparticles comprising the active agent. Further details for synthesis, preparation, and use of diketopiperazines and diketopiperazine microparticles are disclosed in U.S. Pat. Nos. 6,071,497; 6,331,318; 6,428,771 and U.S. Patent Publication Nos.
- compositions comprising diketopiperazine particles are disclosed in U.S. Pat. No. 6,991,779 and U.S. Patent Publication No. 20040038865; each incorporated herein by reference in their entirety.
- diketopiperazines contemplated in the present invention include 3,6-di(4-aminobutyl)-2,5-diketopiperazine; 3,6-di(succinyl-4-aminobutyl)-2,5-diketopiperazine (succinyl diketopiperazine or SDKP); 3,6-di(maleyl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(citraconyl-4-aminobutyl)-2-5-diketopiperazine; 3,6-di(glutaryl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(malonyl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(oxalyl-4-aminobuty))-2,5-diketopiperazine and derivatives therefrom.
- Diketopiperazine salts may also be utilized in the present invention and may included, for example, a pharmaceutically acceptable salt such as the Na, K, Li, Mg, Ca, ammonium, or mono-, di- or tri-alkylammonium (as derived from triethylamine, butylamine, diethanolamine, triethanolamine, or pyridines, and the like).
- the salt may be a mono-, di-, or mixed salt. Higher order salts are also contemplated for diketopiperazines in which the R groups contain more than one acid group.
- a basic form of the agent may be mixed with the diketopiperazine in order to form a salt linkage between the drug and the diketopiperazine, such that the drug is a counter cation of the diketopiperazine.
- DKP salts for drug delivery are disclosed in a further detail in U.S. Patent Application Publication No. 20060040953 which is herein incorporated by reference in its entirety.
- Adsorbing active agent to the surface of a crystalline microparticle can involve
- altering the properties of the active agent in a solution or fluid suspension under various solution conditions thereby promoting adsorption to the microparticle surface and reducing the amount of active agent remaining in solution.
- Alteration or modifications to the active agent may occur with the use of modifiers such as, but not limited to, chaotropes and kosmotropes, salts, organics such as, but not limited to, alcohols, osmolytes, and surfactants.
- modifiers can act on the active agent to alter its chemical potential and thereby its structure, flexibility, rigidity or stability, without chemically altering the agent itself.
- the term “chemical potential” is well known to one of ordinary skill.
- “chemical potential” refers to the free energy necessary to drive a chemical reaction such as, for example, interaction between an active agent and a solvent or the adsorption of active agent onto a microparticle.
- the term “energetically favorable” as used herein refers to the lowering of the free energy levels of the absorbed states of the active agent onto the microparticle in relation to the free energy level of uncoated microparticle, or unbound active agent and/or the insoluble forms (including aggregation or precipitation) of the active agent.
- structure refers to the secondary structure of the active agent molecule and includes the alpha-helical formation, beta sheets, or random coil (unordered) of the active agent molecule, such as a protein.
- structure may also include teritary and quaternary structures of the molecule but is not limited to such and may also refer to the self association, aggregation, multimerization, dimerization, and the like, of a molecule.
- stability refers to the stabilization or destabilization of the structure of the active agent in the presence of the modifier.
- altering the properties of the active agent in a solution or fluid suspension are likely to affect the interactions due to hydrophobic properties, hydrogen bonding properties, and electrostatic properties of the active agent and/or microparticle.
- Hydrophobic interactions are associations of non-polar groups with each other in aqueous solutions because of their insolubility in water. Hydrophobic interactions can affect a number of molecular processes including, but not limited to, structure stabilization (of single molecules, complexes of two or three molecules, or larger assemblies) and dynamics, and make important contributions to protein-protein and protein-ligand binding processes. These interactions are also known to play a role in early events of protein folding, and are involved in complex assembly and self-assembly phenomena (e.g., formation of membranes).
- Hydrogen bonding interactions are especially strong dipole-dipole forces between molecules; a hydrogen atom in a polar bond (e.g., H—F, H—O or H—N) can experience an attractive force with a neighboring electronegative molecule or ion, which has an unshared pair of electrons (typically an F, O, or N atom on another molecule). Hydrogen bonds are responsible for the unique properties of water and are very important in the organization of biological molecules, especially in influencing the structure of proteins and DNA.
- a hydrogen atom in a polar bond e.g., H—F, H—O or H—N
- Hydrogen bonds are responsible for the unique properties of water and are very important in the organization of biological molecules, especially in influencing the structure of proteins and DNA.
- Electrostatic interactions are attractions between opposite charges or repulsions between like charges that grow stronger as the charges come closer to each other. Electrostatic interactions constitute a key component in understanding interactions between charged bodies in ionic solutions. For example, the stability of colloidal particles dispersed in a solvent can be explained by considering the competition between repulsive electrostatic interactions and the attractive van der Waals interactions. Electrostatic interactions are also of importance when considering interaction and adhesion between particles.
- the properties of the active are in some embodiments of the present invention.
- a salt such as, but not limited to, sodium chloride.
- Active agents for example, PTH and GLP-1, undergo noticeable structural changes in the presence of salt. As shown in Example 5 ( FIG. 4 D ), the presence of salt increases the secondary structure of PTH by promoting a more helical conformation of the peptide. Salt has also been shown to affect the structure of GLP-1, as disclosed in U.S. Provisional Patent Application, Ser. No. 60/744,882, filed on Apr. 14, 2006 and incorporated herein by reference in its entirety.
- salts and other ionic compounds are capable of either stabilizing or destabilizing proteins and peptides, especially when the difference between the pH of the solution and the pI of the protein or peptide becomes greater, by binding to specifically charged residues (Antosiewiez J, et al., J. Mol. Biol. 238:415-436, 1994).
- Chaotropes as are well known in the art, are ions that exhibit weak
- chaotropes include, but are not limited to, NaSCN, (CH3)3N—HCl, Na2NO3, and NaClO4 and cesium chloride (CsCl).
- Kosmotropes or lyotropes are ions that display strong interactions with water and generally stabilize macromolecules such as proteins and peptides. This stabilization effect is brought about by increasing the order of water and increasing its surface tension.
- kosmotropes include, but are not limited to, sodium citrate (Na Citrate), and sodium sulfate (Na2SO4).
- Another class of modifier of active agent employed in the present invention is
- Alcohols are able to disrupt the native structure of proteins and peptides and are also able to stabilize and induce 0-helical conformations in macromolecules, most notably within unstructured proteins and polypeptides.
- Such alcohols may include, but are not limited to, methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), and hexafluoroisopropanol (HFIP).
- MeOH methanol
- EtOH ethanol
- TFE trifluoroethanol
- HFIP hexafluoroisopropanol
- TFE and HFIP are two of the most potent alcohols for inducing helical transitions in peptides and proteins (Hirota et al., Protein Sci., 6:416-421; 1997, incorporated herein by reference for all it contains regarding helical transitions in peptides and proteins).
- Osmolytes as are well known to the skilled artisan, are small compounds that are produced by the cells of most organisms in high stress situations (such as extreme temperature fluctuations, high salt environments, etc.) to stabilize their macromolecules. They do not interact with the macromolecule directly but act by altering the solvent properties in the cellular environment and so their presence indirectly modifies the stability of proteins. These compounds include various polyols, sugars, polysaccharides, organic solvents, and various amino acids and their derivatives.
- Osmolytes as contemplated in the present invention, include in a non-limiting manner, hexylene-glycol (Hex-Gly), trehalose, glycine, polyethylene glycol (PEG), trimethylamine N-oxide (TMAO), mannitol, and proline.
- the components of this system may be combined in any order.
- the modifier and active agent are combined with each other prior to that mixture being combined with a suspension of microparticles.
- the agent and microparticles are first combined and then the modifier is added.
- the active agent or modifier is provided and combined with another component, or components, as a solution.
- any of the components can be provided in solid form and dissolved, or in the case of the microparticles, suspended, in the liquid medium containing another of the components. Further variations will be apparent to one of skill in the art.
- the microparticles are formed prior to being combined with the other components of the system, and as such are present as a suspension. Nonetheless the liquid medium in which the microparticles are suspended is at times referred to herein as a solvent.
- the liquid medium utilized in the method is most often aqueous. However in some instances the liquid medium can comprise more of an organic compound, for example an alcohol used as a modifier, than it does water.
- the active agent Upon assembly of all components of the system, the active agent will adsorb to the surface of the microparticle. In increasingly preferred embodiments of the present invention, at least 50, 60, 70, 80, 90, 95%, or substantially all, of the active agent in the system will adsorb to the microparticles, up to 100%. In some embodiments of the present invention, the accessible surface area of the microparticles with be sufficient for all of the adsorbed active agent to be in direct contact with the microparticle surface, that is, the coating is a monolayer. However it is to be understood that additional interactions can be present. In some instances, for example, self-association of the active agent can also be energetically favored so that multiple layers of active agent coat the particle.
- Multimerization is characterized by specific intermolecular interactions and fixed stoichiometry.
- Aggregation is characterized by unspecific intermolecular interactions and undefined stoichiometry.
- multimeric active agents can be adsorbed in the multimeric state, or dissociated into monomers, or lower order multimers, and adsorbed to the surface in that state. In either case aggregation can mediate layering of the active agent onto the microparticle.
- the loaded microparticles constitute a drug delivery composition that can be utilized in a variety of forms.
- the particles can be used as powders, in solid dosage forms such as tablets or contained in capsules, or suspended in a liquid carrier. Generally this will require exchange and/or removal of the liquid medium in which the loading took place. This can be accomplished by any of a variety of means including physical methods such as, but not limited to, sedimentation or filtration, and evaporative methods such as, but not limited to, lyophilization or spray-drying. These techniques are known to those skilled in the art. In one embodiment of the present invention, solvent is removed by spray-drying. Methods of spray-drying diketopiperazine microparticles are disclosed in, for example, U.S. Provisional Patent Application No. 60/776,605 filed on Feb. 22, 2006, incorporated by reference herein for all it contains regarding spray-drying diketopiperazine microparticles.
- embodiments of the invention using physical methods of solvent removal will typically loose the unadsorbed active agent, but for example can be useful to ensure that coating does not progress beyond a monolayer.
- embodiments using evaporative drying for solvent removal can in some cases deposit additional active agent on the particle and thereby avoid its loss, but the adsorptive interactions involved can differ from those established by the molecules bound in the earlier steps of the method.
- evaporative solvent removal does not result in significant further deposition of active agent, including the case in which substantially all of the active agent was already adsorbed to the particle.
- the active agents insulin, PTH, ghrelin and GLP-1 were either purchased from American Peptide (Sunnyvale, CA) or AnaSpec (San Jose, CA), or prepared in house (MannKind Corporation, Valencia, CA). Aqueous samples at varying pH and at 20° C. (unless otherwise noted) were analyzed. Samples were generally prepared fresh and were mixed with the particular additive (e.g., salt, pH buffer, etc., if any), prior to the addition of FDKP microparticles.
- the particular additive e.g., salt, pH buffer, etc., if any
- DKP diketopiperazine
- Varying conditions promoting adsorption of active agent onto the surfaces of preformed FDKP particles were studied.
- a 15 mg/mL FDKP microparticle suspension was combined with 3 X pH buffer and 3 ⁇ solution of an additive or excipient.
- the final solution contained a FDKP microparticle concentration of 5 mg/mL and a GLP-1 concentration of 0.25 mg/mL (5% w/w), or a PTH concentration of 0.25 mg/mL (5% w/w), or an insulin concentration of 0.75 mg/mL (15% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w).
- Unbound active agent in the supernatant was filtered off the suspension.
- the FDKP particles with the associated active agent were dissolved (reconstituted) in 100 mM ammonium bicarbonate and filtered to separate out any aggregated active agent molecules.
- the amount of active agent in both the supernatant and reconstituted fractions was quantitated by HPLC.
- a series of experiments were conducted in which conditions employed included use of additives such as salts, osmolytes, chaotropes and kosmotropes, and alcohols. The results from these studies are described below.
- Ionic species that affect the structure of water and proteins were studied to investigate the adsorption of active agent onto a FDKP microparticle surface by a hydrophobic mechanism (at low pH).
- Loading of the active agent onto FDKP particles was performed at 5 mg/mL microparticles and a GLP-1 concentration of 0.25 mg/mL (5% w/w), or a PTH concentration of 0.25 mg/mL (5% w/w), or an insulin concentration of 0.75 mg/mL (15% w/w).
- the concentration of the chaotrope or kosmotrope in the samples was held constant at 100 mM and the pH varied from 2.0 to 5.0.
- Chaotropes or kosmotropes were selected from the following: NaSCN, CsCl, Na2SO4, (CH3)3N—HCl, Na2NO3, Na Citrate, and NaClO4. The control indicates no chaotrope or kosmotrope were added.
- FIGS. 1 A- 1 C depict the loading curves for insulin, GLP-1 and PTH respectively, onto the FDKP microparticle surface as a function of pH in the presence of the various chaotropes or kosmotropes.
- pH 3.0
- pH 4 this effect was not observed (FIG.
- the chaotropes and kosmotropes interfered with the adsorption of insulin to the microparticle surface, as compared to control, by precipitating the insulin protein.
- these agents promoted binding of insulin to the FDKP particles at lower pH, but have little or even a detrimental effect at the higher pH conditions.
- GLP-1 in the presence of chaotropes and kosmotropes, showed an improved affinity for the FDKP microparticles at pH 2.0-4.0 with a greater effect at lower pH ( FIG. 1 A ). Similar observations were disclosed in U.S. Provisional Application Ser. No. 60/744,882. There it was noted, that approximately 0.02-0.04 mg/mL of the GLP-1 peptide (which corresponds to mass ratios of 0.004 to 0.008) was detected in the reconstituted microparticle-free control samples in the presence of NaSCN, NaClO4, Na2SO4, NaNO3 and Na citrate, indicating that a small proportion of the GLP-1 precipitated rather than adsorbing to the particle.
- the affinity of PTH for the FDKP microparticle surface was greater at pH of 4.0 to about 4.5 in the presence of strong chaotropes NaSCN and NaClO4 ( FIG. 1 C ).
- chaotropic and kosmotropic agents play a role in promoting adsorption of the active agent to FDKP microparticle surfaces, most notably at low pH. Since these modifiers have a greater effect at low pH, where the microparticle surface is less ionic, it is likely that adsorption results from a hydrophobic mechanism. The decrease in adsorption observed at higher pH may result from the more highly charged surface of the particle in combination with effects chaotropic and kosmotropic agents have on increasing the hydrophobicity of the active agents. Additionally, as ionic species, these agents may compete with the active agent for binding to the microparticle, or disrupt the electrostatic interactions between the active agent and the microparticle. Finally it is also noted that Debye shielding can contribute to the decrease in adsorption to the more highly charged surface.
- FIGS. 2 A- 2 C show the loading curves for insulin ( FIG. 2 A ), GLP-1 ( FIG. 2 B ) and ghrelin ( FIG. 2 C ) onto FDKP particles as a function of pH in the presence of common stabilizers (osmolytes).
- Loading of the active agent onto FDKP microparticles was performed at 5 mg/mL of microparticles and an insulin concentration of 0.75 mg/mL (15% w/w), or a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w).
- the concentration of the osmolyte (stabilizer) in the samples was held constant at 100 mM and the pH varied from about 2.0 to about 5.0.
- the osmolytes were selected from hexylene-glycol (Hex-Gly), trehalose, glycine, PEG, TMAO, mannitol and proline; the control indicates no osmolyte.
- insulin showed significantly improved affinity for the FDKP particle surface in the presence of osmolytes (PEG, glycine, trehalose, mannitol and Hex-Gly) over a pH range of 3.0 to 5.0 ( FIG. 2 A ).
- PEG and proline improved the affinity for adsorption of the GLP-1 onto FDKP particle surface over a pH range from 2.0 to 4.0.
- the osmolyte TMAO was more effective than PEG or proline at binding GLP-1 onto the FDKP microparticle surface at low pH (2.0) but was modestly detrimental at pH 3.0 and above ( FIG. 2 B ).
- Ghrelin however, showed greater affinity for the microparticle surface in the presence of 100 mM mannitol, PEG, glycine, Hex-Gly, and trehalose when compared to the control over the pH range of about 4.0 to 5.0 ( FIG. 2 C ).
- Alcohols known to induce helical conformation in unstructured peptides and proteins by increasing hydrogen-bonding strength were evaluated to determine the role that helical confirmation plays in adsorption of active agent to FDKP particles surface.
- Active agents such as GLP-1 and ghrelin were analyzed. Loading of the active agent on FDKP particles was performed at 5 mg/mL of microparticles and a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w).
- the effect of each alcohol was observed over a pH range of 2.0 to 5.0.
- the alcohols used were trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP). Each alcohol was evaluated at varying concentrations which include 5%, 10%, 15%, or 20% v/v.
- FIGS. 3 A- 3 D show the loading curves for active agent onto FDKP microparticles as a function of pH for each alcohol and each active agent.
- pH 2.0-4.0 ghrelin showed greatly improved affinity for the microparticle surface in the presence of HFIP and TFE at all concentrations tested (5%, 10%, 15% and 20%), as demonstrated by the mass ratio of ghrelin to FDKP particles ( FIGS. 3 A- 3 B ).
- GLP-1 showed improved affinity for the microparticle surface in the presence of HFIP and TFE at the concentrations shown (5% and 10%) ( FIGS. 3 C- 3 D ).
- the effect of TFE was less pronounced, and at the lower pHs tested was detrimental. It was noted that a substantial amount of GLP-1 peptide (0.13-0.19 mg/mL, which corresponds to mass ratios of 0.026 to 0.038) was detected in the reconstituted microparticle-free control samples in the presence of 10% HFIP and TFE at pH 4.0, indicating that some of the GLP-1 had precipitated.
- Loading of the active agent onto FDKP microparticles was performed at 5 mg/mL of microparticles and an insulin concentration of 0.75 mg/mL (15% w/w), or a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a PTH concentration of 0.25 mg/mL (5% w/w) in the presence of 0, 25, 50, 100, 250, and 500 mM NaCl ( FIGS. 4 A- 4 C ).
- Loading of PTH onto FDKP particles was also assessed at 1000 mM NaCl.
- the amount of active agent detected in reconstituted microparticle-free control samples as a function of pH and NaCl concentration was assessed. The pH was controlled with a 20 mM potassium phosphate/20 mM potassium acetate mixture.
- salt is capable of altering the structure of active agents.
- circular dichroism measurements with PTH showed that as the salt concentration increased the secondary structure of the peptide adopted a more helical conformation ( FIG. 4 D ). This suggests that change in the structure of PTH may promote its binding to the microparticle surface at low pH.
- Cyclosporin A a lipophilic cyclic polypeptide, was studied in order to show how a hydrophobic molecule can be made to adsorb to microparticles.
- the size of cyclosporin A (1202.61 MW) was utilized to demonstrate the loading capacities of microparticles for smaller compounds.
- a solvent/anti-solvent method was employed.
- the basic principle of this methodology is to dissolve the compound in a solvent (methanol) and then use anti-solvent (water) to drive the compound out of solution and onto the surface of the microparticles. Utilizing this solvent/anti-solvent approach, cyclosporin A was successfully loaded onto the surface of microparticles.
- FDKP microparticles were suspended in methanol solutions of cyclosporin A. Water was then added in a stepwise fashion to final concentrations of 60, 80, and 90%. Half of the sample was pelleted and the other half lyophilized. Each half was then redissolved such that the final percentages were 20% FDKP microparticles/cyclosporin A, 20% 0.5 M ammonium bicarbonate (AmBicarb), and 60% methanol (the concentrations necessary for the dissolution of both microparticle and cyclosporin A). The cyclosporin A content of each was analyzed by HPLC and compared to determine the proportion that had become adsorbed to the particle. The results are presented in FIG. 5 A .
- the loading capacity of the microparticles for cyclosporin A was analyzed at the 90% anti-solvent level by varying the input of cyclosporin A so that the final content of the recovered solids would be from 2% to 20%, assuming all of the cyclosporin A became adsorbed. It was observed that as the input increased over this range the percent of available cyclosporin A bound to the microparticle increased from 50% to 95% of the input ( FIG. 5 B ). It is to be noted that, taking into account that the solubility of cyclosporin A is 0.05 mg/mL at 90% H2O, these results indicated that substantially all of the insoluble cyclosporin A became adsorbed to the particles rather than precipitating out.
- cyclosporin A/FDKP microparticles To examine the pharmacokinetics of cyclosporin A/FDKP microparticles, plasma concentrations of cyclosporin A were evaluated in female Sprague Dawley rats administered various formulations of cyclosporin A/FDKP microparticles via pulmonary insufflation or intravenous injection. These studies were conducted using cyclosporin A/FDKP microparticles made at 90% anti-solvent and a theoretical maximum mass ratio of 0.05, 0.10 or 0.20 as described in the example above. These are referred to as the 5%, 10% and 20% loads.
- a single dose of 2.5 mg cyclosporin A/FDKP microparticles was delivered to eight groups of rats via pulmonary insufflation or intravenous injection. Blood samples were taken on the day of dosing for each group at pre-dose (time 0), and at 5, 20, 40, 60, 240, 480 minutes and at 24 hrs post dose. At each time point, approximately 100 eL whole blood was collected from the lateral tail vein into a cryovial, inverted and stored on ice. Blood samples were centrifuged at 4000 rpm and approximately 40 eL plasma was pipetted into 96-well plates which were stored at ⁇ 80° C. until analyzed.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Inorganic Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Virology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Methods are provided for promoting the adsorption of an active agent to microparticles by modifying the structural properties of the active agent in order to facilitate favorable association to the microparticle.
Description
- The present application is a divisional of U.S. patent application Ser. No. 17/443,344, filed Jul. 26, 2021, which is a divisional of U.S. patent application Ser. No. 16/151,736, filed Oct. 4, 2018, which is a divisional of U.S. patent application Ser. No. 15/233,794, filed Aug. 10, 2016, which is a continuation of U.S. patent application Ser. No. 14/746,656 filed Jun. 22, 2015, which is a divisional of U.S. patent application Ser. No. 12/883,369 filed Sep. 16, 2010, which is a continuation of U.S. patent application Ser. No. 11/532,065 filed Sep. 14, 2006 and claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 60/717,524 filed on Sep. 14, 2005, and 60/744,882, filed on Apr. 14, 2006, the entire contents of each which are hereby incorporated by reference in their entirety.
- This invention relates to drug formulations and is particularly related to methods. More specifically, binding or adsorbing active agents onto the surface of crystalline microparticles is disclosed.
- Delivery of therapeutic agents has been a major problem. Oral administration is one of the most common and preferred routes of delivery due to ease of administration, patient compliance, and decreased cost. However, the disadvantages of this route include low or variable potency and inefficient adsorption of the therapeutic. This is particularly evident when the compound to be delivered is unstable under conditions encountered in the gastrointestinal tract. A variety of coatings and encapsulation methods have been developed in the art, but only a few are effective in addressing this issue. Still, there are therapeutic compounds that tend to be less active in the conditions of the gastrointestinal tract and must be administered in higher dosages to be adsorbed into the bloodstream in an effective amount.
- A broad range of drug formulation systems have been developed to address the problem of optimal drug delivery and are based on incorporation of drug into a matrix that acts as a carrier. Factors considered in drug formulation include requirements that the system be non-toxic and non-reactive with the drug to be delivered, economical to manufacture, formed of readily available components, and consistent with respect to final composition and physical characteristics, including stability and release rate. It is also preferable that the drug delivery system is formed of materials easily removed from the body by normal physiologic processes.
- Advancements in microparticle technology have aided in the development of improved drug formulations. However, despite these advances there is still a need in the art for stable drug formulations having long term effectiveness and optimal adsorption when administered as a pharmaceutical, particularly by pulmonary means. One approach in addressing this deficiency is to target the structural characteristics/properties of the active agent that would promote its adsorption to the microparticle surface and decrease its tendency to remain in solution.
- Methods are provided for binding, coating or adsorbing an active agent onto a crystalline microparticle surface. In general, microparticles are coated with an active agent by modifying the system comprising the microparticles and the dissolved active agent such that the active agent has a greater affinity for the microparticle surface than for remaining in solution. In particular the present invention seeks to further promote the adsorption of an active agent to the microparticle surface by modifying/utilizing the properties of the active agent under a number of conditions in solution.
- Thus, in the present invention there is provided a method for promoting binding of an active agent to a preformed crystalline microparticle in suspension comprising the steps of: i) modifying the chemical potential of the active agent wherein the modifying allows for an energetically favorable interaction between the active agent and microparticle independent of removal of solvent; and ii) adsorbing the active agent onto the surface of the microparticle.
- In particular embodiments of the present invention, modifying the chemical potential comprises modifying the structure, flexibility, rigidity, solubility or stability of the active agent, individually or in combination. Modifying the chemical potential of the active agent comprises altering solution conditions. Altering solution conditions comprises adding an active agent modifier to the solution.
- In particular embodiments, the active agent modifier is selected from the group consisting of salts, surfactants, ions, osmolytes, alcohols, chaotropes, kosmotropes, acids, bases, and organic solvents. In one embodiment, the salt is sodium chloride.
- In still yet another embodiment of the present invention, the method further comprises the step of dissolving the active agent in the fluid phase of a suspension of microparticles and changing the pH of the fluid phase. In one aspect the step of dissolving the active agent in a fluid phase refers to the dissolving of a solid. In another aspect the step of dissolving the active agent refers to the addition of a concentrated solution of the active agent.
- In another embodiment of the present invention, the active agent modifier improves the structural stability of the active agent.
- In yet another embodiment of the present invention the active agent is a protein, peptide, polypeptide, small molecule, or nucleic acid molecule. In another embodiment of the present invention the active agent is selected from the group consisting of insulin, ghrelin, growth hormone, and parathyroid hormone (PTH). The active agent can comprise an antibody or antibody fragment. In various aspects of the invention the antibody can recognize a disease-associated antigen including, without limitation, a tumor-associated antigen or an infectious pathogen-related antigen.
- In still yet another embodiment of the present invention, the small molecule is an ionizable molecule or a hydrophobic molecule such as, but not limited to, cyclosporin A.
- In another embodiment of the present invention, modifying the chemical potential of the active agent comprises modulating one or more energetically favorable interactions such as, but not limited to, electrostatic interactions, hydrophobic interactions, and/or hydrogen bonding interactions between the active agent and the microparticle surface. In one embodiment, the microparticle comprises a diketopiperazine such as, but not limited to, fumaryl diketopiperazine.
- In yet another embodiment of the present invention, the method further comprises a step for removing or exchanging the solvent. Solvent, as used herein, refers to the fluid medium in which the active agent and microparticle are “bathed.” It should not be interpreted to require that all components are in solution. Indeed in many instances it may be used to refer to the liquid medium in which the microparticles are suspended.
- In another embodiment of the present invention, there is provided a process for preparing a drug delivery composition comprising an active agent and a crystalline microparticle comprising the steps of: providing an active agent solution comprising an active agent molecule; modifying the chemical potential of the active agent; providing a microparticle in a suspension or powder; and combining the active agent solution with the microparticle suspension or powder. The powder can be, for example, filtered but not dried.
- In another embodiment of the present invention, the process of modifying the chemical potential of the active agent allows for interaction between the active agent and a microparticle. In one embodiment, modifying the chemical potential of the active agent comprises adding an active agent modifier to the solution. Such an active agent modifier can be selected from the group consisting of salts, surfactants, ions, osmolytes, alcohols, chaotropes, kosmotropes, acid, base, and organic solvents. In yet another embodiment, the modifier decreases the solubility of the active agent molecule, promotes association between the active agent and a microparticle such as a diketopiperazine particle, and/or improves the structural stability of the active agent molecule.
- The following drawings form part of the present specification and are included to further demonstrate certain aspects of the examples disclosed herein. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
-
FIGS. 1A-1C depict the effects of chaotropes and kosmotropes on loading curves for active agents onto fumaryl diketopiperazine (FDKP) microparticles as a function of pH and 100 mM chaotropic/kosmotropic agent according to the teachings of the present invention.FIG. 1A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of chaotropes and kosmotropes at pH 3.0-5.0.FIG. 1B depicts the loading of 0.25 mg/mL glucagon-like peptide 1 (GLP-1) onto 5 mg/mL FDKP microparticles in the presence of chaotropes and kosmotropes at pH 2.0-4.0.FIG. 1C depicts the loading of 0.25 mg/mL parathyroid hormone (PTH) onto 5 mg/mL FDKP microparticles in the presence of the strong chaotropes, NaSCN and NaClO4, between pH 4.0-5.0. -
FIGS. 2A-2C depict the effects of osmolytes on loading curves for active agents onto FDKP microparticles as a function of pH and osmolytes (100 mM) according to the teachings of the present invention.FIG. 2A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of osmolytes at pH 3.0-5.0.FIG. 2B depicts the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles in the presence of osmolytes between pH 2.0-4.0.FIG. 2C depicts the loading of 0.10 mg/mL ghrelin peptide onto 5 mg/mL FDKP microparticles in the presence of strong osmolytes at pH 4.0-5.0. -
FIGS. 3A-3D depict the effects of alcohols on loading curves for active agents onto FDKP microparticles as a function of pH and alcohols according to the teachings of the present invention.FIG. 3A depicts the loading of 0.10 mg/mL ghrelin onto 5 mg/mL FDKP microparticles in the presence of hexafluoroisopropanol (HFIP) at 5%, 10%, 15%, and 20% v/v between pH 2.0-4.0.FIG. 3B depicts the loading of 0.10 mg/mL ghrelin onto 5 mg/mL FDKP microparticles in the presence of trifluoroethanol (TFE) at 5%, 10%, 15%, and 20% v/v between pH 2.0-4.0.FIGS. 3C and 3D depict the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles at pH 2.0-5.0 in the presence of HFIP and TFE, respectively. -
FIGS. 4A-4D depict the effects of salt on loading curves for active agents onto FDKP microparticles as a function of pH and NaCl concentration according to the teachings of the present invention.FIG. 4A depicts the loading of 0.75 mg/mL insulin onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH 2.0-5.0.FIG. 4B depicts the loading of 0.25 mg/mL GLP-1 onto 5 mg/mL FDKP microparticles in the presence of 0-500 mM NaCl at pH 2.0-5.0.FIG. 4C depicts the loading of 0.25 mg/mL PTH peptide onto 5 mg/mL FDKP microparticles in the presence of 0-1000 mM NaCl at pH 2.0-5.0.FIG. 4D depicts the secondary structural analysis of PTH at various salt concentrations (20° C.). The far-UV CD of 4.3 mg/mL PTH at pH 5.8 illustrates that as the concentration of NaCl increases the secondary structure of the peptide adopts a more helical conformation. -
FIGS. 5A-5B depict the adsorption of hydrophobic molecules onto microparticles according to the teachings of the present invention.FIG. 5A depicts the binding of cyclosporin A to FDKP microparticles with increasing anti-solvent (water) at 60%, 80% and 90% concentration.FIG. 5B depicts the percent of theoretical maximum load achieved for cyclosporin A at varying mass ratios of cyclosporin A/FDKP microparticles in the presence of 90% anti-solvent. -
FIG. 6 depicts the pharmacokinetics of single intravenous injection (IV) and pulmonary insufffaltion (IS) in rats using various mass ratios of cyclosporin A/FDKP microparticles at 90% anti-solvent according to the teachings of the present invention. - Described herein are methods useful for stabilizing pharmaceutical active agents in combination with crystalline microparticles. The resulting compositions provide stable active agents coated onto the crystalline microparticle surfaces.
- The substance to be coated or adsorbed onto the crystalline microparticle is referred to herein as active agent. Examples of classes of active agent include pharmaceutical compositions, synthetic compounds, and organic macromolecules that have therapeutic, prophylactic, and/or diagnostic utility.
- Generally, most active agents can be coated or adsorbed onto the surface of crystalline microparticles including, but not limited to, organic macromolecules, nucleic acids, synthetic organic compounds, polypeptides, peptides, proteins, polysaccharides and other sugars, and lipids. Peptides, proteins, and polypeptides are all chains of amino acids linked by peptide bonds. Peptides are generally considered to be less than 30 amino acid residues but may include more. Proteins are polymers that can contain more than 30 amino acid residues. The term polypeptide as is know in the art and as used herein, can refer to a peptide, a protein, or any other chain of amino acids of any length containing multiple peptide bonds, though generally containing at least 10 amino acids. The active agents used in the coating formulation can fall under a variety of biological activity classes, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antivirals, antigens, and antibodies.
- Examples of active agents that may be employed in the present invention include, in a non-limiting manner: growth hormone, antibodies and fragments thereof alkynes, cyclosporins (e.g. cyclosporin A), PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone, CMFDA (5-chloromethylfluorescein diacetate), Texas Red, clopiogrel, granulocyte macrophage colony stimulating factor (GM-CSF), glucagon-like peptide 1 (GLP-1), ghrelin, parathyroid hormone (PTH), insulin and insulin analogs (e.g., aspart insulin and insulin) and antibodies and fragments thereof, including, but not limited to: humanized or chimeric antibodies; F(ab), F(ab)2, or single-chain antibody alone or fused to other polypeptides; therapeutic or diagnostic monoclonal antibodies to cancer antigens, cytokines, infectious agents, inflammatory mediators, hormones, and cell surface antigens. Non-limiting examples of antibodies to tumor antigens include anti-SSX-241-49 (synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumor associated antigen), anti-PRAME (preferentially expressed antigen of melanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A (melanoma tumor associated antigen), anti-tyrosinase (melanoma tumor associated antigen), and anti-MOPC-21 (myeloma plasma—cell protein).
- Essentially, the term “microparticle” refers to a particle with a diameter of
- about 0.5-1000 dm, irrespective of the precise exterior or interior structure. Within the broad category of microparticles, “microspheres” refers to microparticles with uniform spherical shape. Crystalline microparticles as used herein refers to microparticles that have the internal structure, though not necessarily the external form, of a crystal and have a regular arrangement of atoms in a space lattice. Ionizable crystalline surfaces refer to crystalline microparticles that have the additional capacity to carry an electrical charge. In some embodiments the microparticle can be a single regularly shaped crystal. In various preferred embodiments the microparticle is irregularly shaped, is porous, has dissolved active agent-accessible interior surfaces, or comprises multiple crystals, in any combination. Such characteristics will generally increase surface area and thereby loading capacity. Such characteristics can also contribute to advantageous aerodynamic properties, important if the active agent is to be delivered by inhalation of a dry powder comprising the microparticles.
- Preferably, the chemical substance composing the crystalline microparticle is reversibly reactive with the active agent to be delivered, non-toxic, as well as non-metabolized by rodents and humans. The foregoing notwithstanding, some levels of toxicity are tolerable, depending, for example, on the severity of the condition to be treated or the amount of the substance to which a patient is exposed. Similarly, it is not required that the substance be completely metabolically inert. In addition, the crystalline structure of preferred microparticles is not substantially disrupted in the process of coating or binding with active agent. The composition of the crystalline microparticle determines what type of chemical interactions can be manipulated to drive adsorption of an active agent to the microparticle surface.
- A number of substances can be used to form crystalline microparticles. Microparticles as such have surfaces, the properties of which can be manipulated in the coating process as disclosed in copending U.S. patent application Ser. No. 11/532,063 (Attorney Docket No. 51300-00025), filed on the same date as the instant application, and U.S. Provisional Application Ser. No. 60/717,524 filed on Sep. 14, 2005, each of which is hereby incorporated by reference in its entirety. Representative materials from which crystalline microparticles can be formed include, but are not limited to, aromatic amino acids, or compounds with limited solubility in a defined pH range such as diketopiperazines and morpholine sulfates.
- One particular example of microparticles as contemplated in the present invention are diketopiperazine (DKP) microparticles. As discussed herein, DKP microparticles are employed to facilitate the adsorption of the active agent. U.S. Pat. Nos. 5,352,461 and 5,503,852, each of which is incorporated herein by reference in its entirety, describe a drug delivery system based on formation of diketopiperazine (DKP) microparticles from diketopiperazine derivatives such as 3,6-bis[N-fumaryl-N-(n-butyl)amino] (also referred to as fumaryl diketopiperazine or FDKP; also termed (E)-3,6-bis[4-(N-carboxy-2-propenyl)amidobutyl]-2,5-diketopiperazine) that are stable at low pH and dissolve at the pH of blood or the small intestine. A system based on diketopiperazine structural elements or one of its substitution derivatives, including, but not limited to, diketomorpholines and diketodioxanes, forms microparticles with desirable size distributions and pH ranges as well as good payload tolerance. A wide range of stable, reproducible characteristics can be generated with appropriate manipulations of the substituent groups. These patents disclosed precipitation of the DKP in the presence of the active agent to form microparticles comprising the active agent. Further details for synthesis, preparation, and use of diketopiperazines and diketopiperazine microparticles are disclosed in U.S. Pat. Nos. 6,071,497; 6,331,318; 6,428,771 and U.S. Patent Publication Nos. 20060040953 and 20060041133, each incorporated herein by reference in their entirety. Compositions comprising diketopiperazine particles are disclosed in U.S. Pat. No. 6,991,779 and U.S. Patent Publication No. 20040038865; each incorporated herein by reference in their entirety.
- Other diketopiperazines contemplated in the present invention include 3,6-di(4-aminobutyl)-2,5-diketopiperazine; 3,6-di(succinyl-4-aminobutyl)-2,5-diketopiperazine (succinyl diketopiperazine or SDKP); 3,6-di(maleyl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(citraconyl-4-aminobutyl)-2-5-diketopiperazine; 3,6-di(glutaryl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(malonyl-4-aminobuty))-2,5-diketopiperazine; 3,6-di(oxalyl-4-aminobuty))-2,5-diketopiperazine and derivatives therefrom. Diketopiperazine salts may also be utilized in the present invention and may included, for example, a pharmaceutically acceptable salt such as the Na, K, Li, Mg, Ca, ammonium, or mono-, di- or tri-alkylammonium (as derived from triethylamine, butylamine, diethanolamine, triethanolamine, or pyridines, and the like). The salt may be a mono-, di-, or mixed salt. Higher order salts are also contemplated for diketopiperazines in which the R groups contain more than one acid group. In other aspects of the invention, a basic form of the agent may be mixed with the diketopiperazine in order to form a salt linkage between the drug and the diketopiperazine, such that the drug is a counter cation of the diketopiperazine. DKP salts for drug delivery are disclosed in a further detail in U.S. Patent Application Publication No. 20060040953 which is herein incorporated by reference in its entirety.
- U.S. Pat. Nos. 6,444,226, and 6,652,885, each herein incorporated by reference in their entirety, describe preparing and providing microparticles of DKP in aqueous suspension to which a solution of active agent is added, and then the critical step of lyophilizing the suspension to yield microparticles having a coating of active agent. The basis for this formulation is that the coating of microparticle with active agent is driven by removal of the liquid medium by lyophilization. (See also U.S. Pat. No. 6,440,463 which is incorporated herein by reference in its entirety). In contrast to teachings in the prior art, the present invention provides means for adjusting the association of active agent with the microparticle prior to solvent removal. Thus, removal of the liquid medium by bulk physical methods (e.g., filtration or sedimentation) or evaporative methods (e.g., lyophilization or spray-drying) can result in comparable loads.
- Adsorbing active agent to the surface of a crystalline microparticle can involve
- altering the properties of the active agent in a solution or fluid suspension under various solution conditions, thereby promoting adsorption to the microparticle surface and reducing the amount of active agent remaining in solution. Alteration or modifications to the active agent may occur with the use of modifiers such as, but not limited to, chaotropes and kosmotropes, salts, organics such as, but not limited to, alcohols, osmolytes, and surfactants. These modifiers can act on the active agent to alter its chemical potential and thereby its structure, flexibility, rigidity or stability, without chemically altering the agent itself. The term “chemical potential” is well known to one of ordinary skill. In embodiments of the present invention, “chemical potential” refers to the free energy necessary to drive a chemical reaction such as, for example, interaction between an active agent and a solvent or the adsorption of active agent onto a microparticle. The term “energetically favorable” as used herein refers to the lowering of the free energy levels of the absorbed states of the active agent onto the microparticle in relation to the free energy level of uncoated microparticle, or unbound active agent and/or the insoluble forms (including aggregation or precipitation) of the active agent. The term “structure” as used herein refers to the secondary structure of the active agent molecule and includes the alpha-helical formation, beta sheets, or random coil (unordered) of the active agent molecule, such as a protein. Additionally, the term structure may also include teritary and quaternary structures of the molecule but is not limited to such and may also refer to the self association, aggregation, multimerization, dimerization, and the like, of a molecule. The term “stability” as used herein refers to the stabilization or destabilization of the structure of the active agent in the presence of the modifier.
- In addition, altering the properties of the active agent in a solution or fluid suspension are likely to affect the interactions due to hydrophobic properties, hydrogen bonding properties, and electrostatic properties of the active agent and/or microparticle.
- Hydrophobic interactions are associations of non-polar groups with each other in aqueous solutions because of their insolubility in water. Hydrophobic interactions can affect a number of molecular processes including, but not limited to, structure stabilization (of single molecules, complexes of two or three molecules, or larger assemblies) and dynamics, and make important contributions to protein-protein and protein-ligand binding processes. These interactions are also known to play a role in early events of protein folding, and are involved in complex assembly and self-assembly phenomena (e.g., formation of membranes).
- Hydrogen bonding interactions are especially strong dipole-dipole forces between molecules; a hydrogen atom in a polar bond (e.g., H—F, H—O or H—N) can experience an attractive force with a neighboring electronegative molecule or ion, which has an unshared pair of electrons (typically an F, O, or N atom on another molecule). Hydrogen bonds are responsible for the unique properties of water and are very important in the organization of biological molecules, especially in influencing the structure of proteins and DNA.
- Electrostatic interactions are attractions between opposite charges or repulsions between like charges that grow stronger as the charges come closer to each other. Electrostatic interactions constitute a key component in understanding interactions between charged bodies in ionic solutions. For example, the stability of colloidal particles dispersed in a solvent can be explained by considering the competition between repulsive electrostatic interactions and the attractive van der Waals interactions. Electrostatic interactions are also of importance when considering interaction and adhesion between particles.
- In some embodiments of the present invention, the properties of the active
- agent are altered using a salt such as, but not limited to, sodium chloride. Active agents, for example, PTH and GLP-1, undergo noticeable structural changes in the presence of salt. As shown in Example 5 (
FIG. 4D ), the presence of salt increases the secondary structure of PTH by promoting a more helical conformation of the peptide. Salt has also been shown to affect the structure of GLP-1, as disclosed in U.S. Provisional Patent Application, Ser. No. 60/744,882, filed on Apr. 14, 2006 and incorporated herein by reference in its entirety. Furthermore, salts and other ionic compounds are capable of either stabilizing or destabilizing proteins and peptides, especially when the difference between the pH of the solution and the pI of the protein or peptide becomes greater, by binding to specifically charged residues (Antosiewiez J, et al., J. Mol. Biol. 238:415-436, 1994). - Chaotropes, as are well known in the art, are ions that exhibit weak
- interactions with water and therefore destabilize molecules such as proteins or peptides. These compounds break down the hydrogen-bonded network of water and decrease its surface tension, thus promoting more structural freedom and denaturation of proteins and peptides. Examples of chaotropes include, but are not limited to, NaSCN, (CH3)3N—HCl, Na2NO3, and NaClO4 and cesium chloride (CsCl).
- Kosmotropes or lyotropes, on the other hand, are ions that display strong interactions with water and generally stabilize macromolecules such as proteins and peptides. This stabilization effect is brought about by increasing the order of water and increasing its surface tension. Examples of kosmotropes include, but are not limited to, sodium citrate (Na Citrate), and sodium sulfate (Na2SO4).
- Another class of modifier of active agent employed in the present invention is
- alcohols. Alcohols are able to disrupt the native structure of proteins and peptides and are also able to stabilize and induce 0-helical conformations in macromolecules, most notably within unstructured proteins and polypeptides. Such alcohols may include, but are not limited to, methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), and hexafluoroisopropanol (HFIP). Of those, TFE and HFIP are two of the most potent alcohols for inducing helical transitions in peptides and proteins (Hirota et al., Protein Sci., 6:416-421; 1997, incorporated herein by reference for all it contains regarding helical transitions in peptides and proteins). These alcohols may affect the structure of proteins and peptides through their ability to disrupt the hydrogen-bonding properties of the solvent (see Eggers and Valentine, Protein Sci., 10:250-261; 2001, incorporated herein by reference for all it contains regarding the effect of alcohols on the structure of proteins).
- Another class of modifier that affects the active agent affinity for the
- microparticle is osmolytes. Osmolytes, as are well known to the skilled artisan, are small compounds that are produced by the cells of most organisms in high stress situations (such as extreme temperature fluctuations, high salt environments, etc.) to stabilize their macromolecules. They do not interact with the macromolecule directly but act by altering the solvent properties in the cellular environment and so their presence indirectly modifies the stability of proteins. These compounds include various polyols, sugars, polysaccharides, organic solvents, and various amino acids and their derivatives. Although the mechanism of osmolytes are yet to be elucidated, it is speculated that these compounds likely act by raising the chemical potential of the denatured state relative to the native state, thereby increasing the (positive) Gibbs energy difference (□G) between the native and denatured ensembles (Arakawa and Timasheff, Biochemistry 29:19141923; 1990).
- Osmolytes as contemplated in the present invention, include in a non-limiting manner, hexylene-glycol (Hex-Gly), trehalose, glycine, polyethylene glycol (PEG), trimethylamine N-oxide (TMAO), mannitol, and proline.
- In the methods of the present invention, at least three components are
- combined in a liquid medium: at least one active agent, (preformed) microparticles, and at least one active agent modifier as described above. The components of this system may be combined in any order. In some embodiments the modifier and active agent are combined with each other prior to that mixture being combined with a suspension of microparticles. In other embodiments the agent and microparticles are first combined and then the modifier is added. In some embodiments the active agent or modifier is provided and combined with another component, or components, as a solution. In other embodiments any of the components can be provided in solid form and dissolved, or in the case of the microparticles, suspended, in the liquid medium containing another of the components. Further variations will be apparent to one of skill in the art.
- The microparticles are formed prior to being combined with the other components of the system, and as such are present as a suspension. Nonetheless the liquid medium in which the microparticles are suspended is at times referred to herein as a solvent. The liquid medium utilized in the method is most often aqueous. However in some instances the liquid medium can comprise more of an organic compound, for example an alcohol used as a modifier, than it does water.
- Upon assembly of all components of the system, the active agent will adsorb to the surface of the microparticle. In increasingly preferred embodiments of the present invention, at least 50, 60, 70, 80, 90, 95%, or substantially all, of the active agent in the system will adsorb to the microparticles, up to 100%. In some embodiments of the present invention, the accessible surface area of the microparticles with be sufficient for all of the adsorbed active agent to be in direct contact with the microparticle surface, that is, the coating is a monolayer. However it is to be understood that additional interactions can be present. In some instances, for example, self-association of the active agent can also be energetically favored so that multiple layers of active agent coat the particle. It is not required that any of these layers be complete or that the thickness of the coating be uniform. Two forms of self-association can be recognized: multimerization and aggregation. Multimerization is characterized by specific intermolecular interactions and fixed stoichiometry. Aggregation is characterized by unspecific intermolecular interactions and undefined stoichiometry. It should be understood that multimeric active agents can be adsorbed in the multimeric state, or dissociated into monomers, or lower order multimers, and adsorbed to the surface in that state. In either case aggregation can mediate layering of the active agent onto the microparticle.
- The loaded microparticles constitute a drug delivery composition that can be utilized in a variety of forms. The particles can be used as powders, in solid dosage forms such as tablets or contained in capsules, or suspended in a liquid carrier. Generally this will require exchange and/or removal of the liquid medium in which the loading took place. This can be accomplished by any of a variety of means including physical methods such as, but not limited to, sedimentation or filtration, and evaporative methods such as, but not limited to, lyophilization or spray-drying. These techniques are known to those skilled in the art. In one embodiment of the present invention, solvent is removed by spray-drying. Methods of spray-drying diketopiperazine microparticles are disclosed in, for example, U.S. Provisional Patent Application No. 60/776,605 filed on Feb. 22, 2006, incorporated by reference herein for all it contains regarding spray-drying diketopiperazine microparticles.
- If loading is not substantially complete, embodiments of the invention, using physical methods of solvent removal will typically loose the unadsorbed active agent, but for example can be useful to ensure that coating does not progress beyond a monolayer. Conversely, embodiments using evaporative drying for solvent removal can in some cases deposit additional active agent on the particle and thereby avoid its loss, but the adsorptive interactions involved can differ from those established by the molecules bound in the earlier steps of the method. In other embodiments evaporative solvent removal does not result in significant further deposition of active agent, including the case in which substantially all of the active agent was already adsorbed to the particle.
- The following examples are included to demonstrate preferred embodiments of the present invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. While discussion may focus on a particular mechanism it should be understood that some modifiers can have multiple effect on the agent, or indeed on the particle surface as well, each of which can contribute to promoting adsorption of the agent to the particle. However, those of skill in the art, in light of the present disclosure, will appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
- The active agents insulin, PTH, ghrelin and GLP-1 were either purchased from American Peptide (Sunnyvale, CA) or AnaSpec (San Jose, CA), or prepared in house (MannKind Corporation, Valencia, CA). Aqueous samples at varying pH and at 20° C. (unless otherwise noted) were analyzed. Samples were generally prepared fresh and were mixed with the particular additive (e.g., salt, pH buffer, etc., if any), prior to the addition of FDKP microparticles.
- The association of active agent with diketopiperazine (DKP) particles in suspension was evaluated by conducting adsorption studies. The parameters investigated in the adsorption studies explored the effects of electrostatic interactions, hydrogen bonding, water structure, protein flexibility, and specific salt-pairing interactions on the active agent/fumaryl diketopiperazine (FDKP) microparticle interaction. In addition, several common protein stabilizers were tested for interference with active agent adsorption to FDKP microparticle surfaces.
- Varying conditions promoting adsorption of active agent onto the surfaces of preformed FDKP particles were studied. A 15 mg/mL FDKP microparticle suspension was combined with 3X pH buffer and 3× solution of an additive or excipient. The final solution contained a FDKP microparticle concentration of 5 mg/mL and a GLP-1 concentration of 0.25 mg/mL (5% w/w), or a PTH concentration of 0.25 mg/mL (5% w/w), or an insulin concentration of 0.75 mg/mL (15% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w). Unbound active agent in the supernatant was filtered off the suspension. The FDKP particles with the associated active agent were dissolved (reconstituted) in 100 mM ammonium bicarbonate and filtered to separate out any aggregated active agent molecules. The amount of active agent in both the supernatant and reconstituted fractions was quantitated by HPLC. A series of experiments were conducted in which conditions employed included use of additives such as salts, osmolytes, chaotropes and kosmotropes, and alcohols. The results from these studies are described below.
- Effect of Chaotropes and Kosmotropes on Adsorption of Active Agent onto FDKP Particles
- Ionic species that affect the structure of water and proteins (chaotropes and kosmotropes) were studied to investigate the adsorption of active agent onto a FDKP microparticle surface by a hydrophobic mechanism (at low pH). Loading of the active agent onto FDKP particles was performed at 5 mg/mL microparticles and a GLP-1 concentration of 0.25 mg/mL (5% w/w), or a PTH concentration of 0.25 mg/mL (5% w/w), or an insulin concentration of 0.75 mg/mL (15% w/w). The concentration of the chaotrope or kosmotrope in the samples was held constant at 100 mM and the pH varied from 2.0 to 5.0. Chaotropes or kosmotropes were selected from the following: NaSCN, CsCl, Na2SO4, (CH3)3N—HCl, Na2NO3, Na Citrate, and NaClO4. The control indicates no chaotrope or kosmotrope were added.
-
FIGS. 1A-1C depict the loading curves for insulin, GLP-1 and PTH respectively, onto the FDKP microparticle surface as a function of pH in the presence of the various chaotropes or kosmotropes. At low pH (3.0) all chaotropes and kosmotropes analyzed improved the affinity of insulin for the microparticle surface and showed significant loading compared to the control. At pH 4, this effect was not observed (FIG. At higher pH (5.0), the chaotropes and kosmotropes interfered with the adsorption of insulin to the microparticle surface, as compared to control, by precipitating the insulin protein. Thus these agents promoted binding of insulin to the FDKP particles at lower pH, but have little or even a detrimental effect at the higher pH conditions. - GLP-1, in the presence of chaotropes and kosmotropes, showed an improved affinity for the FDKP microparticles at pH 2.0-4.0 with a greater effect at lower pH (
FIG. 1A ). Similar observations were disclosed in U.S. Provisional Application Ser. No. 60/744,882. There it was noted, that approximately 0.02-0.04 mg/mL of the GLP-1 peptide (which corresponds to mass ratios of 0.004 to 0.008) was detected in the reconstituted microparticle-free control samples in the presence of NaSCN, NaClO4, Na2SO4, NaNO3 and Na citrate, indicating that a small proportion of the GLP-1 precipitated rather than adsorbing to the particle. - The affinity of PTH for the FDKP microparticle surface was greater at pH of 4.0 to about 4.5 in the presence of strong chaotropes NaSCN and NaClO4 (
FIG. 1C ). - The data supports that chaotropic and kosmotropic agents play a role in promoting adsorption of the active agent to FDKP microparticle surfaces, most notably at low pH. Since these modifiers have a greater effect at low pH, where the microparticle surface is less ionic, it is likely that adsorption results from a hydrophobic mechanism. The decrease in adsorption observed at higher pH may result from the more highly charged surface of the particle in combination with effects chaotropic and kosmotropic agents have on increasing the hydrophobicity of the active agents. Additionally, as ionic species, these agents may compete with the active agent for binding to the microparticle, or disrupt the electrostatic interactions between the active agent and the microparticle. Finally it is also noted that Debye shielding can contribute to the decrease in adsorption to the more highly charged surface.
- To assess the importance of active agent stability on adsorption, the effect of osmolytes on the binding of active agent to FDKP particles was examined by HPLC analysis.
FIGS. 2A-2C show the loading curves for insulin (FIG. 2A ), GLP-1 (FIG. 2B ) and ghrelin (FIG. 2C ) onto FDKP particles as a function of pH in the presence of common stabilizers (osmolytes). Loading of the active agent onto FDKP microparticles was performed at 5 mg/mL of microparticles and an insulin concentration of 0.75 mg/mL (15% w/w), or a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w). The concentration of the osmolyte (stabilizer) in the samples was held constant at 100 mM and the pH varied from about 2.0 to about 5.0. The osmolytes were selected from hexylene-glycol (Hex-Gly), trehalose, glycine, PEG, TMAO, mannitol and proline; the control indicates no osmolyte. - Of the active agents studied, insulin showed significantly improved affinity for the FDKP particle surface in the presence of osmolytes (PEG, glycine, trehalose, mannitol and Hex-Gly) over a pH range of 3.0 to 5.0 (
FIG. 2A ). Of the osmolytes studied, PEG and proline improved the affinity for adsorption of the GLP-1 onto FDKP particle surface over a pH range from 2.0 to 4.0. The osmolyte TMAO was more effective than PEG or proline at binding GLP-1 onto the FDKP microparticle surface at low pH (2.0) but was modestly detrimental at pH 3.0 and above (FIG. 2B ). Ghrelin however, showed greater affinity for the microparticle surface in the presence of 100 mM mannitol, PEG, glycine, Hex-Gly, and trehalose when compared to the control over the pH range of about 4.0 to 5.0 (FIG. 2C ). - These loading curves suggested that osmolytes are capable of enhancing the adsorption of the active agent to FDKP microparticle surface. It is likely that this effect resulted from the modifiers ability to stabilize the active agent, which enabled adsorption to be more energetically favorable.
- In assessing the effect of modifiers on the active agent that allows for adsorption to the microparticle surface by a hydrophobic mechanism, the effect of alcohols were examined. Alcohols known to induce helical conformation in unstructured peptides and proteins by increasing hydrogen-bonding strength were evaluated to determine the role that helical confirmation plays in adsorption of active agent to FDKP particles surface. Active agents such as GLP-1 and ghrelin were analyzed. Loading of the active agent on FDKP particles was performed at 5 mg/mL of microparticles and a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a ghrelin concentration of 0.10 mg/mL (2% w/w). The effect of each alcohol was observed over a pH range of 2.0 to 5.0. The alcohols used were trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP). Each alcohol was evaluated at varying concentrations which include 5%, 10%, 15%, or 20% v/v.
-
FIGS. 3A-3D show the loading curves for active agent onto FDKP microparticles as a function of pH for each alcohol and each active agent. At pH 2.0-4.0, ghrelin showed greatly improved affinity for the microparticle surface in the presence of HFIP and TFE at all concentrations tested (5%, 10%, 15% and 20%), as demonstrated by the mass ratio of ghrelin to FDKP particles (FIGS. 3A-3B ). - At pH 2.0-5.0, GLP-1 showed improved affinity for the microparticle surface in the presence of HFIP and TFE at the concentrations shown (5% and 10%) (
FIGS. 3C-3D ). The effect of TFE was less pronounced, and at the lower pHs tested was detrimental. It was noted that a substantial amount of GLP-1 peptide (0.13-0.19 mg/mL, which corresponds to mass ratios of 0.026 to 0.038) was detected in the reconstituted microparticle-free control samples in the presence of 10% HFIP and TFE at pH 4.0, indicating that some of the GLP-1 had precipitated. However, at lower pH (2.0-3.0), the amount of GLP-1 peptide detected in the reconstituted microparticle-free control in the presence of 10% HFIP or TFE was significantly decreased. At pH 3.0, GLP-1 peptide at 0 to 0.02 mg/mL, (which corresponding to a mass ratio of 0 to 0.004) was detected, whereas no GLP-1 was detected for the control samples at pH 2.0. The mass ratios inFIGS. 3C-D reflect both adsorbed and precipitated active agent although precipitation is an increasingly minor component as the pH decreased toward 3.0. - The data indicated that alcohols are able to improve the adsorption of the active agent onto FDKP microparticles. This increase in adsorption likely resulted from enhanced hydrophobic interactions between the active agent and surface of the microparticle in the presence of alcohols.
- To further address the hydrophobic mechanism of binding, the effects of salt on adsorption of active agent to FDKP microparticles were observed by HPLC analysis.
- Loading of the active agent onto FDKP microparticles was performed at 5 mg/mL of microparticles and an insulin concentration of 0.75 mg/mL (15% w/w), or a GLP-1 concentration of 0.25 mg/mL (5% w/w) or a PTH concentration of 0.25 mg/mL (5% w/w) in the presence of 0, 25, 50, 100, 250, and 500 mM NaCl (
FIGS. 4A-4C ). Loading of PTH onto FDKP particles was also assessed at 1000 mM NaCl. The amount of active agent detected in reconstituted microparticle-free control samples as a function of pH and NaCl concentration was assessed. The pH was controlled with a 20 mM potassium phosphate/20 mM potassium acetate mixture. - As observed in
FIG. 4A , increased binding (adsorption) of insulin onto FDKP particles was evident at high salt concentrations of 100-500 mM at pH from about 2.5 to about 3.5. At a pH from about 4.0 to about 5.0, for all salt concentrations tested, a reduction in the adsorption of insulin to the FDKP particle was observed. - At a pH from about 2.0 to about 3.5 enhanced binding (adsorption) of GLP-1 to FDKP particles was evident at all the salt concentrations tested (
FIG. 4B ). At pH 4.0 and above, a reduction in binding was also noted. - Similar studies using PTH as the active agent showed enhanced binding of PTH to the FDKP particles at high salt concentrations of 250 to 1000 mM at pH from about 2.0 to about 3.5 (
FIG. 4C ). At pH from about 3.5 to about 5.0 binding of PTH to the microparticle decreased in the presence of salt. - At low pH, where adsorption is not favorable, the addition of salt was able to modify the chemical potential of the active agent so as to increase its affinity for the microparticle surface. Such enhancement of binding likely resulted from a hydrophobic mechanism. Furthermore, the data indicated that as the pH was raised, adsorption decreased with increased salt concentration. As the microparticle surface became more charged with increasing pH, the hypothesized hydrophobic mechanism can be expected to be less effective at promoting the adsorption of the active agent. This reduction may also have resulted from salt competing for the binding sites on the surface of the microparticle. It is noted that Debye shielding may also contribute to the reduced adsorption observed.
- The data also showed that salt is capable of altering the structure of active agents. For example, circular dichroism measurements with PTH showed that as the salt concentration increased the secondary structure of the peptide adopted a more helical conformation (
FIG. 4D ). This suggests that change in the structure of PTH may promote its binding to the microparticle surface at low pH. - In an aqueous solution, the presence of salt was also shown to partition the dye Texas Red onto the surface of the microparticle.
- The effects on the adsorption of small hydrophobic molecules onto FDKP particles was investigated both in vitro and in vivo using cyclosporin A as the active agent. Adsorption was promoted by altering the solubility of the active agent.
- Cyclosporin A, a lipophilic cyclic polypeptide, was studied in order to show how a hydrophobic molecule can be made to adsorb to microparticles. In addition, the size of cyclosporin A (1202.61 MW) was utilized to demonstrate the loading capacities of microparticles for smaller compounds.
- To accomplish loading, a solvent/anti-solvent method was employed. The basic principle of this methodology is to dissolve the compound in a solvent (methanol) and then use anti-solvent (water) to drive the compound out of solution and onto the surface of the microparticles. Utilizing this solvent/anti-solvent approach, cyclosporin A was successfully loaded onto the surface of microparticles.
- In a preliminary experiment to determine a solubility profile, cyclosporin A was dissolved to 10 mg/mL in methanol and its solubility at 1 mg/mL with varying concentrations of anti-solvent (10-90% H2O in 10% increments) was analyzed by HPLC. The cyclosporin A peak areas were compared against the sample containing methanol alone, to determine the percent loss to precipitation. It was observed that solubility was largely retained below 60% H2O. At 70% H2O, a significant majority of the agent was insoluble and at 80-90% H2O less than 5% solubility remained.
- To assess particle loading, FDKP microparticles were suspended in methanol solutions of cyclosporin A. Water was then added in a stepwise fashion to final concentrations of 60, 80, and 90%. Half of the sample was pelleted and the other half lyophilized. Each half was then redissolved such that the final percentages were 20% FDKP microparticles/cyclosporin A, 20% 0.5 M ammonium bicarbonate (AmBicarb), and 60% methanol (the concentrations necessary for the dissolution of both microparticle and cyclosporin A). The cyclosporin A content of each was analyzed by HPLC and compared to determine the proportion that had become adsorbed to the particle. The results are presented in
FIG. 5A . At 60% H2O it was observed that about 20% of the cyclosporin A had bound to the particle. At 80% and 90% H2O the loads were about 90% and 95%, respectively, indicating the strong binding of cyclosporin A to FDKP microparticles. - The loading capacity of the microparticles for cyclosporin A was analyzed at the 90% anti-solvent level by varying the input of cyclosporin A so that the final content of the recovered solids would be from 2% to 20%, assuming all of the cyclosporin A became adsorbed. It was observed that as the input increased over this range the percent of available cyclosporin A bound to the microparticle increased from 50% to 95% of the input (
FIG. 5B ). It is to be noted that, taking into account that the solubility of cyclosporin A is 0.05 mg/mL at 90% H2O, these results indicated that substantially all of the insoluble cyclosporin A became adsorbed to the particles rather than precipitating out. - To examine the pharmacokinetics of cyclosporin A/FDKP microparticles, plasma concentrations of cyclosporin A were evaluated in female Sprague Dawley rats administered various formulations of cyclosporin A/FDKP microparticles via pulmonary insufflation or intravenous injection. These studies were conducted using cyclosporin A/FDKP microparticles made at 90% anti-solvent and a theoretical maximum mass ratio of 0.05, 0.10 or 0.20 as described in the example above. These are referred to as the 5%, 10% and 20% loads.
- A single dose of 2.5 mg cyclosporin A/FDKP microparticles was delivered to eight groups of rats via pulmonary insufflation or intravenous injection. Blood samples were taken on the day of dosing for each group at pre-dose (time 0), and at 5, 20, 40, 60, 240, 480 minutes and at 24 hrs post dose. At each time point, approximately 100 eL whole blood was collected from the lateral tail vein into a cryovial, inverted and stored on ice. Blood samples were centrifuged at 4000 rpm and approximately 40 eL plasma was pipetted into 96-well plates which were stored at −80° C. until analyzed.
- As shown in
FIG. 6 , administration of 2.5 mg FDKP microparticles/cyclosporin A via pulmonary insufflation resulted in maximal serum cyclosporin levels 24 hours post dose in female Sprague Dawley rats. The 10% load achieved a Cmax of 32.4 ng/mL at that time point. Animals administered 2.5 mg of FDKP microparticles/cyclosporin A in 0.1 mL via intravenous injection showed minimal levels of cyclosporin out to 24 hours post dose. It was observed that FDKP microparticle levels peaked at 20 minutes post dose and returned to baseline levels in 4 hours for both the intravenous and pulmonary insufflation groups. - Overall, the data shows the bioavailability of cyclosporin A/FDKP microparticle. It is noted that the single peak at 240 minutes is an anomaly. For all animals treated, the pathology as determined by gross and microscopic observation was normal.
- Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
- The terms “a” and “an” and “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
- The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
- Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
- Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
- Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.
- Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.
- Further, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
Claims (5)
1. A process for making a pharmaceutical composition comprising microparticles of crystalline fumaryl diketopiperazine coated with a vasoactive agent comprising:
(i) dissolving the fumaryl diketopiperazine in a solution;
(ii) obtaining crystalline fumaryl diketopiperazine microparticles in a suspension having a fluid phase;
(iii) dissolving said vasoactive agent in the fluid phase of said suspension;
(iv) increasing the pH of the fluid phase to about 4 to about 5;
(v) adsorbing of said vasoactive agent onto a surfaces of said crystalline fumaryl diketopiperazine microparticles to provide a coating of said vasoactive agent on said crystalline fumaryl diketopiperazine microparticles;
(vi) removing or exchanging said solvent from the suspension;
(vii) forming a dry powder comprising the crystalline fumaryl diketopiperazine microparticles coated with the vasoactive agent.
2. The process of claim 1 , further comprising the step of dissolving said vasoactive agent in an alcohol prior to dissolving said vasoactive agent in the fluid phase.
3. The process of claim 2 , wherein the alcohol is selected from one or more of the group consisting of: ethanol, methanol, trifluoroethanol and hexafluoroisopropanol.
4. The process of claim 2 , wherein the alcohol is ethanol.
5. The process of claim 2 , wherein the alcohol is about 5% to about 20% w/v between pH 2.0-4.0 in the suspension.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/235,592 US20230390206A1 (en) | 2005-09-14 | 2023-08-18 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US71752405P | 2005-09-14 | 2005-09-14 | |
US74488206P | 2006-04-14 | 2006-04-14 | |
US11/532,065 US7803404B2 (en) | 2005-09-14 | 2006-09-14 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US12/883,369 US9089497B2 (en) | 2005-09-14 | 2010-09-16 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US14/746,656 US9446001B2 (en) | 2005-09-14 | 2015-06-22 | Increasing drug affinity for crystalline microparticle surfaces |
US15/233,794 US10143655B2 (en) | 2005-09-14 | 2016-08-10 | Method of drug formulation |
US16/151,736 US11103459B2 (en) | 2005-09-14 | 2018-10-04 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US17/443,344 US20210353544A1 (en) | 2005-09-14 | 2021-07-26 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US18/235,592 US20230390206A1 (en) | 2005-09-14 | 2023-08-18 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/443,344 Division US20210353544A1 (en) | 2005-09-14 | 2021-07-26 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230390206A1 true US20230390206A1 (en) | 2023-12-07 |
Family
ID=37726824
Family Applications (15)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/532,065 Active US7803404B2 (en) | 2005-09-14 | 2006-09-14 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US11/532,063 Active US7799344B2 (en) | 2005-09-14 | 2006-09-14 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US12/815,276 Active 2027-04-15 US8420604B2 (en) | 2005-09-14 | 2010-06-14 | Method of drug formulation of compositions comprising crystalline microparticle surfaces |
US12/830,557 Active 2028-06-06 US8729019B2 (en) | 2005-09-14 | 2010-07-06 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US12/883,369 Active 2030-03-27 US9089497B2 (en) | 2005-09-14 | 2010-09-16 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US13/797,657 Active US9066881B2 (en) | 2005-09-14 | 2013-03-12 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US14/249,621 Active US9283193B2 (en) | 2005-09-14 | 2014-04-10 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US14/746,656 Active US9446001B2 (en) | 2005-09-14 | 2015-06-22 | Increasing drug affinity for crystalline microparticle surfaces |
US15/017,153 Active US9717689B2 (en) | 2005-09-14 | 2016-02-05 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US15/233,794 Active US10143655B2 (en) | 2005-09-14 | 2016-08-10 | Method of drug formulation |
US15/629,636 Active US10357459B2 (en) | 2005-09-14 | 2017-06-21 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US16/151,736 Active US11103459B2 (en) | 2005-09-14 | 2018-10-04 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US16/439,252 Active US11013692B2 (en) | 2005-09-14 | 2019-06-12 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US17/443,344 Abandoned US20210353544A1 (en) | 2005-09-14 | 2021-07-26 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US18/235,592 Pending US20230390206A1 (en) | 2005-09-14 | 2023-08-18 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
Family Applications Before (14)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/532,065 Active US7803404B2 (en) | 2005-09-14 | 2006-09-14 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US11/532,063 Active US7799344B2 (en) | 2005-09-14 | 2006-09-14 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US12/815,276 Active 2027-04-15 US8420604B2 (en) | 2005-09-14 | 2010-06-14 | Method of drug formulation of compositions comprising crystalline microparticle surfaces |
US12/830,557 Active 2028-06-06 US8729019B2 (en) | 2005-09-14 | 2010-07-06 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US12/883,369 Active 2030-03-27 US9089497B2 (en) | 2005-09-14 | 2010-09-16 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US13/797,657 Active US9066881B2 (en) | 2005-09-14 | 2013-03-12 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US14/249,621 Active US9283193B2 (en) | 2005-09-14 | 2014-04-10 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US14/746,656 Active US9446001B2 (en) | 2005-09-14 | 2015-06-22 | Increasing drug affinity for crystalline microparticle surfaces |
US15/017,153 Active US9717689B2 (en) | 2005-09-14 | 2016-02-05 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US15/233,794 Active US10143655B2 (en) | 2005-09-14 | 2016-08-10 | Method of drug formulation |
US15/629,636 Active US10357459B2 (en) | 2005-09-14 | 2017-06-21 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US16/151,736 Active US11103459B2 (en) | 2005-09-14 | 2018-10-04 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
US16/439,252 Active US11013692B2 (en) | 2005-09-14 | 2019-06-12 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
US17/443,344 Abandoned US20210353544A1 (en) | 2005-09-14 | 2021-07-26 | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces |
Country Status (16)
Country | Link |
---|---|
US (15) | US7803404B2 (en) |
EP (3) | EP1937219B1 (en) |
JP (4) | JP5167133B2 (en) |
KR (7) | KR20160022404A (en) |
CN (3) | CN104324366B (en) |
AU (2) | AU2006290870B2 (en) |
BR (2) | BRPI0616071B8 (en) |
CA (2) | CA2620758C (en) |
DK (3) | DK1928423T3 (en) |
ES (3) | ES2555310T3 (en) |
HK (2) | HK1116088A1 (en) |
HU (2) | HUE028623T2 (en) |
IN (1) | IN2014DN09128A (en) |
MX (2) | MX358592B (en) |
RU (3) | RU2394550C2 (en) |
WO (2) | WO2007033372A2 (en) |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
DK1196430T3 (en) * | 1999-06-29 | 2012-05-21 | Mannkind Corp | Purification and stabilization of peptides and proteins in pharmaceutical agents |
DE60318938T2 (en) | 2002-03-20 | 2009-01-22 | Mannkind Corp., Valencia | INHALER |
US20080260838A1 (en) * | 2003-08-01 | 2008-10-23 | Mannkind Corporation | Glucagon-like peptide 1 (glp-1) pharmaceutical formulations |
WO2010080964A1 (en) | 2009-01-08 | 2010-07-15 | Mannkind Corporation | Method for treating hyperglycemia with glp-1 |
US8921311B2 (en) | 2003-08-01 | 2014-12-30 | Mannkind Corporation | Method for treating hyperglycemia |
ES2385934T3 (en) | 2004-08-20 | 2012-08-03 | Mannkind Corporation | CATALYSIS OF THE SYNTHESIS OF DICETOPIPERAZINA. |
EP2314298B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Microparticles comprising diketopiperazine salts for drug delivery |
KR20160022404A (en) | 2005-09-14 | 2016-02-29 | 맨카인드 코포레이션 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
MX2008010721A (en) | 2006-02-22 | 2008-09-01 | Mannkind Corp | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent. |
KR101438839B1 (en) * | 2006-04-14 | 2014-10-02 | 맨카인드 코포레이션 | Glucagon-like peptide 1 (glp-1)pharmaceutical formulations |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
WO2009055740A2 (en) * | 2007-10-24 | 2009-04-30 | Mannkind Corporation | Method of preventing adverse effects by glp-1 |
WO2009055742A2 (en) * | 2007-10-24 | 2009-04-30 | Mannkind Corporation | Delivery of active agents |
EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
MX2010014240A (en) | 2008-06-20 | 2011-03-25 | Mankind Corp | An interactive apparatus and method for real-time profiling of inhalation efforts. |
CA2729764A1 (en) * | 2008-07-01 | 2010-01-07 | Nitto Denko Corporation | Pharmaceutical composition containing surface-coated microparticles |
TWI614024B (en) * | 2008-08-11 | 2018-02-11 | 曼凱公司 | Use of ultrarapid acting insulin |
MX353900B (en) | 2008-11-07 | 2018-02-01 | Massachusetts Inst Technology | Aminoalcohol lipidoids and uses thereof. |
JP5788806B2 (en) | 2008-12-29 | 2015-10-07 | マンカインド コーポレイション | Substituted diketopiperazines and salts thereof for drug delivery agents, therapeutic compositions containing them, fine particle compositions and dry powder compositions, and methods for preparing the same |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
US8551528B2 (en) | 2009-06-12 | 2013-10-08 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
WO2010144785A2 (en) | 2009-06-12 | 2010-12-16 | Mannkind Corporation | Diketopiperazine microparticles with defined isomer contents |
US8642548B2 (en) | 2009-08-07 | 2014-02-04 | Mannkind Corporation | Val (8) GLP-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome |
SG10201406835XA (en) | 2009-11-02 | 2014-11-27 | Mannkind Corp | Apparatus And Method For Cryogranulating A Pharmaceutical Composition |
US8491848B2 (en) | 2009-11-02 | 2013-07-23 | Mannkind Corporation | Reactor for producing pharmaceutical particles in a precipitation process |
EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
EP2567219B1 (en) | 2010-05-07 | 2019-09-18 | MannKind Corporation | Method and apparatus for determining weight percent of microparticles of diketopiperazine in suspension using raman spectroscopy |
BR112012033060A2 (en) * | 2010-06-21 | 2018-02-27 | Mannkind Corp | Dry powder drug release system methods |
US10140619B2 (en) * | 2010-06-22 | 2018-11-27 | Sizmek Technologies, Inc. | Dynamic creative creation and delivery |
MX340112B (en) | 2010-11-09 | 2016-06-27 | Mannkind Corp | Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines. |
KR101940832B1 (en) | 2011-04-01 | 2019-01-21 | 맨카인드 코포레이션 | Blister package for pharmaceutical cartridges |
SG10201604560TA (en) | 2011-04-12 | 2016-07-28 | Moerae Matrix Inc | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
US9890200B2 (en) | 2011-04-12 | 2018-02-13 | Moerae Matrix, Inc. | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
EP2776053A1 (en) | 2011-10-24 | 2014-09-17 | MannKind Corporation | Methods and compositions for treating pain |
PE20150041A1 (en) | 2011-10-27 | 2015-01-28 | Massachusetts Inst Technology | DERIVATIVES OF AMINO ACIDS FUNCTIONALIZED IN THE N TERMINAL, CAPABLE OF FORMING DRUG ENCAPSULATING MICROSPHERES |
US20130261372A1 (en) * | 2012-03-30 | 2013-10-03 | Elwha LLC, a limited liability company of the State of Delaware | Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions |
SG11201500218VA (en) | 2012-07-12 | 2015-03-30 | Mannkind Corp | Dry powder drug delivery systems and methods |
KR20150047606A (en) * | 2012-08-29 | 2015-05-04 | 맨카인드 코포레이션 | Method and composition for treating hyperglycemia |
WO2014043110A2 (en) * | 2012-09-11 | 2014-03-20 | University Of Massachusetts | Crosslinked polymer nano-assemblies and uses thereof |
UA116217C2 (en) | 2012-10-09 | 2018-02-26 | Санофі | Exendin-4 derivatives as dual glp1/glucagon agonists |
EP2911690A1 (en) | 2012-10-26 | 2015-09-02 | MannKind Corporation | Inhalable influenza vaccine compositions and methods |
JP2016503771A (en) | 2012-12-21 | 2016-02-08 | サノフイ | Exendin-4 derivative |
EP3587404B1 (en) * | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR122019026637B1 (en) | 2013-07-18 | 2023-09-26 | Mannkind Corporation | PHARMACEUTICAL DRY POWDER FORMULATIONS AND METHOD FOR MANUFACTURING A DRY POWDER FORMULATION |
CA2920488C (en) | 2013-08-05 | 2022-04-26 | Mannkind Corporation | Insufflation apparatus and methods |
EP3080149A1 (en) | 2013-12-13 | 2016-10-19 | Sanofi | Dual glp-1/glucagon receptor agonists |
WO2015086729A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/gip receptor agonists |
EP3080150B1 (en) | 2013-12-13 | 2018-08-01 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
TW201609796A (en) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | Non-acylated EXENDIN-4 peptide analogues |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
TW201625669A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Peptidic dual GLP-1/glucagon receptor agonists derived from Exendin-4 |
TW201625670A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Dual GLP-1/glucagon receptor agonists derived from EXENDIN-4 |
TW201625668A (en) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists |
US10336788B2 (en) | 2014-04-17 | 2019-07-02 | Moerae Matrix, Inc. | Inhibition of cardiac fibrosis in myocardial infarction |
EP3148552B1 (en) | 2014-05-30 | 2019-07-31 | Translate Bio, Inc. | Biodegradable lipids for delivery of nucleic acids |
US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
AU2015279968B2 (en) | 2014-06-24 | 2019-11-14 | Translate Bio, Inc. | Stereochemically enriched compositions for delivery of nucleic acids |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
KR20170083063A (en) | 2014-11-17 | 2017-07-17 | 모레 매트릭스 인코포레이티드 | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
US9999655B2 (en) | 2015-03-12 | 2018-06-19 | Moerae Matrix, Inc. | Use of MKS inhibitor peptide-containing compositions for treating non-small cell lung cancer with same |
AR105319A1 (en) | 2015-06-05 | 2017-09-27 | Sanofi Sa | PROPHARMS THAT INCLUDE A DUAL AGONIST GLU-1 / GLUCAGON CONJUGATE HIALURONIC ACID CONNECTOR |
JP6800410B2 (en) | 2015-06-19 | 2020-12-16 | マサチューセッツ インスティテュート オブ テクノロジー | Alkenyl Substituents 2,5-Piperazinediones and Their Use in Compositions for Delivering Agents to Subjects or Cells |
AR105284A1 (en) | 2015-07-10 | 2017-09-20 | Sanofi Sa | DERIVATIVES OF EXENDINA-4 AS SPECIFIC DUAL PEPTIDE AGONISTS OF GLP-1 / GLUCAGÓN RECEPTORS |
WO2017132601A1 (en) * | 2016-01-29 | 2017-08-03 | Mannkind Corporation | Dry powder inhaler |
CA3102967A1 (en) * | 2018-06-07 | 2019-12-12 | Mannkind Corporation | Composition and method for inhalation |
CN114471750A (en) * | 2020-10-23 | 2022-05-13 | 南京工业大学 | Method for reliably synthesizing nano/submicron droplets by inducing liquid-liquid phase separation and application thereof |
Family Cites Families (1114)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB475440A (en) | 1935-09-23 | 1937-11-19 | Mine Safety Appliances Co | Improvements in or relating to apparatus for determining the flow resistance of breathing apparatus elements |
US2549303A (en) | 1949-04-20 | 1951-04-17 | Bristol Lab Inc | Inhaler for crystalline pencilllin or the like |
BE509861A (en) | 1952-03-13 | |||
US2754276A (en) | 1953-02-12 | 1956-07-10 | Du Pont | Cellular compositions utilizing dinitrosopentamethylene-tetramine as the blowing agent |
US3337740A (en) | 1962-02-13 | 1967-08-22 | Deering Milliken Res Corp | Process for separating acrylic acid from impurities |
US4187129A (en) | 1962-05-14 | 1980-02-05 | Aerojet-General Corporation | Gelled mechanically stable high energy fuel composition containing metal platelets |
FR1451293A (en) | 1964-05-18 | 1966-01-07 | Entoleter | Composite material and its preparation process |
US3407203A (en) | 1965-03-22 | 1968-10-22 | Union Carbide Corp | Novel process for the preparation of diketopiperazines |
US3669113A (en) | 1966-03-07 | 1972-06-13 | Fisons Ltd | Inhalation device |
US3518340A (en) | 1968-04-15 | 1970-06-30 | Dow Corning | Method of forming silicone rubber drug carriers |
US3622053A (en) | 1969-12-10 | 1971-11-23 | Schering Corp | Aerosol inhaler with flip-up nozzle |
US3673698A (en) | 1970-11-25 | 1972-07-04 | Albert S Guerard | Process for freeze drying with carbon dioxide |
BE794951A (en) | 1972-02-03 | 1973-05-29 | Parke Davis & Co | WATER SOLUBLE PACKAGING |
US3873651A (en) | 1972-05-12 | 1975-03-25 | Atomic Energy Commission | Freeze drying method for preparing radiation source material |
US3823843A (en) | 1972-10-26 | 1974-07-16 | Lilly Co Eli | Locking capsule |
US3856142A (en) | 1973-01-24 | 1974-12-24 | Mine Safety Appliances Co | Inhalant package |
FR2224175B1 (en) | 1973-04-04 | 1978-04-14 | Isf Spa | |
US3980074A (en) | 1973-07-18 | 1976-09-14 | Beecham Group Limited | Device for the administration of powders |
GB1479283A (en) | 1973-07-23 | 1977-07-13 | Bespak Industries Ltd | Inhaler for powdered medicament |
GB1459488A (en) | 1974-03-19 | 1976-12-22 | Wyeth John & Brother Ltd | Piperazinedione derivatives |
IT1017153B (en) | 1974-07-15 | 1977-07-20 | Isf Spa | APPARATUS FOR INHALATIONS |
US4018619A (en) | 1974-09-23 | 1977-04-19 | Iu Technology Corporation | Highly activated mixtures for constructing load bearing surfaces and method of making the same |
US4005711A (en) | 1975-01-13 | 1977-02-01 | Syntex Puerto Rico, Inc. | Inhalation device |
DE2502251A1 (en) | 1975-01-17 | 1976-07-22 | Schering Ag | DEVICE FOR INHALATION OF POWDERED SOLIDS |
US4040536A (en) | 1975-05-05 | 1977-08-09 | R. P. Scherer Corporation | Locking hard gelatin capsule |
DK252076A (en) | 1975-06-09 | 1976-12-10 | Nat Distillers Chem Corp | PROCEDURE TO MAKE ETHYLENE-VINYL POLYMER RESISTANT TO AGGLOMATION |
US4153689A (en) | 1975-06-13 | 1979-05-08 | Takeda Chemical Industries, Ltd. | Stable insulin preparation for nasal administration |
US3998226A (en) | 1975-09-22 | 1976-12-21 | Edward G. Gomez | Inhalation device for encapsulated concentrates |
GB1509979A (en) | 1975-11-28 | 1978-05-10 | Fisons Ltd | Pharmaceutical compositions containing aspirin or indomethacin |
US4102953A (en) | 1976-05-25 | 1978-07-25 | The United States Of America As Represented By The Secretary Of The Navy | Method for making extruded, solventless, composite-modified double base propellant |
USD252707S (en) | 1977-01-03 | 1979-08-21 | Joel Besnard | Inhaler |
GB1598081A (en) | 1977-02-10 | 1981-09-16 | Allen & Hanburys Ltd | Inhaler device for dispensing medicaments |
US4171000A (en) | 1977-03-23 | 1979-10-16 | Uhle Klaus P | Smoking device |
IE46865B1 (en) | 1977-04-29 | 1983-10-19 | Allen & Hanburys Ltd | Device for dispensing medicaments |
US4148308A (en) | 1977-05-31 | 1979-04-10 | Sayer William J | Mouthpiece with a tongue retractor |
US4110240A (en) | 1977-07-29 | 1978-08-29 | Wyrough And Loser, Inc. | Coprecipitation process |
US4091077A (en) | 1977-08-12 | 1978-05-23 | The United States Of America As Represented By The United States Department Of Energy | Process for recovering filler from polymer |
US4211769A (en) | 1977-08-24 | 1980-07-08 | Takeda Chemical Industries, Ltd. | Preparations for vaginal administration |
US4268460A (en) | 1977-12-12 | 1981-05-19 | Warner-Lambert Company | Nebulizer |
CA1113044A (en) | 1977-12-16 | 1981-11-24 | J. Paul Leblond | Personal repellant device |
US4356167A (en) | 1978-01-27 | 1982-10-26 | Sandoz, Inc. | Liposome drug delivery systems |
US4175556A (en) | 1978-04-07 | 1979-11-27 | Freezer Winthrop J | Inhaler with flow-through cap |
US4196196A (en) | 1978-06-19 | 1980-04-01 | Tiholiz Ivan C | Divalen/monovalent bipolar cation therapy for enhancement of tissue perfusion and reperfusion in disease states |
US4168002A (en) | 1978-08-03 | 1979-09-18 | Crosby Leslie O | Multiple-seed package card |
US4272398A (en) | 1978-08-17 | 1981-06-09 | The United States Of America As Represented By The Secretary Of Agriculture | Microencapsulation process |
DE2840442C2 (en) | 1978-09-16 | 1982-02-11 | C.H. Boehringer Sohn, 6507 Ingelheim | Use of the diketopiperazine L-Leu-L-Trp as a flavoring for beverages with a bitter taste |
DE2849493C2 (en) | 1978-11-15 | 1982-01-14 | Carl Heyer Gmbh, Inhalationstechnik, 5427 Bad Ems | Hand-held aerosol dispenser |
USD269463S (en) | 1978-12-08 | 1983-06-21 | Fisons Limited | Container for a medicinal inhaler |
JPS5837833Y2 (en) | 1979-04-27 | 1983-08-26 | 凸版印刷株式会社 | ampoule storage container |
JPS6034925B2 (en) | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
US4407525A (en) | 1979-10-04 | 1983-10-04 | Gao Gesellschaft Fur Automation Und Organisation Mbh | Identification card with hallmark for authentication by incident and transmitted light |
GB2072536B (en) | 1980-03-25 | 1983-12-07 | Malem H | Nebuliser |
US4289759A (en) | 1980-06-23 | 1981-09-15 | Ortho Pharmaceutical Corporation | Immunoregulatory diketopiperazine compounds |
EP0055537B1 (en) | 1980-12-12 | 1984-12-05 | Combi Co., Ltd. | Inhaler |
US4900730A (en) | 1981-01-14 | 1990-02-13 | Toyo Jozo Co., Ltd. | Preparation which promotes the absorption of peptides |
GB2092136B (en) | 1981-01-17 | 1985-06-05 | Mitsui Toatsu Chemicals | Production of n-substituted amide compounds |
JPS58140026A (en) | 1982-01-14 | 1983-08-19 | Toyo Jozo Co Ltd | Pharmaceutical having improved absorbability |
IT1220979B (en) | 1981-06-04 | 1990-06-21 | Lofarma Farma Lab | CAPSULES CONTAINING AN ALLERGEN AND PROCEDURE FOR THEIR PREPARATION |
SE438261B (en) | 1981-07-08 | 1985-04-15 | Draco Ab | USE IN A DOSHALATOR OF A PERFORED MEMBRANE |
CY1492A (en) | 1981-07-08 | 1990-02-16 | Draco Ab | Powder inhalator |
US5260306A (en) | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
USD276654S (en) | 1981-09-15 | 1984-12-04 | Aktiebolaget Draco | Medical aerosol inhalation device |
KR890000664B1 (en) | 1981-10-19 | 1989-03-22 | 바리 안소니 뉴우샘 | Preparation method for micronised be clomethasone dispropionate mono-hydrate |
US4659696A (en) | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
US4483922A (en) | 1982-05-14 | 1984-11-20 | Amf Inc. | Inactivation of enzymes |
US4526804A (en) | 1982-08-30 | 1985-07-02 | Ball Corporation | Method for providing sheet metal stock with finely divided powder |
US4487327A (en) | 1982-12-21 | 1984-12-11 | Grayson Robert E | Locking capsule |
JPS59163313A (en) | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
US4481139A (en) | 1983-04-13 | 1984-11-06 | Board Of Regents, The University Of Texas System | Peptide antagonists of substance P |
AU90762S (en) | 1983-06-29 | 1985-08-15 | Glaxo Group Ltd | Inhaler |
US4581020A (en) | 1983-07-18 | 1986-04-08 | Trimedyne, Inc. | Medication delivery device and system for percutaneous administration of medication |
GB8325529D0 (en) | 1983-09-23 | 1983-10-26 | Lilly Industries Ltd | Medicinal forms |
CH661878A5 (en) | 1983-11-04 | 1987-08-31 | Warner Lambert Co | CAPSULE DOSING FORMS. |
WO1995013796A1 (en) | 1993-11-16 | 1995-05-26 | Depotech Corporation | Vesicles with controlled release of actives |
US4671954A (en) | 1983-12-13 | 1987-06-09 | University Of Florida | Microspheres for incorporation of therapeutic substances and methods of preparation thereof |
USD295321S (en) | 1984-03-13 | 1988-04-19 | Glaxo Group Limited | Inhaler container for a medical aerosol |
JPS60248618A (en) | 1984-05-24 | 1985-12-09 | Nippon Zoki Pharmaceut Co Ltd | Dipeptide-containing remedy for ulcer |
US4927555A (en) | 1984-08-13 | 1990-05-22 | Colgate-Palmolive Company | Process for making thixotropic detergent compositions |
USD288852S (en) | 1984-08-29 | 1987-03-17 | Aruman Co., Ltd. | Disposable inhaler |
US4757066A (en) | 1984-10-15 | 1988-07-12 | Sankyo Company Limited | Composition containing a penem or carbapenem antibiotic and the use of the same |
IE58468B1 (en) | 1984-10-25 | 1993-09-22 | Warner Lambert Co | Method for sealing capsules and capsule |
US4592348A (en) | 1984-12-17 | 1986-06-03 | Waters Iv William C | Aerosol inhaler |
US4946828A (en) | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
SE448277B (en) | 1985-04-12 | 1987-02-09 | Draco Ab | INDICATOR DEVICE WITH A DOSAGE DEVICE FOR MEDICINAL PRODUCTS |
JPS6320301Y2 (en) | 1985-04-18 | 1988-06-06 | ||
US5785989A (en) | 1985-05-01 | 1998-07-28 | University Utah Research Foundation | Compositions and methods of manufacturing of oral dissolvable medicaments |
US4615817A (en) | 1985-05-17 | 1986-10-07 | Mccoy Frederic C | Additives containing polytetrafluoroethylene for making stable lubricants |
CA1318730C (en) | 1985-05-30 | 1993-06-01 | C. Edward Capes | Method of separating carbonaceous components from particulate coal containing inorganic solids and apparatus therefor |
US5098590A (en) | 1988-02-04 | 1992-03-24 | Colgate Palmolive Co. | Thixotropic aqueous automatic dishwasher detergent compositions with improved stability |
PH26882A (en) | 1985-07-30 | 1992-11-16 | Glaxo Group Ltd | Devices for administering medicaments to patients |
AT384552B (en) | 1985-08-01 | 1987-12-10 | Hurka Wilhelm | INHALATION DEVICE FOR DOSING AND DISTRIBUTING SOLID BODIES INTO THE BREATHING AIR |
US4624861A (en) | 1985-09-05 | 1986-11-25 | Gte Products Corporation | Rare earth oxysulfide phosphors and processes for creating same |
US4742156A (en) | 1985-09-30 | 1988-05-03 | Mcneilab, Inc. | Peptide antagonists of neurokinin B and opthalmic solutions containing them |
PT83613B (en) | 1985-10-28 | 1988-11-21 | Lilly Co Eli | Process for the selective chemical removal of a protein amino-terminal residue |
US4847091A (en) | 1985-11-29 | 1989-07-11 | Fisons Plc | Pharmaceutical composition including sodium cromoglycate |
LU86258A1 (en) | 1986-01-21 | 1987-09-03 | Rech Dermatologiques C I R D S | BENZAMIDO AROMATIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS |
SE453566B (en) | 1986-03-07 | 1988-02-15 | Draco Ab | POWDER INHALATOR DEVICE |
US4849227A (en) | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US6849708B1 (en) | 1986-05-05 | 2005-02-01 | The General Hospital Corporation | Insulinotropic hormone and uses thereof |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US4926852B1 (en) | 1986-06-23 | 1995-05-23 | Univ Johns Hopkins | Medication delivery system phase one |
USD301273S (en) | 1986-07-10 | 1989-05-23 | Leonard G Darin | Hand held fly suction device |
JPS6320301A (en) | 1986-07-11 | 1988-01-28 | Dainichi Color & Chem Mfg Co Ltd | Chitosan microparticle |
US5042975A (en) | 1986-07-25 | 1991-08-27 | Rutgers, The State University Of New Jersey | Iontotherapeutic device and process and iontotherapeutic unit dose |
JP2765700B2 (en) | 1986-08-11 | 1998-06-18 | イノベータ・バイオメド・リミテツド | Pharmaceutical composition containing microcapsules |
EP0545913B1 (en) | 1986-08-18 | 1999-02-24 | Emisphere Technologies, Inc. | Delivery systems for pharmacological agents |
USRE35862E (en) | 1986-08-18 | 1998-07-28 | Emisphere Technologies, Inc. | Delivery systems for pharmacological agents encapsulated with proteinoids |
ES2032831T5 (en) | 1986-08-19 | 2001-02-16 | Genentech Inc | DEVICE AND DISPERSION FOR INTRAPULMONARY SUPPLY OF POLYPEPTIDE AND CYTOKIN GROWTH FACTORS. |
DE3639836A1 (en) | 1986-11-21 | 1988-06-01 | Sigrid Bechter | Mouthpiece for an inhaler |
KR890003520Y1 (en) | 1986-12-20 | 1989-05-27 | 주식회사 서흥캅셀 | Medicinal capsule |
US4861627A (en) | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
US4981295A (en) | 1987-05-11 | 1991-01-01 | City Of Hope | Respiratory training using feedback |
US6645504B1 (en) | 1987-06-24 | 2003-11-11 | Autoimmune Inc. | Bystander suppression of type I diabetes by oral administration of glucagon |
US4913173A (en) | 1987-06-25 | 1990-04-03 | International Beauty Distributors, Inc. | High efficiency wrap package, and process, for nails |
DE3727894A1 (en) | 1987-08-21 | 1989-03-02 | Stephan Dieter | CAPSULE FOR PHARMACEUTICAL ACTIVE INGREDIENTS OF A DRUG |
GB8723846D0 (en) | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
US4887722A (en) | 1987-12-11 | 1989-12-19 | Greenward Sr Edward H | Method for beneficiating by carbonaceous refuse |
DE3801326A1 (en) | 1988-01-19 | 1989-07-27 | Asea Brown Boveri | METHOD FOR PRODUCING A CERAMIC SUSPENSION |
US4981625A (en) | 1988-03-14 | 1991-01-01 | California Institute Of Technology | Monodisperse, polymeric microspheres produced by irradiation of slowly thawing frozen drops |
CH675267A5 (en) | 1988-03-16 | 1990-09-14 | Geberit Ag | |
GB8813338D0 (en) | 1988-06-06 | 1988-07-13 | Osprey Metals Ltd | Powder production |
USD316902S (en) | 1988-09-02 | 1991-05-14 | Hoelfing H Curt | Meter hose inhaler reservoir |
GB8821287D0 (en) | 1988-09-12 | 1988-10-12 | Ici Plc | Device |
EP0360340A1 (en) | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
USD321570S (en) | 1988-09-30 | 1991-11-12 | Blasdell Richard J | Inhaler |
EP0363060B1 (en) | 1988-10-04 | 1994-04-27 | The Johns Hopkins University | Aerosol inhaler |
JPH02104531A (en) | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | Physiologically active peptide composition for nasal application |
US4984158A (en) | 1988-10-14 | 1991-01-08 | Hillsman Dean | Metered dose inhaler biofeedback training and evaluation system |
JPH02115154A (en) | 1988-10-25 | 1990-04-27 | Kao Corp | Imide compound and use thereof |
USD326517S (en) | 1988-10-27 | 1992-05-26 | Glaxo Group Limited | Inhalator |
JP2692742B2 (en) | 1988-11-30 | 1997-12-17 | 株式会社ツムラ | New lignans |
US5006343A (en) | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
US5075027A (en) | 1989-02-06 | 1991-12-24 | Colgate Palmolive Co. | Thixotropic aqueous scented automatic dishwasher detergent compositions |
US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
IT1228459B (en) | 1989-02-23 | 1991-06-19 | Phidea S R L | INHALER WITH REGULAR AND COMPLETE EMPTYING OF THE CAPSULE. |
IT1228460B (en) | 1989-02-23 | 1991-06-19 | Phidea S R L | DISPOSABLE INHALER WITH PRE-PERFORATED CAPSULE |
US4983402A (en) | 1989-02-24 | 1991-01-08 | Clinical Technologies Associates, Inc. | Orally administerable ANF |
SE466684B (en) | 1989-03-07 | 1992-03-23 | Draco Ab | DEVICE INHALATOR AND PROCEDURE TO REGISTER WITH THE DEVICE INHALATOR MEDICATION |
US5358734A (en) | 1989-03-30 | 1994-10-25 | Gte Products Corporation | Process for producing a blue emitting lamp phosphor |
US5215739A (en) | 1989-04-05 | 1993-06-01 | Toko Yakuhin Kogyo Kabushiki Kaisha | Spray gel base and spray gel preparation using thereof |
US5067500A (en) | 1989-04-24 | 1991-11-26 | Philip Morris Incorporated | Container for additive materials for smoking articles |
US4991605A (en) | 1989-04-24 | 1991-02-12 | Philip Morris Incorporated | Container for additive materials for smoking articles |
GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
AU643435B2 (en) | 1989-04-28 | 1993-11-18 | Riker Laboratories, Inc. | Dry powder inhalation device |
US5019400A (en) | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
CA2030551C (en) | 1989-05-01 | 1998-08-25 | Wayne Gombotz | Process for producing small particles of biologically active molecules |
US5017383A (en) | 1989-08-22 | 1991-05-21 | Taisho Pharmaceutical Co., Ltd. | Method of producing fine coated pharmaceutical preparation |
GB8919131D0 (en) | 1989-08-23 | 1989-10-04 | Riker Laboratories Inc | Inhaler |
US5270305A (en) | 1989-09-08 | 1993-12-14 | Glaxo Group Limited | Medicaments |
GB8921222D0 (en) | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
DK544589D0 (en) | 1989-11-01 | 1989-11-01 | Novo Nordisk As | MANUALLY OPERATED DEVICE FOR DISPENSING A PRESCRIBED QUANTITY OF A POWDER-SHAPED SUBSTANCE |
JPH0741428Y2 (en) | 1989-11-04 | 1995-09-27 | アップリカ葛西株式会社 | Baby bath |
CA2071867A1 (en) * | 1989-11-06 | 1991-05-07 | Edith Mathiowitz | Method for producing protein microspheres |
US5188837A (en) | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
US5105291A (en) * | 1989-11-20 | 1992-04-14 | Ricoh Company, Ltd. | Liquid crystal display cell with electrodes of substantially amorphous metal oxide having low resistivity |
AU6774790A (en) | 1989-12-06 | 1991-06-13 | Canon Kabushiki Kaisha | Package for ink jet cartridge |
USD331106S (en) | 1989-12-30 | 1992-11-17 | Ing. Erich Pfeiffer Gmbh & Co. Kg | Single use inhaler |
GB9001635D0 (en) | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
US5201308A (en) | 1990-02-14 | 1993-04-13 | Newhouse Michael T | Powder inhaler |
SK280967B6 (en) | 1990-03-02 | 2000-10-09 | Glaxo Group Limited | Inhalation device |
UA26230A (en) | 1990-03-02 | 1999-07-19 | Глексо Груп Лімітед | SHARED USER INHALATOR WITH TREATMENT UNIT AND TREATMENT UNIT |
US6536427B2 (en) | 1990-03-02 | 2003-03-25 | Glaxo Group Limited | Inhalation device |
US5615670A (en) | 1990-03-07 | 1997-04-01 | Fisons Plc | Powder inhaler with centrifugal force used to meter powder |
IT1240750B (en) | 1990-04-12 | 1993-12-17 | Chiesi Farma Spa | DEVICE FOR THE ADMINISTRATION OF MEDICAMENTOUS POWDER SUBSTANCES |
JPH05963A (en) | 1990-04-13 | 1993-01-08 | Toray Ind Inc | Polypeptide composition |
US5328464A (en) | 1990-04-24 | 1994-07-12 | Science Incorporated | Closed drug delivery system |
USD338268S (en) | 1990-05-04 | 1993-08-10 | Omron Corporation | Heating inhaler |
AU7908791A (en) | 1990-05-08 | 1991-11-27 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
IL111254A (en) | 1990-06-14 | 1998-10-30 | Rhone Poulenc Rorer Ltd | Powder inhalers |
DE4021263C2 (en) | 1990-07-04 | 1996-04-11 | Pfeiffer Erich Gmbh & Co Kg | Discharge device for media |
GB9015522D0 (en) | 1990-07-13 | 1990-08-29 | Braithwaite Philip W | Inhaler |
US6331318B1 (en) | 1994-09-30 | 2001-12-18 | Emisphere Technologies Inc. | Carbon-substituted diketopiperazine delivery systems |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US5447728A (en) | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5451410A (en) | 1993-04-22 | 1995-09-19 | Emisphere Technologies, Inc. | Modified amino acids for encapsulating active agents |
US5693338A (en) | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
US5541155A (en) | 1994-04-22 | 1996-07-30 | Emisphere Technologies, Inc. | Acids and acid salts and their use in delivery systems |
JPH04103585A (en) | 1990-08-24 | 1992-04-06 | Nisshin Flour Milling Co Ltd | Compound having pyrrolidine ring |
US5074418A (en) | 1990-09-12 | 1991-12-24 | Pitney Bowes Inc. | Ink replenishing system transport and storage container |
SE9002895D0 (en) | 1990-09-12 | 1990-09-12 | Astra Ab | INHALATION DEVICES FOR DISPENSING POWDERS I |
EP0503031B1 (en) | 1990-09-26 | 1998-04-01 | Pharmachemie B.V. | Inhaler devices provided with a reservoir for several doses of medium for inhaling, transporting device, whirl chamber |
US5170801A (en) | 1990-10-02 | 1992-12-15 | Glaxo Inc. | Medical capsule device actuated by radio-frequency (rf) signal |
FR2667509B1 (en) | 1990-10-04 | 1995-08-25 | Valois | POWDER INHALER, DEVICE FOR PACKAGING POWDER MICRODOSES IN THE FORM OF BANDS SUITABLE FOR USE IN A POWDER INHALER, AND METHOD FOR MANUFACTURING SUCH BANDS. |
IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Pharmaceutical oral, enteral or by-inhalation dosage form for suppressing an autoimmune response associated with type i diabetes |
GB9024760D0 (en) | 1990-11-14 | 1991-01-02 | Riker Laboratories Inc | Inhalation device and medicament carrier |
US5124291A (en) | 1990-11-15 | 1992-06-23 | The Standard Oil Company | Method for deagglomerating and re-exposing catalyst in a fluid bed reactor |
GB9026191D0 (en) | 1990-12-01 | 1991-01-16 | Harris Pharma Ltd | Breath actuated dispensing device |
GB9027234D0 (en) | 1990-12-15 | 1991-02-06 | Harris Pharma Ltd | An inhalation device |
WO1992011050A1 (en) | 1990-12-17 | 1992-07-09 | Minnesota Mining And Manufacturing Company | Inhaler |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
GB2253200A (en) | 1991-02-01 | 1992-09-02 | Harris Pharma Ltd | Inhalation apparatus and fracturable capsule for use therewith |
WO1992014449A1 (en) | 1991-02-20 | 1992-09-03 | Nova Pharmaceutical Corporation | Controlled release microparticulate delivery system for proteins |
US5208998A (en) | 1991-02-25 | 1993-05-11 | Oyler Jr James R | Liquid substances freeze-drying systems and methods |
US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
US5394866A (en) | 1991-03-05 | 1995-03-07 | Aradigm Corporation | Automatic aerosol medication delivery system and methods |
JP3532204B2 (en) | 1991-03-05 | 2004-05-31 | アラダイム コーポレーション | Method and apparatus for correcting drift offset of a flow sensor pressure sensor |
USD338062S (en) | 1991-03-06 | 1993-08-03 | Innovata Biomed Limited | Inhaler |
USD347057S (en) | 1991-03-14 | 1994-05-17 | Technosystem Limited | Inhaler |
JPH05273772A (en) | 1991-03-28 | 1993-10-22 | Mita Ind Co Ltd | Hydrazone compound and photosensitive body using it |
US5797391A (en) | 1991-03-28 | 1998-08-25 | Rhone-Poulenc Rorer Limited | Inhaler |
US5413804A (en) | 1991-04-23 | 1995-05-09 | Cacique, Inc. | Process for making whey-derived fat substitute product and products thereof |
US5244653A (en) | 1991-05-01 | 1993-09-14 | Isp Chemicals Inc. | Glycine anhydride dimethylol as a biocide and preservative |
US5327883A (en) | 1991-05-20 | 1994-07-12 | Dura Pharmaceuticals, Inc. | Apparatus for aerosolizing powdered medicine and process and using |
US6060069A (en) | 1991-05-20 | 2000-05-09 | Dura Pharmaceuticals, Inc. | Pulmonary delivery of pharmaceuticals |
US5492112A (en) | 1991-05-20 | 1996-02-20 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US6055980A (en) | 1991-05-20 | 2000-05-02 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
FR2676929B1 (en) | 1991-05-30 | 1994-02-11 | Aerosols Bouchage Ste Fse | POWDER INHALER. |
CA2070061C (en) | 1991-06-07 | 2004-02-10 | Shigeyuki Takama | Physiologically active polypeptide-containing pharmaceutical composition |
IT1248059B (en) | 1991-06-14 | 1995-01-05 | Miat Spa | MULTI-DOSE INSUFFLATOR FOR POWDER DRUGS |
US6681767B1 (en) | 1991-07-02 | 2004-01-27 | Nektar Therapeutics | Method and device for delivering aerosolized medicaments |
AU662919B2 (en) | 1991-07-02 | 1995-09-21 | Inhale, Inc. | Method and device for delivering aerosolized medicaments |
US5203768A (en) | 1991-07-24 | 1993-04-20 | Alza Corporation | Transdermal delivery device |
US5337740A (en) | 1991-08-01 | 1994-08-16 | New England Pharmaceuticals, Inc. | Inhalation devices |
GB9116610D0 (en) | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
US5139878A (en) | 1991-08-12 | 1992-08-18 | Allied-Signal Inc. | Multilayer film constructions |
DE69211450T2 (en) | 1991-08-16 | 1996-12-05 | Sandoz Ag | Inhaler for the administration of powdered substances |
US5287850A (en) | 1991-08-20 | 1994-02-22 | Habley Medical Technology Corporation | Timing and velocity controlled powered pharmaceutical inhaler |
US6119688A (en) | 1991-08-26 | 2000-09-19 | 3M Innovative Properties Company | Powder dispenser |
USD337636S (en) | 1991-09-12 | 1993-07-20 | Devilbiss Health Care, Inc. | Ultrasonic medicament nebulizer |
US5167506A (en) | 1991-10-24 | 1992-12-01 | Minnesota Mining And Manufacturing Company | Inhalation device training system |
USD348100S (en) | 1991-10-29 | 1994-06-21 | Fisons Plc | Medicament inhaler |
JPH0828037B2 (en) | 1991-10-31 | 1996-03-21 | 富士通株式会社 | Spindle sink control method |
USD350602S (en) | 1991-11-01 | 1994-09-13 | Rhone-Poulenc Rorer Limited | Combined dry powder inhaler and cap |
US6063910A (en) | 1991-11-14 | 2000-05-16 | The Trustees Of Princeton University | Preparation of protein microparticles by supercritical fluid precipitation |
USD350821S (en) | 1991-11-18 | 1994-09-20 | Smithkline Beecham P.L.C. | Oral inhaler |
SE9103572D0 (en) | 1991-11-29 | 1991-11-29 | Astra Ab | ORGANIC SALTS OF N, N'-DIACETYL CYSTINE |
USD340975S (en) | 1991-12-02 | 1993-11-02 | Thayer Medical Corporation | Combined expansion chamber metered dose inhaler dispenser and adaptor |
US5338837A (en) | 1991-12-13 | 1994-08-16 | The Trustees Of Princeton University | Glycosylated steroid derivatives for transport across biological membranes and process for making same |
DE4211475A1 (en) | 1991-12-14 | 1993-06-17 | Asta Medica Ag | POWDER INHALATOR |
GB2262452B (en) | 1991-12-19 | 1995-12-20 | Minnesota Mining & Mfg | Inhalation device |
JP3121080B2 (en) | 1991-12-19 | 2000-12-25 | アール・ピー・シーラー コーポレイション | Encapsulation solution |
US5363842A (en) | 1991-12-20 | 1994-11-15 | Circadian, Inc. | Intelligent inhaler providing feedback to both patient and medical professional |
US5525519A (en) | 1992-01-07 | 1996-06-11 | Middlesex Sciences, Inc. | Method for isolating biomolecules from a biological sample with linear polymers |
US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
WO1993013752A1 (en) | 1992-01-21 | 1993-07-22 | Sri International | Improved process for preparing micronized polypeptide drugs |
DE9209050U1 (en) | 1992-02-13 | 1992-10-01 | Schrader, Barthold von, 2400 Travemünde | Inhalation device |
US5476093A (en) | 1992-02-14 | 1995-12-19 | Huhtamaki Oy | Device for more effective pulverization of a powdered inhalation medicament |
US5469971A (en) | 1992-02-26 | 1995-11-28 | Estee Lauder Inc. | Method and apparatus for deagglomerating powder |
EP0558879B1 (en) | 1992-03-04 | 1997-05-14 | Astra Aktiebolag | Disposable inhaler |
US5639441A (en) | 1992-03-06 | 1997-06-17 | Board Of Regents Of University Of Colorado | Methods for fine particle formation |
US5352461A (en) | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
DK36392D0 (en) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | USE OF CHEMICAL COMPOUND |
USD348929S (en) | 1992-04-03 | 1994-07-19 | Norton Healthcare Limited | Medicament inhaler |
CA2096302A1 (en) | 1992-05-15 | 1993-11-16 | David Kilis | Air flow controller and recording system |
USD344796S (en) | 1992-06-11 | 1994-03-01 | Schering Corporation | Combined inhaler and cover |
USD344797S (en) | 1992-06-11 | 1994-03-01 | Schering Corporation | Combined inhaler and cover |
USD350193S (en) | 1992-06-11 | 1994-08-30 | Schering Corporation | Combined inhaler and cover |
USD345013S (en) | 1992-06-11 | 1994-03-08 | Schering Corporation | Combined inhaler and cover |
ES2159524T3 (en) | 1992-06-12 | 2001-10-16 | Teijin Ltd | PHARMACEUTICAL PREPARATION TO BE ADMINISTERED INSIDE THE RESPIRATORY ROADS. |
US5811127A (en) | 1992-06-15 | 1998-09-22 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5792451A (en) | 1994-03-02 | 1998-08-11 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5394868A (en) | 1992-06-25 | 1995-03-07 | Schering Corporation | Inhalation device for powdered medicaments |
GB9213874D0 (en) | 1992-06-30 | 1992-08-12 | Fisons Plc | Process to novel medicament form |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US6509006B1 (en) | 1992-07-08 | 2003-01-21 | Inhale Therapeutic Systems, Inc. | Devices compositions and methods for the pulmonary delivery of aerosolized medicaments |
US5785049A (en) | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
GB9214819D0 (en) | 1992-07-13 | 1992-08-26 | Minnesota Mining & Mfg | Valve assemblies |
GB9216038D0 (en) | 1992-07-28 | 1992-09-09 | Bespak Plc | Dispensing apparatus for powdered medicaments |
GB2269992A (en) | 1992-08-14 | 1994-03-02 | Rh Ne Poulenc Rorer Limited | Powder inhalation formulations |
US5239993A (en) | 1992-08-26 | 1993-08-31 | Glaxo Inc. | Dosage inhalator providing optimized compound inhalation trajectory |
GB2270293A (en) | 1992-09-05 | 1994-03-09 | Medix Ltd | Drug dispensing system |
USD348928S (en) | 1992-09-21 | 1994-07-19 | Schering Corporation | Inhaler |
US5333106A (en) | 1992-10-09 | 1994-07-26 | Circadian, Inc. | Apparatus and visual display method for training in the power use of aerosol pharmaceutical inhalers |
AU5171293A (en) | 1992-10-14 | 1994-05-09 | Regents Of The University Of Colorado, The | Ion-pairing of drugs for improved efficacy and delivery |
KR0177265B1 (en) | 1992-10-19 | 1999-04-01 | 미첼 알. 우드베리 | Dry powder inhaler |
AU121578S (en) | 1992-10-22 | 1994-09-20 | Fisons Plc | An inhalation device |
USD359555S (en) | 1992-11-18 | 1995-06-20 | Nippon Glaxo Limited | Nasal medicine inhaler |
USD352107S (en) | 1992-12-10 | 1994-11-01 | Ciba-Geigy Corporation | Inhaler |
USD349572S (en) | 1992-12-10 | 1994-08-09 | Schering Corporation | Aerosol inhaler |
US6250300B1 (en) | 1992-12-11 | 2001-06-26 | Ab Astra | System for dispensing pharmaceutically active compounds |
SE9203743D0 (en) | 1992-12-11 | 1992-12-11 | Astra Ab | EFFICIENT USE |
CA2152088C (en) | 1992-12-18 | 1999-12-07 | Thomas J. Ambrosio | Inhaler for powdered medications |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
US6880554B1 (en) | 1992-12-22 | 2005-04-19 | Battelle Memorial Institute | Dispensing device |
US6105571A (en) | 1992-12-22 | 2000-08-22 | Electrosols, Ltd. | Dispensing device |
US5896855A (en) | 1992-12-24 | 1999-04-27 | Rhone-Poulenc Rorer Limited | Multi dose inhaler apparatus |
FR2700279B1 (en) | 1993-01-14 | 1995-03-17 | Valois | Portable device for projecting doses of a fluid substance using a stream of compressed air. |
AU119600S (en) | 1993-01-21 | 1994-03-07 | Boehringer Ingelheim Kg | Inhaler device |
US6024090A (en) | 1993-01-29 | 2000-02-15 | Aradigm Corporation | Method of treating a diabetic patient by aerosolized administration of insulin lispro |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
US7448375B2 (en) | 1993-01-29 | 2008-11-11 | Aradigm Corporation | Method of treating diabetes mellitus in a patient |
US5672581A (en) | 1993-01-29 | 1997-09-30 | Aradigm Corporation | Method of administration of insulin |
US6131567A (en) | 1993-01-29 | 2000-10-17 | Aradigm Corporation | Method of use of monomeric insulin as a means for improving the reproducibility of inhaled insulin |
US5888477A (en) | 1993-01-29 | 1999-03-30 | Aradigm Corporation | Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin |
US5441060A (en) | 1993-02-08 | 1995-08-15 | Duke University | Dry powder delivery system |
IL108780A (en) | 1993-02-27 | 1999-06-20 | Fisons Plc | Inhalation device |
AU6360394A (en) * | 1993-03-03 | 1994-09-26 | Mayo Foundation For Medical Education And Research | Vasonatrin peptide and analogs thereof |
US5437271A (en) | 1993-04-06 | 1995-08-01 | Minnesota Mining And Manufacturing Company | Deagglomerators for dry powder inhalers |
US5372128A (en) | 1993-04-14 | 1994-12-13 | Habley Medical Technology Corporation | Fluidizing powder inhaler |
DE69434418T2 (en) | 1993-04-22 | 2005-12-22 | Emisphere Technologies, Inc. | Oral dosage form |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
ZA939608B (en) | 1993-04-22 | 1994-08-24 | Emisphere Tech Inc | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof. |
US5360614A (en) | 1993-04-26 | 1994-11-01 | The Estee Corporation | Method of controlling the release of carbohydrates by encapsulation and composition therefor |
KR100334856B1 (en) | 1993-04-28 | 2002-11-07 | 악조 노벨 엔.브이. | Freeze-dried foods containing gonadotropin |
KR100244690B1 (en) | 1993-05-12 | 2000-02-15 | 야스이 쇼사꾸 | Device and method for dispensing powdered medicine in multiple doses |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
US5533502A (en) | 1993-05-28 | 1996-07-09 | Vortran Medical Technology, Inc. | Powder inhaler with aerosolization occurring within each individual powder receptacle |
USD365876S (en) | 1993-06-16 | 1996-01-02 | Chawla Brindra P S | Medicament inhaler |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
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 |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US5747445A (en) | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
IS1796B (en) | 1993-06-24 | 2001-12-31 | Ab Astra | Inhaled polypeptide formulation composition which also contains an enhancer compound |
US5562909A (en) | 1993-07-12 | 1996-10-08 | Massachusetts Institute Of Technology | Phosphazene polyelectrolytes as immunoadjuvants |
GB9314614D0 (en) | 1993-07-14 | 1993-08-25 | Minnesota Mining & Mfg | Dry powder inhalers |
US5371046A (en) | 1993-07-22 | 1994-12-06 | Taiwan Semiconductor Manufacturing Company | Method to solve sog non-uniformity in the VLSI process |
JPH0741428A (en) | 1993-07-30 | 1995-02-10 | Teijin Ltd | Peptide or protein medicine transnasal-transpulmonary preparation |
JP3545764B2 (en) | 1993-08-18 | 2004-07-21 | フアイソンズ・ピーエルシー | Inhalation device with inspiration rate controller |
US5306453A (en) | 1993-08-18 | 1994-04-26 | Edward Shulman | Apparatus and method of making a non-woven fabric |
US5524613A (en) | 1993-08-25 | 1996-06-11 | Habley Medical Technology Corporation | Controlled multi-pharmaceutical inhaler |
BE1007551A3 (en) | 1993-09-24 | 1995-08-01 | Philips Electronics Nv | Method for in a calculator auto repair of consistency in a hierarchical objektstruktuur after inter action by a user and calculator with such a system for consistency auto repair. |
US5477285A (en) | 1993-10-06 | 1995-12-19 | Thomson Consumer Electronics, Inc. | CRT developing apparatus |
GB9322014D0 (en) | 1993-10-26 | 1993-12-15 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
US5726156A (en) | 1995-03-06 | 1998-03-10 | Trega Biosciences, Inc. | Cytokine regulatory agents and methods of use in pathologies and conditions associated with altered cytokine levels |
EP0655237A1 (en) | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
USD358880S (en) | 1993-12-02 | 1995-05-30 | Tenax Corporation | Dry powder inhalator |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
DE4422710C1 (en) | 1994-06-29 | 1995-09-14 | Boehringer Ingelheim Kg | Inhaler with storage container for aerosol |
PT732952E (en) | 1993-12-18 | 2000-10-31 | Merck Patent Gmbh | PO INHALER |
USD357603S (en) | 1993-12-20 | 1995-04-25 | Wolff Stephen H | Base for displaying or holding items |
US5415162A (en) | 1994-01-18 | 1995-05-16 | Glaxo Inc. | Multi-dose dry powder inhalation device |
US5484606A (en) | 1994-01-24 | 1996-01-16 | The Procter & Gamble Company | Process for reducing the precipitation of difficulty soluble pharmaceutical actives |
PT101450B (en) | 1994-02-02 | 1999-11-30 | Hovione Produtos Farmaceuticos | NEW INHALATION DEVICE |
WO1995022036A1 (en) | 1994-02-09 | 1995-08-17 | Kinerton Limited | Process for drying a material from solution |
SE9400462D0 (en) | 1994-02-11 | 1994-02-11 | Astra Ab | Filling device |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
EP1462096B1 (en) | 1994-03-07 | 2008-12-10 | Nektar Therapeutics | Methods and compositions for pulmonary delivery of insulin |
US5505194A (en) | 1994-03-23 | 1996-04-09 | Abbott Laboratories | Aerosol inhalation device having slideably and rotatably connected elliptical cylinder portions |
AU124387S (en) | 1994-03-25 | 1995-08-11 | Astra Ab | Training device for an inhaler |
US5839429A (en) | 1994-03-25 | 1998-11-24 | Astra Aktiebolag | Method and apparatus in connection with an inhaler |
DK0677263T3 (en) | 1994-04-15 | 1997-10-06 | Fissler Gmbh | Frying and / or cooking utensils adapted for supplying heat energy from the bottom by heat conduction or by electromagnetic induction |
US6395744B1 (en) | 1994-04-22 | 2002-05-28 | Queen's University At Kingston | Method and compositions for the treatment or amelioration of female sexual dysfunction |
FI942196A (en) | 1994-05-11 | 1995-11-12 | Orion Yhtymae Oy | powder inhaler |
KR100384353B1 (en) | 1994-05-18 | 2003-10-04 | 네크타르 테라퓨틱스 | Methods and compositions for preparing dry powder formulations of interferon |
WO1995031979A1 (en) | 1994-05-19 | 1995-11-30 | R.P. Scherer International Corporation | Solutions of aryl or heteroaryl substituted alkanoic acids in lipophilic solvents and soft gelatin capsules containing such solutions |
JP3372105B2 (en) | 1994-05-26 | 2003-01-27 | 株式会社日立ユニシアオートモティブ | Inhalation type dispenser |
FR2720943B1 (en) * | 1994-06-09 | 1996-08-23 | Applic Transferts Technolo | Stable inverse emulsions with a high concentration of fluorinated compound (s) and their use for the pulmonary administration of medicaments and for the manufacture of multiple emulsions. |
US5483954A (en) | 1994-06-10 | 1996-01-16 | Mecikalski; Mark B. | Inhaler and medicated package |
IL110024A (en) | 1994-06-15 | 1998-04-05 | Yissum Res Dev Co | Controlled release oral drug delivery system containing hydrogel- forming polymer |
USD363775S (en) | 1994-06-21 | 1995-10-31 | Rhone-Poulenc Rorer Limited | Multidose dry powder inhaler |
USD362500S (en) | 1994-06-28 | 1995-09-19 | Thayer Medical Corporation | Medication inhaler spacer |
US5641510A (en) | 1994-07-01 | 1997-06-24 | Genentech, Inc. | Method for treating capsules used for drug storage |
US6039208A (en) | 1994-07-29 | 2000-03-21 | Ortho Pharmaceutical Corporation | Variable day start tablet dispenser |
US5562231A (en) | 1994-07-29 | 1996-10-08 | Ortho Pharmaceutical Corporation | Variable day start tablet dispenser |
US5623724A (en) | 1994-08-09 | 1997-04-22 | Northrop Grumman Corporation | High power capacitor |
GB9416884D0 (en) | 1994-08-20 | 1994-10-12 | Danbiosyst Uk | Drug delivery compositions |
USD359153S (en) | 1994-08-25 | 1995-06-13 | Viggiano Bernard J | Muffin top |
US5574008A (en) | 1994-08-30 | 1996-11-12 | Eli Lilly And Company | Biologically active fragments of glucagon-like insulinotropic peptide |
US5547929A (en) | 1994-09-12 | 1996-08-20 | Eli Lilly And Company | Insulin analog formulations |
CZ289029B6 (en) | 1994-09-21 | 2001-10-17 | Inhale Therapeutic Systems | Method for aerosolizing powder, particularly a powdered medicament and apparatus for making the same |
FR2725626A1 (en) | 1994-10-18 | 1996-04-19 | Sofab | DEVICE FOR INHALING POWDERED PRODUCTS |
AU4010395A (en) * | 1994-10-27 | 1996-05-23 | Amgen, Inc. | Compositions for increased bioavailability of orally delivered therapeutic agents |
SE9404140D0 (en) | 1994-11-29 | 1994-11-29 | Astra Ab | Dose indicating device |
AU691361B2 (en) | 1994-12-01 | 1998-05-14 | Toyama Chemical Co. Ltd. | Novel 2,3-diketopiperazine derivative or salt thereof |
SE9404439D0 (en) | 1994-12-21 | 1994-12-21 | Astra Ab | Inhalation device |
AR002009A1 (en) | 1994-12-22 | 1998-01-07 | Astra Ab | PHARMACEUTICAL COMPOSITION, PROCEDURE FOR THE MANUFACTURE OF A PROLIPOSOMA POWDER AS USED IN SUCH COMPOSITION, PROCEDURE FOR LAMANUFACTURE OF SUCH COMPOSITION, USE OF SUCH PHARMACEUTICAL COMPOSITION IN THE MANUFACTURE OF A DISPOSAL MEDICINAL PRODUCT. |
US6485726B1 (en) | 1995-01-17 | 2002-11-26 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
HU221840B1 (en) | 1995-01-23 | 2003-02-28 | Direct-Haler A/S | Inhaler for dosing into airstrom of powdered material |
USD368364S (en) | 1995-02-02 | 1996-04-02 | Reitano Joseph R | Inhaler case |
US5901703A (en) | 1995-02-06 | 1999-05-11 | Unisia Jecs Corporation | Medicine administering device for nasal cavities |
US5660835A (en) | 1995-02-24 | 1997-08-26 | East Carolina University | Method of treating adenosine depletion |
DE69609315T2 (en) | 1995-03-10 | 2001-02-15 | Minnesota Mining & Mfg | VALVE FOR AEROSOL CONTAINERS |
US5653961A (en) | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
US5542539A (en) | 1995-04-04 | 1996-08-06 | Ethicon Endo-Surgery, Inc. | Container for quick release packages for surgical instruments |
USD377215S (en) | 1995-04-13 | 1997-01-07 | Glaxo Group Limited | Inhaler |
US6309671B1 (en) | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
US5990077A (en) | 1995-04-14 | 1999-11-23 | 1149336 Ontario Inc. | Glucagon-like peptide-2 and its therapeutic use |
US5645051A (en) | 1995-04-21 | 1997-07-08 | Dura Pharmaceuticals, Inc. | Unit dose dry powder inhaler |
US5921237A (en) | 1995-04-24 | 1999-07-13 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US5622166A (en) | 1995-04-24 | 1997-04-22 | Dura Pharmaceuticals, Inc. | Dry powder inhaler delivery system |
US6428771B1 (en) * | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
US5809997A (en) | 1995-05-18 | 1998-09-22 | Medtrac Technologies, Inc. | Electronic medication chronolog device |
US5922253A (en) | 1995-05-18 | 1999-07-13 | Alkermes Controlled Therapeutics, Inc. | Production scale method of forming microparticles |
US5924419A (en) | 1995-05-22 | 1999-07-20 | Kotliar; Igor K. | Apparatus for passive hypoxic training and therapy |
DE19519840A1 (en) | 1995-05-31 | 1996-12-05 | Kaewert Klaus | Gelatin capsule as packaging for medication and toiletries |
AU128811S (en) | 1995-06-06 | 1996-12-03 | Orion Yhtymae Oy | A protective cover for example a moisture protective cover for a powder inhaler |
US5714007A (en) | 1995-06-06 | 1998-02-03 | David Sarnoff Research Center, Inc. | Apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate |
US5641861A (en) | 1995-06-07 | 1997-06-24 | Torrey Pines Institute For Molecular Studies | μopioid receptor ligands: agonists and antagonists |
US5824345A (en) | 1995-06-07 | 1998-10-20 | Emisphere Technologies, Inc. | Fragrances and flavorants |
US6193844B1 (en) | 1995-06-07 | 2001-02-27 | Mclaughlin John R. | Method for making paper using microparticles |
US5610271A (en) | 1995-06-07 | 1997-03-11 | Torrey Pines Institute For Molecular Studies | Kappa receptor selective opioid peptides |
US5919897A (en) | 1995-06-07 | 1999-07-06 | Torrey Pines Institute For Molecular Studies | MU opioid receptor ligands: agonists and antagonists |
US6672304B1 (en) | 1995-06-08 | 2004-01-06 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIs) |
US6357442B1 (en) | 1995-06-08 | 2002-03-19 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIS) |
BR9608997A (en) | 1995-06-21 | 1999-06-29 | Asta Medica Ag | Pharmaceutical powder cartridge with integrated measuring device and powder medicine installer |
GB9513218D0 (en) | 1995-06-29 | 1995-09-06 | Fisons Plc | Inhalation device and method |
DE19523516C1 (en) | 1995-06-30 | 1996-10-31 | Asta Medica Ag | Inhaler for administering medication from blister packs |
AU131838S (en) | 1995-07-01 | 1997-10-21 | Glaxo Group Ltd | Inhalation device |
JP3098401B2 (en) | 1995-07-12 | 2000-10-16 | 株式会社エルティーティー研究所 | Formulation for nasal administration |
US5758638A (en) | 1995-07-24 | 1998-06-02 | Kreamer; Jeffry W. | Indicator for a medicament inhaler |
US5642727A (en) | 1995-07-25 | 1997-07-01 | David Sarnoff Research Center, Inc. | Inhaler apparatus using a tribo-electric charging technique |
WO1997004747A1 (en) | 1995-07-27 | 1997-02-13 | Dunn James M | Drug delivery systems for macromolecular drugs |
US6209538B1 (en) | 1995-08-02 | 2001-04-03 | Robert A. Casper | Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament |
SE9502800D0 (en) | 1995-08-10 | 1995-08-10 | Astra Ab | Disposable inhalers |
SE9502799D0 (en) | 1995-08-10 | 1995-08-10 | Astra Ab | Device in inhalers |
JP3317823B2 (en) | 1995-08-11 | 2002-08-26 | 株式会社ユニシアジェックス | Dosing device |
US5980865A (en) | 1995-08-18 | 1999-11-09 | Baker Norton Pharmaceuticals, Inc. | Method for treating late phase allergic reactions and inflammatory diseases |
US5746197A (en) | 1995-08-18 | 1998-05-05 | Williams; Jeffery W. | Extension for metered dose inhaler |
US5690910A (en) | 1995-08-18 | 1997-11-25 | Baker Norton Pharmaceuticals, Inc. | Method for treating asthma |
US6852690B1 (en) | 1995-08-22 | 2005-02-08 | Amylin Pharmaceuticals, Inc. | Method and composition for enhanced parenteral nutrition |
FR2738153B1 (en) | 1995-09-04 | 1998-01-02 | Valois | INHALATION APPARATUS FOR DELIVERING PRECISE AND REPRODUCIBLE DOSES OF POWDERY PRODUCT |
US5617844A (en) | 1995-09-21 | 1997-04-08 | King; Russell W. | Aerosol medication delivery system |
KR0124764Y1 (en) | 1995-09-23 | 1998-09-15 | 양주환 | Medical capsule |
SE9503344D0 (en) | 1995-09-27 | 1995-09-27 | Astra Ab | Inhalation device |
US5766620A (en) | 1995-10-23 | 1998-06-16 | Theratech, Inc. | Buccal delivery of glucagon-like insulinotropic peptides |
US5849322A (en) | 1995-10-23 | 1998-12-15 | Theratech, Inc. | Compositions and methods for buccal delivery of pharmaceutical agents |
WO1997017945A2 (en) | 1995-11-13 | 1997-05-22 | Minimed, Inc. | Methods and compositions for the delivery of monomeric proteins |
DE19545257A1 (en) | 1995-11-24 | 1997-06-19 | Schering Ag | Process for the production of morphologically uniform microcapsules and microcapsules produced by this process |
ES2216418T3 (en) | 1995-12-07 | 2004-10-16 | Jago Research Ag | NOZZLE FOR AN INHALER FOR THE ADMINISTRATION OF VARIOUS DOSE OF A DRY PHARMACOLOGICAL POWDER. |
US7131441B1 (en) | 1995-12-07 | 2006-11-07 | Skyepharma Ag | Inhaler for multiple dosed administration of a pharmacological dry powder |
TR199801265T2 (en) | 1996-01-03 | 1998-10-21 | Glaxo Group Limited | ��e inhaler�. |
US6026809A (en) | 1996-01-25 | 2000-02-22 | Microdose Technologies, Inc. | Inhalation device |
US6470884B2 (en) | 1996-01-29 | 2002-10-29 | Aventis Pharma Limited | Capsule opening arrangement for use in a powder inhaler |
JPH09208485A (en) | 1996-01-31 | 1997-08-12 | Teijin Ltd | Scarcely water-soluble composition of peptide/protein medicine |
BR9707477A (en) | 1996-02-06 | 1999-04-06 | Du Pont | Method for treating the surface of particulate materials Method for preparing a colored composition Colored composition Improvement in apparatus for subatmospheric treatment of particle surfaces and module for dispersing particles |
USD381416S (en) | 1996-02-08 | 1997-07-22 | Astra Aktiebolag | Unit dose inhaler |
EP0883415B1 (en) | 1996-02-21 | 2002-05-02 | Schering Corporation | Powdered medication inhaler |
USD377861S (en) | 1996-02-21 | 1997-02-11 | Medport, Inc. | Inhaler carrying case |
WO1997031626A1 (en) | 1996-02-27 | 1997-09-04 | Teijin Limited | Powdery composition for nasal administration |
US6509313B1 (en) | 1996-02-28 | 2003-01-21 | Cornell Research Foundation, Inc. | Stimulation of immune response with low doses of cytokines |
US5699789A (en) | 1996-03-11 | 1997-12-23 | Hendricks; Mark R. | Dry powder inhaler |
JP3328132B2 (en) | 1996-03-21 | 2002-09-24 | 株式会社ユニシアジェックス | Inhaler type dispenser |
GB9606188D0 (en) | 1996-03-23 | 1996-05-29 | Danbiosyst Uk | Pollysaccharide microspheres for the pulmonary delivery of drugs |
USD395499S (en) | 1996-04-08 | 1998-06-23 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US5875776A (en) | 1996-04-09 | 1999-03-02 | Vivorx Pharmaceuticals, Inc. | Dry powder inhaler |
US5858099A (en) | 1996-04-09 | 1999-01-12 | Sarnoff Corporation | Electrostatic chucks and a particle deposition apparatus therefor |
IL126701A (en) | 1996-04-29 | 2001-08-08 | Dura Pharma Inc | Inhaler system for inhalation of a dry powder drug |
US5817343A (en) | 1996-05-14 | 1998-10-06 | Alkermes, Inc. | Method for fabricating polymer-based controlled-release devices |
AU132977S (en) | 1996-05-17 | 1998-02-17 | Astrazeneca Ab | Container for inhaling apparatus |
US6503480B1 (en) | 1997-05-23 | 2003-01-07 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5985309A (en) | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
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 |
JPH1053765A (en) | 1996-06-04 | 1998-02-24 | Denso Corp | Smectic liquid crystal composition and liquid crystal cell |
ATE510552T1 (en) | 1996-06-05 | 2011-06-15 | Basil Rapoport | METHOD FOR PRODUCING SECRETED SHORT VARIANTS OF THE HUMAN THYROTROPINE RECEPTOR |
US5871010A (en) | 1996-06-10 | 1999-02-16 | Sarnoff Corporation | Inhaler apparatus with modified surfaces for enhanced release of dry powders |
AUPO066096A0 (en) | 1996-06-26 | 1996-07-18 | Peptide Delivery Systems Pty Ltd | Oral delivery of peptides |
US5769276A (en) | 1996-07-10 | 1998-06-23 | Terronics Development Corporation | Powder atomizer |
US5783556A (en) | 1996-08-13 | 1998-07-21 | Genentech, Inc. | Formulated insulin-containing composition |
AU133903S (en) | 1996-08-19 | 1998-05-29 | Orion Yhtymae Oy | Inhaler device |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
JP3890099B2 (en) | 1996-09-30 | 2007-03-07 | キヤノン株式会社 | Pattern recognition apparatus and method, and storage medium storing the program |
JP3020141B2 (en) | 1996-10-07 | 2000-03-15 | 株式会社富士薬品 | Formulation for nasal administration |
US6532437B1 (en) | 1996-10-23 | 2003-03-11 | Cornell Research Foundation, Inc. | Crystalline frap complex |
UA65549C2 (en) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Use of glucagon-like peptides such as glp-1, glp-1 analog, or glp-1 derivative in methods and compositions for reducing body weight |
US6441172B1 (en) | 1996-11-07 | 2002-08-27 | Torrey Pines Institute For Molecular Studies | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
DE69732572T2 (en) | 1996-11-12 | 2005-12-29 | Novo Nordisk A/S | USE OF GLP-1 PEPTIDES |
DE19647947A1 (en) | 1996-11-20 | 1998-05-28 | Pfeiffer Erich Gmbh & Co Kg | Discharge device for media |
US5868774A (en) | 1996-11-21 | 1999-02-09 | Reil; Vladimir | Unique cartridge and earring stud gun system |
US6159360A (en) | 1996-11-22 | 2000-12-12 | Heinkel Industriezentrifugen Gmbh & Co. | Invertible filter centrifuge including a solids drier |
ES2175491T3 (en) | 1996-12-11 | 2002-11-16 | Earth Sciences Ltd | PROCEDURE AND APPARATUS FOR THE TRANSFORMATION AND TREATMENT OF MATERIAL IN PARTICLES. |
USD390651S (en) | 1996-12-12 | 1998-02-10 | Inhale Therapeutics Systems | Medicament inhaler housing |
GB9626233D0 (en) | 1996-12-18 | 1997-02-05 | Chawla Brinda P S | Medicament packaging and deliveery device |
GB9626263D0 (en) | 1996-12-18 | 1997-02-05 | Innovata Biomed Ltd | Powder inhaler |
GB2320489A (en) | 1996-12-20 | 1998-06-24 | Norton Healthcare Ltd | Inhaler dose counter |
WO1998029141A1 (en) | 1996-12-31 | 1998-07-09 | Inhale Therapeutic Systems, Inc. | Processes for spray drying solutions of hydrophobic drugs with hydrophilic excipients and compositions prepared by such processes |
USD397435S (en) | 1997-01-03 | 1998-08-25 | GGU Gesellschaft fuer Gesundheits-und Umweltforschung mbH | Combined inhaler and cover |
US5794613A (en) | 1997-01-09 | 1998-08-18 | Sepracor, Inc. | Multiple-dose dispenser for dry powder inhalers |
USD389238S (en) | 1997-01-24 | 1998-01-13 | Healthscan Products, Inc. | Inhaler mask |
US6884435B1 (en) * | 1997-01-30 | 2005-04-26 | Chiron Corporation | Microparticles with adsorbent surfaces, methods of making same, and uses thereof |
EP1350532B1 (en) | 1997-01-30 | 2008-04-09 | Hitachi, Ltd. | Capsule type powder Inhaler |
SE9700424D0 (en) | 1997-02-07 | 1997-02-07 | Astra Ab | Powder inhales |
SE9700422D0 (en) | 1997-02-07 | 1997-02-07 | Astra Ab | Single dose inhaler II |
SE9700423D0 (en) | 1997-02-07 | 1997-02-07 | Astra Ab | Disposable inhalers |
SE9700421D0 (en) | 1997-02-07 | 1997-02-07 | Astra Ab | Single dose inhalation I |
JP3011898B2 (en) | 1997-02-20 | 2000-02-21 | フォルテ グロウ メディカル株式会社 | Aspirator |
DE19708406A1 (en) | 1997-03-03 | 1998-09-10 | Alfred Von Schuckmann | Device for dispensing substances |
USD390653S (en) | 1997-03-04 | 1998-02-10 | Blasdell Richard J | Inhaler |
SE9700940D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhales IV |
SE9700936D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Inhalation device |
SE9700943D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhales V |
SE9700935D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Inhalation device |
SE9700938D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler II and a method of construction thereof |
SE9700937D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhales I |
SE9700948D0 (en) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhales X |
TW469832U (en) | 1997-03-14 | 2001-12-21 | Astra Ab | Inhalation device |
US6043214A (en) | 1997-03-20 | 2000-03-28 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
US6006747A (en) | 1997-03-20 | 1999-12-28 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US8391104B2 (en) | 1997-03-28 | 2013-03-05 | Carlos De La Huerga | Interactive medication container labeling |
US5904139A (en) | 1997-03-28 | 1999-05-18 | Hauser; Stephen G. | Breath coordinated inhaler |
JP2002510193A (en) | 1997-03-31 | 2002-04-02 | イーライ・リリー・アンド・カンパニー | Glucagon-like peptide-1 analog |
PT1015352E (en) | 1997-04-01 | 2007-09-24 | Cima Labs Inc | Blister package and packaged tablets |
YU49699A (en) | 1997-04-02 | 2002-12-10 | Purdue Research Foundation | Pharmaceutical compositions and process for their production |
PT101988B (en) | 1997-04-04 | 2004-02-27 | Hovione Farmaciencia Sa | SYSTEM OF ORIENTATION AND POSITIONING OF AN OBJECT |
USD410541S (en) | 1997-06-30 | 1999-06-01 | Novartis Ag | Inhaler |
SE9702796D0 (en) | 1997-07-25 | 1997-07-25 | Pharmacia & Upjohn Ab | A device at a pharmaceutical container or inhaler |
CA2212430A1 (en) | 1997-08-07 | 1999-02-07 | George Volgyesi | Inhalation device |
GB2327895B (en) | 1997-08-08 | 2001-08-08 | Electrosols Ltd | A dispensing device |
US5855564A (en) | 1997-08-20 | 1999-01-05 | Aradigm Corporation | Aerosol extrusion mechanism |
US5846447A (en) | 1997-08-26 | 1998-12-08 | E. I. Du Pont De Nemours And Company | Process for forming a dispersion of polytetrafluoroethylene |
USD416085S (en) | 1997-09-05 | 1999-11-02 | Pharmacia & Upjohn | Inhaler |
USD417271S (en) | 1997-09-10 | 1999-11-30 | Medic-Aid Limited | Drug delivery device |
ES2222613T3 (en) | 1997-09-12 | 2005-02-01 | Pharis Biotec Gmbh | COMPOSITION FOR THE THERAPY OF MELLITUS DIABETES AND OBESITY. |
US5848589A (en) | 1997-09-18 | 1998-12-15 | Welnetz; Robert J. | Altitude mask simulator |
AU135340S (en) | 1997-09-24 | 1998-10-12 | Innovata Biomed Ltd | An inhaler |
US6394085B1 (en) | 1997-09-25 | 2002-05-28 | Norton Healthcare Ltd. | Inhaler spacer |
US6073629A (en) | 1997-09-25 | 2000-06-13 | Norton Healthcare Ltd. | Inhaler spacer |
USD463544S1 (en) | 1997-09-26 | 2002-09-24 | 1263152 Ontario Inc. | Aerosol medication delivery inhaler |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
EP1029536B1 (en) | 1997-10-01 | 2007-11-28 | Novadel Pharma Inc. | Buccal non-polar spray |
US6228394B1 (en) | 1997-10-14 | 2001-05-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Supercritical fluid extraction of mould lubricant from hard shell capsules |
NZ504021A (en) | 1997-10-17 | 2003-04-29 | Systemic Pulmonary Delivery Lt | Method and apparatus for delivering aerosolized medication having air discharged through air tube directly into plume of aerosolized medication |
USD398992S (en) | 1997-10-21 | 1998-09-29 | Schering-Plough Healthcare Products, Inc. | Nasal inhaler |
ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
IN188720B (en) | 1997-11-06 | 2002-11-02 | Panacea Biotec Ltd | |
SE9704184D0 (en) | 1997-11-14 | 1997-11-14 | Astra Ab | Inhalation device |
AU135120S (en) | 1997-11-14 | 1998-09-21 | Astrazeneca Ab | Inhaler |
USD412978S (en) | 1997-12-02 | 1999-08-17 | Dura Pharmaceuticals, Inc. | Inhaler |
US6116238A (en) | 1997-12-02 | 2000-09-12 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
USD418600S (en) | 1997-12-04 | 2000-01-04 | Charmaine Haerle | Inhaler clip |
CA2312190A1 (en) | 1997-12-05 | 1999-06-17 | Eli Lilly And Company | Glp-1 formulations |
US6192876B1 (en) | 1997-12-12 | 2001-02-27 | Astra Aktiebolag | Inhalation apparatus and method |
US6380357B2 (en) | 1997-12-16 | 2002-04-30 | Eli Lilly And Company | Glucagon-like peptide-1 crystals |
US5965701A (en) | 1997-12-23 | 1999-10-12 | Ferring Bv | Kappa receptor opioid peptides |
US6077940A (en) | 1997-12-24 | 2000-06-20 | Genentech, Inc. | Free solution ligand interaction molecular separation method |
US6358058B1 (en) | 1998-01-30 | 2002-03-19 | 1263152 Ontario Inc. | Aerosol dispensing inhaler training device |
JP3530004B2 (en) | 1998-02-06 | 2004-05-24 | 株式会社日立ユニシアオートモティブ | Inhalation type dispenser |
US6158431A (en) | 1998-02-13 | 2000-12-12 | Tsi Incorporated | Portable systems and methods for delivery of therapeutic material to the pulmonary system |
USD421800S (en) | 1998-02-19 | 2000-03-21 | Pierre Fabre Medicament | Powder and compressed-air inhaler |
USD412979S (en) | 1998-02-27 | 1999-08-17 | Diemolding Corporation | Metered dose inhaler spacer |
US7143764B1 (en) | 1998-03-13 | 2006-12-05 | Astrazeneca Ab | Inhalation device |
BR9908771A (en) | 1998-03-16 | 2000-12-12 | Inhale Therapeutic Syst | Processes for the release of an active agent and insulin into the lungs of a human patient, a device for increasing the bioavailability of an active agent, and devices for the release of an active agent and insulin into the lungs of a human patient |
US6998387B1 (en) | 1998-03-19 | 2006-02-14 | Amylin Pharmaceuticals, Inc. | Human appetite control by glucagon-like peptide receptor binding compounds |
SE9801078D0 (en) | 1998-03-27 | 1998-03-27 | Shl Medical Ab | Inhaler |
AU138847S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
AU138848S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
AU138849S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
NZ507151A (en) | 1998-04-08 | 2002-11-26 | Lilly Co Eli | Pulmonary and nasal delivery of raloxifene |
DE59909854D1 (en) | 1998-04-09 | 2004-08-05 | Celanese Ventures Gmbh | PARTICULAR ACTIVE SUBSTANCE FOR PULMONAL APPLICATION |
FR2777283B1 (en) | 1998-04-10 | 2000-11-24 | Adir | NOVEL GLUCAGON-PEPTIDE- 1 (7-37) ANALOGUE PEPTIDE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
US6578571B1 (en) | 1998-04-20 | 2003-06-17 | Infamed Ltd. | Drug delivery device and methods therefor |
GB9810126D0 (en) | 1998-05-13 | 1998-07-08 | Glaxo Group Ltd | |
US6257233B1 (en) | 1998-06-04 | 2001-07-10 | Inhale Therapeutic Systems | Dry powder dispersing apparatus and methods for their use |
SE9802080D0 (en) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and / or irritable bowel syndrome and new use of substances therein |
CA2334872C (en) | 1998-06-12 | 2014-08-19 | Bionebraska, Inc. | Use of exendin-4 to treat impaired glucose tolerance |
US6152130A (en) | 1998-06-12 | 2000-11-28 | Microdose Technologies, Inc. | Inhalation device with acoustic control |
USD412572S (en) | 1998-06-19 | 1999-08-03 | Gray Gene W | Nasal inhaler adaptor for left and right nostril |
NZ508618A (en) | 1998-06-22 | 2002-05-31 | Astrazeneca Ab | Device for emptying cavities containing powder by means of suction |
EP1094781B1 (en) * | 1998-07-07 | 2008-07-02 | Transdermal Technologies Inc. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
DE19831525A1 (en) | 1998-07-14 | 2000-01-20 | Pfeiffer Erich Gmbh & Co Kg | Media Donor |
US6703381B1 (en) | 1998-08-14 | 2004-03-09 | Nobex Corporation | Methods for delivery therapeutic compounds across the blood-brain barrier |
US6087334A (en) | 1998-08-21 | 2000-07-11 | Amylin Pharmaceuticals, Inc. | Anti-diabetic peptides |
JP4338313B2 (en) | 1998-08-26 | 2009-10-07 | 帝人株式会社 | Powdered nasal composition |
AR022368A1 (en) | 1998-08-28 | 2002-09-04 | Lilly Co Eli | PROCEDURE FOR MANAGING INSULINOTROPIC PEPTIDES |
US6720407B1 (en) | 1998-08-28 | 2004-04-13 | Eli Lilly And Company | Method for administering insulinotropic peptides |
BR9913927A (en) | 1998-09-24 | 2001-06-19 | Astrazeneca Ab | Inhaler for inhalation drug delivery |
US20020088458A1 (en) | 1998-09-24 | 2002-07-11 | Astrazeneca Ab | Inhaler |
GB9820937D0 (en) | 1998-09-26 | 1998-11-18 | Glaxo Group Ltd | Inhalation device |
GB9820886D0 (en) | 1998-09-26 | 1998-11-18 | Glaxo Group Ltd | Inhalation device |
US6187291B1 (en) | 1998-09-28 | 2001-02-13 | Robert Weinstein | Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus |
USD411005S (en) | 1998-09-29 | 1999-06-15 | Pharmadesign Inc. | Arthritic aid for metered dose inhaler |
UA73924C2 (en) | 1998-10-09 | 2005-10-17 | Nektar Therapeutics | Device for delivering active agent formulation to lungs of human patient |
US6279511B1 (en) | 1998-10-23 | 2001-08-28 | Instech Laboratories, Inc. | Powered multichannel infusion and monitoring system |
US6263871B1 (en) | 1998-10-29 | 2001-07-24 | Richard I. Brown | Mouthpiece with coupler |
US6235725B1 (en) | 1998-10-30 | 2001-05-22 | Baker Norton Pharmaceuticals, Inc. | Methods and compositions for the prevention of tolerance to medications |
JP3747134B2 (en) | 1998-11-04 | 2006-02-22 | キヤノン株式会社 | Inkjet printhead cartridge storage container |
US6261594B1 (en) | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
US6540672B1 (en) | 1998-12-09 | 2003-04-01 | Novo Nordisk A/S | Medical system and a method of controlling the system for use by a patient for medical self treatment |
GB9827145D0 (en) | 1998-12-09 | 1999-02-03 | Co Ordinated Drug Dev | Improvements in or relating to powders |
US6375975B1 (en) | 1998-12-21 | 2002-04-23 | Generex Pharmaceuticals Incorporated | Pharmaceutical compositions for buccal and pulmonary application |
US6552024B1 (en) | 1999-01-21 | 2003-04-22 | Lavipharm Laboratories Inc. | Compositions and methods for mucosal delivery |
SE9900215D0 (en) | 1999-01-26 | 1999-01-26 | Pharmacia & Upjohn Ab | New use |
JP2000217917A (en) | 1999-01-27 | 2000-08-08 | Unisia Jecs Corp | Inhaler type medicine administration tool |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
PT1158958E (en) | 1999-03-05 | 2007-08-13 | Chiesi Farma Spa | Improved powdery pharmaceutical compositions for inhalation |
IT1309592B1 (en) | 1999-03-05 | 2002-01-24 | Chiesi Farma Spa | VEHICLE PARTICLES MODIFIED FOR USE IN THE PREPARATION OF PHARMACEUTICAL FORMULATIONS IN THE FORM OF POLYMERS FOR INHALATION AND |
US6632258B1 (en) | 1999-03-16 | 2003-10-14 | The United States Of America As Represented By The United States Department Of Energy | Coal beneficiation by gas agglomeration |
US6803044B1 (en) | 1999-03-24 | 2004-10-12 | Zengen, Inc. | Antimicrobial and anti-inflammatory peptides for use in human immunodeficiency virus |
US6630169B1 (en) | 1999-03-31 | 2003-10-07 | Nektar Therapeutics | Particulate delivery systems and methods of use |
CA2367131C (en) | 1999-04-05 | 2007-07-03 | Solomon S. Steiner | Methods for fine powder formation |
USD441859S1 (en) | 1999-04-06 | 2001-05-08 | Istituto Biochimico Pavese Pharma S.P.A. | Disposable dry-powder inhaler |
AU763786B2 (en) | 1999-05-07 | 2003-07-31 | Imerys Pigments, Inc. | A method of treating an aqueous suspension of kaolin |
US6417920B1 (en) | 1999-05-11 | 2002-07-09 | Shimadzu Corporation | Particle size analyzer based on laser diffraction method |
US6514500B1 (en) | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
GB9911388D0 (en) | 1999-05-18 | 1999-07-14 | Glaxo Group Ltd | Dispenser |
WO2000071154A2 (en) * | 1999-05-20 | 2000-11-30 | Pharmasol Gmbh | Stability, biocompatibility optimized adjuvant (sba) for enhancing humoral and cellular immune response |
US7919119B2 (en) | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
DE19924277A1 (en) | 1999-05-27 | 2000-11-30 | Beiersdorf Ag | Preparations of emulsion type W / O with increased water content containing medium polar lipids and silicone emulsifiers and optionally cationic polymers |
EP1060741B1 (en) * | 1999-06-14 | 2003-09-03 | Baxter International Inc. | Sustained release microspheres |
US6644315B2 (en) | 1999-06-18 | 2003-11-11 | Saeed Ziaee | Nasal mask |
SE516826C2 (en) | 1999-06-18 | 2002-03-05 | Shl Medical Ab | Breath-operated device for use with an inhaler includes a return mechanism for deactivating a canister to close when airflow drops below a certain threshold value |
US7169889B1 (en) | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
EP1849475A1 (en) | 1999-06-21 | 2007-10-31 | Eli Lilly & Company | Synergistic use of thiazolidinediones with glucagon-like peptide-1 and agonists thereof to treat non-insulin dependent diabetes |
US6858199B1 (en) | 2000-06-09 | 2005-02-22 | Advanced Inhalation Research, Inc. | High efficient delivery of a large therapeutic mass aerosol |
GB2353222B (en) | 1999-06-23 | 2001-09-19 | Cambridge Consultants | Inhalers |
USD444226S1 (en) | 1999-06-24 | 2001-06-26 | Novo Nordisk A/S | Inhaler |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
DK1196430T3 (en) | 1999-06-29 | 2012-05-21 | Mannkind Corp | Purification and stabilization of peptides and proteins in pharmaceutical agents |
US6606992B1 (en) | 1999-06-30 | 2003-08-19 | Nektar Therapeutics | Systems and methods for aerosolizing pharmaceutical formulations |
ITMI991582A1 (en) | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | DUST CONSTITUTED FROM PARTICLES HAVING THE PERFECTLY SMOOTH SURFACE FOR USE AS VEHICLES FOR THE PREPARATION OF INALA MIXTURES |
PL353026A1 (en) | 1999-07-22 | 2003-10-06 | Aventis Pharmaceuticals, Inc. | Preserved pharmaceutical formulations |
ATE339981T1 (en) | 1999-07-23 | 2006-10-15 | Mannkind Corp | DRY POWDER INHALER |
US7464706B2 (en) | 1999-07-23 | 2008-12-16 | Mannkind Corporation | Unit dose cartridge and dry powder inhaler |
US7305986B1 (en) | 1999-07-23 | 2007-12-11 | Mannkind Corporation | Unit dose capsules for use in a dry powder inhaler |
US20010036481A1 (en) | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
CN1175961C (en) | 1999-09-17 | 2004-11-17 | 株式会社新王磁材 | Method and device for cutting rare-earth alloy |
USD438612S1 (en) | 1999-09-27 | 2001-03-06 | G-Intek Co., Ltd. | Snivel inhaler |
JP2003511107A (en) | 1999-10-06 | 2003-03-25 | ゴルデマン・ラウル | Dry powder respiratory control inhaler and method of uniformly distributing and mixing dry powder in air |
NZ518401A (en) | 1999-10-29 | 2004-01-30 | Nektar Therapeutics | Dry powder compositions having improved dispersivity |
SE9903990D0 (en) | 1999-11-02 | 1999-11-02 | Shl Medical Ab | Inhaler with aerosolizing unit |
GB9928311D0 (en) | 1999-11-30 | 2000-01-26 | Novartis Ag | Organic compounds |
IT1308581B1 (en) | 1999-12-03 | 2002-01-08 | Medel Italiana Srl | APPARATUS FOR SPRAYING A LIQUID, IN PARTICULAR FOR MEDICAL USE. |
SE9904706D0 (en) | 1999-12-21 | 1999-12-21 | Astra Ab | An inhalation device |
CO5270018A1 (en) | 1999-12-11 | 2003-04-30 | Glaxo Group Ltd | MEDICINAL DISTRIBUTOR |
US7022674B2 (en) | 1999-12-16 | 2006-04-04 | Eli Lilly And Company | Polypeptide compositions with improved stability |
US7204250B1 (en) | 1999-12-16 | 2007-04-17 | Compumedics Limited | Bio-mask |
DE19961300A1 (en) | 1999-12-18 | 2001-06-21 | Asta Medica Ag | Storage system for medicinal products in powder form and inhaler equipped with them |
AU2729101A (en) | 1999-12-21 | 2001-07-03 | Rxkinetix, Inc. | Particulate drug-containing products and method of manufacture |
US7080642B2 (en) | 1999-12-22 | 2006-07-25 | 3M Innovative Properties Company | Refillable device with counting means |
SK11142002A3 (en) | 1999-12-30 | 2004-09-08 | Chiron Corporation | Pharmaceutical composition for interleukine-2 administration and stabilized freeze-dried or spray-dried pharmaceutical composition containing interleukine-2 |
US6894026B1 (en) | 2000-01-11 | 2005-05-17 | Atossa Healthcare, Inc. | Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders |
WO2001051071A2 (en) | 2000-01-11 | 2001-07-19 | Novo Nordisk A/S | Transepithelial delivery of glp-1 derivatives |
US6555127B2 (en) | 2000-01-19 | 2003-04-29 | Pharmaceutical Discovery Corporation | Multi-spike release formulation for oral drug delivery |
AU2001231000A1 (en) | 2000-01-19 | 2001-07-31 | Pharmaceutical Discovery Corporation | Dry powder formulations of antihistamine for nasal administration |
US6443307B1 (en) | 2000-01-25 | 2002-09-03 | Michael D. Burridge | Medication dispenser with an internal ejector |
US6540983B1 (en) | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
US6540982B1 (en) | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
KR20020073184A (en) | 2000-01-27 | 2002-09-19 | 일라이 릴리 앤드 캄파니 | Process for Solubilizing Glucagon-Like Peptide 1 Compounds |
US7171965B2 (en) | 2000-02-01 | 2007-02-06 | Valois S.A.S. | Breath actuated dry powder inhaler and tape dose strip |
US6427688B1 (en) | 2000-02-01 | 2002-08-06 | Dura Pharmaceuticals, Icn. | Dry powder inhaler |
USD439325S1 (en) | 2000-02-08 | 2001-03-20 | Baker Norton Pharmaceuticals, Inc. | Cover for a nasal inhaler |
EP1129705A1 (en) | 2000-02-17 | 2001-09-05 | Rijksuniversiteit te Groningen | Powder formulation for inhalation |
GB0004456D0 (en) | 2000-02-26 | 2000-04-19 | Glaxo Group Ltd | Medicament dispenser |
CA2401288A1 (en) | 2000-02-28 | 2001-09-07 | Vectura Limited | Improvements in or relating to the delivery of oral drugs |
USD439656S1 (en) | 2000-03-06 | 2001-03-27 | Astrazeneca Uk Limited | Inhaler |
US6443151B1 (en) | 2000-03-08 | 2002-09-03 | Aradigm Corporation | Fluid velocity-sensitive trigger mechanism |
DE60129214T2 (en) | 2000-03-10 | 2008-04-10 | University Of North Carolina At Chapel Hill | DRY POWDER INHALATORS, MULTIDOSIS DRY POWDER MEDICINES, CONTROL SYSTEMS AND METHOD |
US6608038B2 (en) | 2000-03-15 | 2003-08-19 | Novartis Ag | Methods and compositions for treatment of diabetes and related conditions via gene therapy |
GB2360218A (en) | 2000-03-18 | 2001-09-19 | Astrazeneca Uk Ltd | Inhaler |
GB0006525D0 (en) | 2000-03-18 | 2000-05-10 | Astrazeneca Uk Ltd | Inhaler |
GB2360216A (en) | 2000-03-18 | 2001-09-19 | Astrazeneca Uk Ltd | Inhaler |
US6823863B2 (en) | 2000-03-18 | 2004-11-30 | Astrazeneca Ab | Inhaler |
SE0000935D0 (en) | 2000-03-21 | 2000-03-21 | Astrazeneca Ab | An inhalation device |
USD449684S1 (en) | 2000-03-24 | 2001-10-23 | Astrazeneca Ab | Inhaler |
US6432383B1 (en) | 2000-03-30 | 2002-08-13 | Generex Pharmaceuticals Incorporated | Method for administering insulin |
AU5173701A (en) | 2000-04-03 | 2001-10-15 | Iep Pharmaceutical Devices Inc | Method for improving lung delivery of pharmaceutical aerosols |
US6998137B2 (en) | 2000-04-07 | 2006-02-14 | Macromed, Inc. | Proteins deposited onto sparingly soluble biocompatible particles for controlled protein release into a biological environment from a polymer matrix |
EP1272243B1 (en) | 2000-04-11 | 2005-10-26 | Trudell Medical International | Aerosol delivery apparatus with positive expiratory pressure capacity |
DE10019879A1 (en) | 2000-04-20 | 2001-10-25 | Degussa | Production of known and new 2,5-diketopiperazine derivatives useful for the synthesis of bioactive compounds, e.g. cyclo(Lys-Lys) |
MY136453A (en) | 2000-04-27 | 2008-10-31 | Philip Morris Usa Inc | "improved method and apparatus for generating an aerosol" |
US6447750B1 (en) | 2000-05-01 | 2002-09-10 | Aeropharm Technology Incorporated | Medicinal aerosol formulation |
US6468507B1 (en) | 2000-05-01 | 2002-10-22 | Aeropharm Technology, Inc. | Non-aqueous aerosol formulation comprising rosiglitazone maleate, a non-aqueous carrier, and an amino acid stabilizer |
USD442685S1 (en) | 2000-05-02 | 2001-05-22 | Salter Labs | Medication inhaler spacer |
US20010039442A1 (en) | 2000-05-06 | 2001-11-08 | Sal Gorge | Headache relief device |
US6948494B1 (en) | 2000-05-10 | 2005-09-27 | Innovative Devices, Llc. | Medicament container with same side airflow inlet and outlet and method of use |
US20020000225A1 (en) | 2000-06-02 | 2002-01-03 | Carlos Schuler | Lockout mechanism for aerosol drug delivery devices |
CN1141974C (en) | 2000-06-07 | 2004-03-17 | 张昊 | Colon-releasing oral biological preparation |
BR0111562A (en) | 2000-06-16 | 2003-04-15 | Lilly Co Eli | Glucagon-like peptide 1 analogs |
RU2181297C2 (en) | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Method of treatment of pathological syndrome and medicinal agent |
GB0015034D0 (en) | 2000-06-21 | 2000-08-09 | Glaxo Group Ltd | Inhalation device |
GB0015043D0 (en) | 2000-06-21 | 2000-08-09 | Glaxo Group Ltd | Medicament dispenser |
US6562807B2 (en) | 2000-06-23 | 2003-05-13 | Novo Nordisk A/S | Glucagon antagonists/inverse agonists |
TWI224513B (en) | 2000-06-23 | 2004-12-01 | Norton Healthcare Ltd | Dose counter for medicament inhaler |
TWI224515B (en) | 2000-06-23 | 2004-12-01 | Norton Healthcare Ltd | Pre-metered dose magazine for breath-actuated dry powder inhaler |
TWI224511B (en) | 2000-06-23 | 2004-12-01 | Norton Healthcare Ltd | De-agglomerator for breath-actuated dry powder inhaler |
USD452910S1 (en) | 2000-06-29 | 2002-01-08 | Innovata Biomend Limited | Inhaler |
USD450117S1 (en) | 2000-06-29 | 2001-11-06 | Innovata Biomed Limited | Inhaler |
JP2004502690A (en) | 2000-07-04 | 2004-01-29 | ノボ ノルディスク アクティーゼルスカブ | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
US6363932B1 (en) | 2000-07-06 | 2002-04-02 | Clinical Technologies, Inc. | Aerosol enhancement device |
US6951215B1 (en) | 2000-07-14 | 2005-10-04 | Tufts University | Drug delivery device for animals |
US6360929B1 (en) | 2000-07-17 | 2002-03-26 | Mccarthy Madeleine | Medicinal atomizing inhaler pouch/retainer |
GB2364919A (en) | 2000-07-21 | 2002-02-13 | Cambridge Consultants | Inhalers |
SE516555C2 (en) | 2000-08-04 | 2002-01-29 | Microdrug Ag | electrostatic Powder |
EP1311269B1 (en) | 2000-08-04 | 2012-02-29 | DMI Biosciences, Inc. | Method of using diketopiperazines and composition containing them |
WO2002012201A1 (en) | 2000-08-04 | 2002-02-14 | Dmi Biosciences, Inc. | Method of synthesizing diketopiperazines |
AU7576001A (en) | 2000-08-05 | 2002-02-18 | Glaxo Group Ltd | 6.alpha., 9.alpha.-difluoro-17.alpha.-`(2-furanylcarboxyl) oxy]-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4,-diene-17-carbothioic acid s-fluoromethyl ester as an anti-inflammatory agent |
TWI283182B (en) | 2000-08-07 | 2007-07-01 | Nektar Therapeutics | Inhalable spray dried 4-helix bundle protein powders having minimized aggregation |
AU2001283546A1 (en) | 2000-08-14 | 2002-02-25 | Advanced Inhalation Research, Inc. | Inhalation device and method |
US6704255B2 (en) | 2000-08-22 | 2004-03-09 | Ricoh Company, Ltd. | Lens actuator |
US6613308B2 (en) | 2000-09-19 | 2003-09-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US6514482B1 (en) | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
CA2422941A1 (en) | 2000-09-20 | 2003-03-19 | Franco Del Bon | Inhalator and pertaining atomizer |
USD460173S1 (en) | 2000-09-20 | 2002-07-09 | P.A. Knowledge Limited | Inhaler device |
SE517225C2 (en) | 2000-09-21 | 2002-05-14 | Microdrug Ag | Optimization of an electrostatically dosed dry powder inhaler |
SE517228C2 (en) | 2000-09-25 | 2002-05-14 | Microdrug Ag | Dry powder inhaler with respiratory activation |
SE517226C2 (en) | 2000-09-25 | 2002-05-14 | Microdrug Ag | Inhaler with air brake for dry powder |
GB0023653D0 (en) | 2000-09-27 | 2000-11-08 | Cambridge Consultants | Device for dispensing particulate material |
EP1320397B1 (en) | 2000-09-29 | 2010-01-20 | Pfizer Limited | Medical Inhalation-Device |
US6756062B2 (en) * | 2000-11-03 | 2004-06-29 | Board Of Regents University Of Texas System | Preparation of drug particles using evaporation precipitation into aqueous solutions |
WO2002043703A1 (en) | 2000-11-29 | 2002-06-06 | Itoham Foods Inc. | Powdery preparations and proecss for producing the same |
GB0029562D0 (en) | 2000-12-04 | 2001-01-17 | Novartis Ag | Organic compounds |
USD455208S1 (en) | 2000-12-05 | 2002-04-02 | Clinical Designs Limited | Inhaler |
CA2431173A1 (en) | 2000-12-13 | 2002-06-20 | Eli Lilly And Company | Chronic treatment regimen using glucagon-like insulinotropic peptides |
WO2002055101A2 (en) | 2000-12-21 | 2002-07-18 | Inhale Therapeutic Syst | Storage stable powder compositions of interleukin-4 receptor |
US6799572B2 (en) | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
US7077130B2 (en) | 2000-12-22 | 2006-07-18 | Chrysalis Technologies Incorporated | Disposable inhaler system |
WO2002053190A2 (en) | 2000-12-29 | 2002-07-11 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
US20020141946A1 (en) | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
US6626173B2 (en) | 2001-01-08 | 2003-09-30 | Iep Pharmaceutical Devices Inc. | Dry powder inhaler |
US6644309B2 (en) | 2001-01-12 | 2003-11-11 | Becton, Dickinson And Company | Medicament respiratory delivery device and method |
FI20010144A0 (en) | 2001-01-24 | 2001-01-24 | Valtion Teknillinen | Method and apparatus for studying aerosol sources |
AUPR272901A0 (en) * | 2001-01-25 | 2001-02-22 | Gainful Plan Limited | Method of preparing biological materials and preparations produced using same |
US20040022861A1 (en) | 2001-01-30 | 2004-02-05 | Williams Robert O. | Process for production of nanoparticles and microparticles by spray freezing into liquid |
WO2002067995A1 (en) | 2001-02-26 | 2002-09-06 | Council Of Scientific And Industrial Research | Carrier systems comprising vitamin b12 - biodegradable micro particulate conju gates for peroral delivery of drugs, peptides/proteins and vaccines |
DE60101451T2 (en) | 2001-03-05 | 2004-10-21 | Pera Ivo E | Inhaler for distributing powdered medication in a capsule through the respiratory tract |
US6698422B2 (en) | 2001-03-12 | 2004-03-02 | Birdsong Medical Devices, Inc. | Canister inhaler having a spacer and easy to operate lever mechanism and a flexible, elastic mouthpiece |
US6523536B2 (en) | 2001-03-12 | 2003-02-25 | Birdsong Medical Devices, Inc. | Dual-canister inhaler having a spacer and easy to operate lever mechanism |
USD453264S1 (en) | 2001-03-30 | 2002-02-05 | Benjamin Acevedo, Jr. | Pouch for medical inhaler |
GB0108213D0 (en) | 2001-04-02 | 2001-05-23 | Glaxo Group Ltd | Medicament dispenser |
SE0101233L (en) | 2001-04-05 | 2002-10-01 | Microdrug Ag | Method and apparatus for releasing powder and inhaler device for administering medical powder |
US6652838B2 (en) | 2001-04-05 | 2003-11-25 | Robert E. Weinstein | Method for treating diabetes mellitus |
US6774112B2 (en) | 2001-04-11 | 2004-08-10 | Bristol-Myers Squibb Company | Amino acid complexes of C-aryl glucosides for treatment of diabetes and method |
US6766799B2 (en) | 2001-04-16 | 2004-07-27 | Advanced Inhalation Research, Inc. | Inhalation device |
US6447751B1 (en) | 2001-04-18 | 2002-09-10 | Robert E. Weinstein | Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus |
WO2002085281A1 (en) | 2001-04-19 | 2002-10-31 | Technology Innovation Limited | Medicament container |
US7232897B2 (en) | 2001-04-24 | 2007-06-19 | Harvard University, President And Fellows Of Harvard College | Compositions and methods for modulating NH2-terminal Jun Kinase activity |
USD451597S1 (en) | 2001-04-24 | 2001-12-04 | G-Intek Co.,Ltd | Snivel inhaler |
JP4663906B2 (en) | 2001-04-26 | 2011-04-06 | 富士フイルム株式会社 | Cellulose acylate film |
WO2002089881A1 (en) | 2001-05-10 | 2002-11-14 | Vectura Delivery Devices Limited | Inhaler |
YU98503A (en) | 2001-05-21 | 2006-05-25 | Nektar Therapeutics | Pulmonary administration of chemically modified insulin |
SE0101825D0 (en) | 2001-05-22 | 2001-05-22 | Astrazeneca Ab | An inhalation device |
JP2005506956A (en) | 2001-06-01 | 2005-03-10 | イーライ・リリー・アンド・カンパニー | Long-acting GLP-1 formulation |
US7035294B2 (en) | 2001-06-04 | 2006-04-25 | Calix Networks, Inc. | Backplane bus |
EG24184A (en) | 2001-06-15 | 2008-10-08 | Otsuka Pharma Co Ltd | Dry powder inhalation system for transpulmonary |
FI20011317A0 (en) | 2001-06-20 | 2001-06-20 | Orion Corp | The powder inhaler |
WO2003000570A1 (en) | 2001-06-22 | 2003-01-03 | 3M Innovative Properties Company | Metering valve for a metered dose inhaler |
US6681768B2 (en) | 2001-06-22 | 2004-01-27 | Sofotec Gmbh & Co. Kg | Powder formulation disintegrating system and method for dry powder inhalers |
US6614197B2 (en) | 2001-06-30 | 2003-09-02 | Motorola, Inc. | Odd harmonics reduction of phase angle controlled loads |
DE10136555A1 (en) | 2001-07-27 | 2003-02-13 | Boehringer Ingelheim Int | Method for determining the size distribution of particles in an aerosol, especially particles of a medicament involves mixing of a carrier medium with the medicament to produce an appropriately conditioned aerosol |
US7414720B2 (en) | 2001-07-27 | 2008-08-19 | Herbert Wachtel | Measuring particle size distribution in pharmaceutical aerosols |
GB0120018D0 (en) | 2001-08-16 | 2001-10-10 | Meridica Ltd | Pack containing medicament and dispensing device |
WO2003018059A2 (en) | 2001-08-22 | 2003-03-06 | Aventis Pharma Deutschland Gmbh | Combination preparations of aryl substituted propanolamine derivatives with other active ingredients and the use thereof |
EP1432730A4 (en) | 2001-08-23 | 2006-10-11 | Lilly Co Eli | Glucagon-like peptide-1 analogs |
JP2005508895A (en) | 2001-08-28 | 2005-04-07 | イーライ・リリー・アンド・カンパニー | Premix of GLP-1 and basal insulin |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
WO2003024396A2 (en) | 2001-09-17 | 2003-03-27 | Glaxo Group Limited | Dry powder medicament formulations |
US6871647B2 (en) | 2001-09-19 | 2005-03-29 | Advent Pharmaceuticals Pty Ltd | Inhaler |
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 |
AU2002340083A1 (en) | 2001-09-28 | 2003-04-07 | Kurve Technology, Inc | Nasal nebulizer |
US7093595B2 (en) | 2001-10-08 | 2006-08-22 | Eli Lilly And Company | Portable medication inhalation kit |
US6916354B2 (en) | 2001-10-16 | 2005-07-12 | International Non-Toxic Composites Corp. | Tungsten/powdered metal/polymer high density non-toxic composites |
USD461239S1 (en) | 2001-10-18 | 2002-08-06 | Anna L. Cassidy | Inhaler sleeve with spring clip |
US7179788B2 (en) | 2001-10-19 | 2007-02-20 | Eli Lilly And Company | Biphasic mixtures of GLP-1 and insulin |
US20040247628A1 (en) | 2001-10-24 | 2004-12-09 | Frank-Christophe Lintz | Kit for the preparation of a pharmaceutical composition |
USD473298S1 (en) | 2001-11-01 | 2003-04-15 | Astrazeneca Ab | Inhaler refill |
DE60238864D1 (en) | 2001-11-07 | 2011-02-17 | Mankind Corp | FOR EPITOPES OF ANTIGENIC ENCODING EXPRESSION VECTORS AND METHOD FOR THEIR DESIGN |
SI1458360T1 (en) | 2001-12-19 | 2011-08-31 | Novartis Ag | Pulmonary delivery of aminoglycosides |
US6994083B2 (en) | 2001-12-21 | 2006-02-07 | Trudell Medical International | Nebulizer apparatus and method |
GB0130857D0 (en) | 2001-12-22 | 2002-02-06 | Glaxo Group Ltd | Medicament dispenser |
USD471273S1 (en) | 2002-01-07 | 2003-03-04 | Aerogen, Inc. | Inhaler for dispensing medication |
USD474536S1 (en) | 2002-01-07 | 2003-05-13 | Aerogen, Inc. | Inhaler for dispensing medications |
US20030198666A1 (en) | 2002-01-07 | 2003-10-23 | Richat Abbas | Oral insulin therapy |
USD479745S1 (en) | 2002-01-07 | 2003-09-16 | Aerogen, Inc. | Inhaler for dispensing medications |
USD469866S1 (en) | 2002-01-07 | 2003-02-04 | Aerogen, Inc. | Inhaler for dispensing medication |
ITMI20020078A1 (en) | 2002-01-16 | 2003-07-16 | Fabrizio Niccolai | DEVICE USABLE IN THE TREATMENT OF RESPIRATORY TRACT AFFECTIONS |
AU2003205226A1 (en) | 2002-01-18 | 2003-09-02 | Mannkind Corporation | Compositions for treatment or prevention of bioterrorism |
US7105489B2 (en) | 2002-01-22 | 2006-09-12 | Amylin Pharmaceuticals, Inc. | Methods and compositions for treating polycystic ovary syndrome |
US7258118B2 (en) | 2002-01-24 | 2007-08-21 | Sofotec Gmbh & Co, Kg | Pharmaceutical powder cartridge, and inhaler equipped with same |
MXPA04008068A (en) | 2002-02-20 | 2004-11-26 | Lilly Co Eli | Method for administering glp-1 molecules. |
US6591832B1 (en) | 2002-02-21 | 2003-07-15 | Saint-Gobain Calmar Inc. | Dry powder dispenser |
US6830149B2 (en) | 2002-03-08 | 2004-12-14 | Musculoskeletal Transplant Foundation | Package with insert for holding allograft implant to preclude lipid transfer |
US7008644B2 (en) | 2002-03-20 | 2006-03-07 | Advanced Inhalation Research, Inc. | Method and apparatus for producing dry particles |
DE60318938T2 (en) | 2002-03-20 | 2009-01-22 | Mannkind Corp., Valencia | INHALER |
UA80123C2 (en) | 2002-04-09 | 2007-08-27 | Boehringer Ingelheim Pharma | Inhalation kit comprising inhalable powder of tiotropium |
US20030235538A1 (en) | 2002-04-09 | 2003-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method for the administration of an anticholinergic by inhalation |
US20030194420A1 (en) | 2002-04-11 | 2003-10-16 | Richard Holl | Process for loading a drug delivery device |
USD475133S1 (en) | 2002-04-18 | 2003-05-27 | Mcluckie Lynne E. | Luminescent-colored inhaler |
US7316748B2 (en) | 2002-04-24 | 2008-01-08 | Wisconsin Alumni Research Foundation | Apparatus and method of dispensing small-scale powders |
US6830046B2 (en) | 2002-04-29 | 2004-12-14 | Hewlett-Packard Development Company, L.P. | Metered dose inhaler |
USD478983S1 (en) | 2002-05-01 | 2003-08-26 | Chrysalis Technologies Incorporated | Inhaler |
US20040151059A1 (en) | 2002-05-01 | 2004-08-05 | Roberts Ii William Leroy | Deagglomerator apparatus and method |
EP1506003A1 (en) | 2002-05-07 | 2005-02-16 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
EP1521589A4 (en) * | 2002-05-07 | 2008-06-04 | Univ California | Bioactivation of particles |
US6889690B2 (en) | 2002-05-10 | 2005-05-10 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister devices, and associated methods of dispensing dry powder substances and fabricating blister packages |
USD473640S1 (en) | 2002-05-13 | 2003-04-22 | Iep Pharmaceutical Devices Inc. | Breath actuated inhaler |
USD492769S1 (en) | 2002-05-24 | 2004-07-06 | Glaxosmithkline K.K. | Lens for an inhaler |
USD477665S1 (en) | 2002-06-12 | 2003-07-22 | Microdrug Ag | Inhaler |
AU154760S (en) | 2002-06-20 | 2004-03-02 | Astrazeneca Ab | Inhaler |
US8003179B2 (en) | 2002-06-20 | 2011-08-23 | Alcan Packaging Flexible France | Films having a desiccant material incorporated therein and methods of use and manufacture |
CA2488976C (en) | 2002-06-28 | 2009-08-25 | Advanced Inhalation Research, Inc. | Inhalable epinephrine |
US20060003316A1 (en) | 2002-07-15 | 2006-01-05 | John Simard | Immunogenic compositions derived from poxviruses and methods of using same |
GB0217198D0 (en) | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicament dispenser |
GB0217382D0 (en) | 2002-07-26 | 2002-09-04 | Pfizer Ltd | Process for making orally consumable dosage forms |
USD489448S1 (en) | 2002-07-31 | 2004-05-04 | Advanced Inhalations Revolutions, Inc. | Vaporization apparatus |
ATE503517T2 (en) | 2002-07-31 | 2011-04-15 | Chiesi Farma Spa | POWDER INHALER |
WO2010080964A1 (en) | 2009-01-08 | 2010-07-15 | Mannkind Corporation | Method for treating hyperglycemia with glp-1 |
JP4828940B2 (en) * | 2002-08-01 | 2011-11-30 | マンカインド コーポレイション | Cell transport compositions and uses thereof |
US20080260838A1 (en) | 2003-08-01 | 2008-10-23 | Mannkind Corporation | Glucagon-like peptide 1 (glp-1) pharmaceutical formulations |
DE10235168A1 (en) | 2002-08-01 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Process for the purification of preproinsulin |
US20040038865A1 (en) | 2002-08-01 | 2004-02-26 | Mannkind Corporation | Cell transport compositions and uses thereof |
US20150283213A1 (en) | 2002-08-01 | 2015-10-08 | Mannkind Corporation | Method for treating hyperglycemia with glp-1 |
GB0315791D0 (en) | 2003-07-07 | 2003-08-13 | 3M Innovative Properties Co | Two component molded valve stems |
US20040121964A1 (en) | 2002-09-19 | 2004-06-24 | Madar David J. | Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV) |
US7322352B2 (en) | 2002-09-21 | 2008-01-29 | Aventis Pharma Limited | Inhaler |
USD509296S1 (en) | 2002-09-21 | 2005-09-06 | Aventis Pharma Limited | Inhaler |
JP2004121061A (en) * | 2002-10-01 | 2004-04-22 | Sanei Gen Ffi Inc | Method for producing powder composition |
BR0306930A (en) | 2002-10-11 | 2004-11-09 | Otsuka Pharma Co Ltd | Dust inhaler |
ITMO20020297A1 (en) | 2002-10-16 | 2004-04-17 | Roberto Oliva | INHALER FOR SINGLE-DOSE PREPARATIONS IN CAPSULES. |
CN1176649C (en) | 2002-10-16 | 2004-11-24 | 上海医药工业研究院 | Inhalant of Shumaputan dry-powder and its preparation method |
BR0315194A (en) | 2002-10-31 | 2005-08-23 | Umd Inc | Therapeutic Compositions for Drug Release to and Through Epithelial Coverage |
GB0225621D0 (en) | 2002-11-02 | 2002-12-11 | Glaxo Group Ltd | Medicament carrier |
AU2003276447A1 (en) | 2002-11-04 | 2004-06-07 | Cambridge Consultants Limited | Inhalers |
USD493220S1 (en) | 2002-11-06 | 2004-07-20 | Merck Patent Gmbh | Inhaler |
US20080015457A1 (en) | 2002-11-07 | 2008-01-17 | Silva Carlos D | Device for Monitoring Respiratory Movements |
USD483860S1 (en) | 2002-11-12 | 2003-12-16 | Pari Gmbh Spezialisten Fur Effektive Inhalation | Electronic inhaler and control unit |
US6904907B2 (en) | 2002-11-19 | 2005-06-14 | Honeywell International Inc. | Indirect flow measurement through a breath-operated inhaler |
GB0227128D0 (en) | 2002-11-20 | 2002-12-24 | Glaxo Group Ltd | A capsule |
US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
US20040138099A1 (en) | 2002-11-29 | 2004-07-15 | Draeger Eberhard Kurt | Insulin administration regimens for the treatment of subjects with diabetes |
EP1581292A1 (en) | 2002-12-02 | 2005-10-05 | The Governors of the University of Alberta | Device and method for deagglomeration of powder for inhalation |
US7284553B2 (en) | 2002-12-12 | 2007-10-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder inhaler comprising a chamber for a capsule for taking up a non-returnable capsule being filled with an active ingredient |
JP2006509825A (en) | 2002-12-13 | 2006-03-23 | 大塚製薬株式会社 | Interferon-γ freeze-dried composition for pulmonary administration and inhalation system thereof |
US7708014B2 (en) | 2002-12-13 | 2010-05-04 | Otsuka Pharmaceutical Co., Ltd. | Inhalation device for transpulmonary administration |
EA008829B1 (en) | 2002-12-17 | 2007-08-31 | Нэстек Фармасьютикал Кампани Инк. | Compositions and methods for enhanced mucosal delivery of y2 receptor-binding peptides and methods for treating and preventing obesity |
US6941947B2 (en) | 2002-12-18 | 2005-09-13 | Quadrant Technologies Limited | Unit dose dry powder inhaler |
US7185650B2 (en) | 2002-12-19 | 2007-03-06 | Arie Huber | Systems and methods for determining a minimum effective dose of an inhaled drug for an individual patient at a given time |
US6962006B2 (en) | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
AU2003303634B2 (en) | 2002-12-27 | 2009-10-01 | Diobex, Inc. | Compositions and methods for the prevention and control of insulin-induced hypoglycemia |
DE10300032B3 (en) | 2003-01-03 | 2004-05-27 | E. Braun Gmbh | Inhaler for powdered medicament has pivoted inhalation tube which shuts off powder supply when in out-of-use position, and doses powder into airflow when in use |
GB0309154D0 (en) | 2003-01-14 | 2003-05-28 | Aventis Pharma Inc | Use of insulin glargine to reduce or prevent cardiovascular events in patients being treated for dysglycemia |
US20040187869A1 (en) | 2003-01-17 | 2004-09-30 | Schering Corporation | Training device for medicament inhalers |
DE50303808D1 (en) * | 2003-01-29 | 2006-07-27 | I & T Innovation Tech Entw | Stripping of flat conductors |
EP1605916A4 (en) | 2003-02-12 | 2012-02-22 | R & P Korea Co Ltd | Solvent system of hardly soluble drug with improved elution rate |
GB0303870D0 (en) | 2003-02-20 | 2003-03-26 | Norton Healthcare Ltd | Pre-metered dose magazine for breath-actuated dry powder inhaler |
US20040171518A1 (en) | 2003-02-27 | 2004-09-02 | Medtronic Minimed, Inc. | Compounds for protein stabilization and methods for their use |
WO2004078198A1 (en) * | 2003-03-04 | 2004-09-16 | The Technology Development Company Ltd. | Long acting injectable insulin composition and methods of making and using thereof |
CN1780655B (en) | 2003-03-04 | 2010-12-15 | 诺顿·希尔思凯尔有限公司 | Medicament dispensing device with a display indicative of the state of an internal medicament reservoir. |
CA2518216C (en) | 2003-03-06 | 2017-05-09 | Emisphere Technologies, Inc. | Oral insulin therapies and protocol |
CA2458288A1 (en) | 2003-03-11 | 2004-09-11 | Institut De Cardiologie De Montreal / Montreal Heart Institute | Method and compound to reduce the incidence of diabetes in a subject with chronic heart failure |
USD499802S1 (en) | 2003-04-01 | 2004-12-14 | Chiesi Farmaceutici S.P.A. | Powder inhaler |
ES2564165T3 (en) | 2003-04-09 | 2016-03-18 | Novartis Ag | Aerosolization device with alignment guide for capsule drilling |
US20040204439A1 (en) | 2003-04-14 | 2004-10-14 | Staniforth John Nicholas | Composition, device, and method for treating sexual dysfunction via inhalation |
EP1468935A1 (en) | 2003-04-16 | 2004-10-20 | Alcan Technology & Management Ltd. | Blister package |
ES2572975T3 (en) | 2003-05-15 | 2016-06-03 | Ampio Pharmaceuticals, Inc. | Treatment of diseases mediated by T lymphocytes |
AU155845S (en) | 2003-05-15 | 2004-07-13 | Glaxo Group Ltd | A dispensing device for example an inhaler device |
WO2004101040A1 (en) | 2003-05-16 | 2004-11-25 | University Of Alberta | Add-on spacer design concept for dry-powder inhalers |
AU155633S (en) | 2003-05-16 | 2004-06-01 | Henkel Kgaa | Blister pack |
GB0312007D0 (en) | 2003-05-24 | 2003-07-02 | Innovata Biomed Ltd | Container |
EP2179729B1 (en) | 2003-06-02 | 2016-07-20 | GlaxoSmithKline Biologicals SA | Immunogenic compositions based on microparticles comprising adsorbed toxoid and a polysaccharide-containing antigen |
WO2004112702A2 (en) | 2003-06-13 | 2004-12-29 | Advanced Inhalation Research, Inc. | Low dose pharmaceutical powders for inhalation |
EP1641671B1 (en) | 2003-06-27 | 2015-06-24 | Portaclave LLP | Portable fuel cartridge for fuel cells |
US7001622B1 (en) | 2003-06-30 | 2006-02-21 | Robert Berndt | Composition and method for treatment and prevention of pruritis |
GB0315509D0 (en) | 2003-07-02 | 2003-08-06 | Meridica Ltd | Dispensing device |
AU158576S (en) | 2003-07-05 | 2006-08-22 | Clinical Designs Ltd | Inhaler |
US7462367B2 (en) | 2003-07-11 | 2008-12-09 | Boehringer Ingelheim International Gmbh | Anticholinergic powder formulations for inhalation |
US8921311B2 (en) | 2003-08-01 | 2014-12-30 | Mannkind Corporation | Method for treating hyperglycemia |
USD569967S1 (en) | 2003-08-06 | 2008-05-27 | Meridica Limited | Inhaler |
DE10338402A1 (en) | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Spray-dried, amorphous BIBN 4096, process for its preparation and its use as inhalant |
US20050043247A1 (en) | 2003-08-18 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Spray-dried amorphous BIBN 4096, process for preparing and the use thereof as inhalative |
US20050056535A1 (en) | 2003-09-15 | 2005-03-17 | Makoto Nagashima | Apparatus for low temperature semiconductor fabrication |
DE10343668A1 (en) | 2003-09-18 | 2005-04-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | pharmaceutical blister |
GB2398065A (en) | 2003-10-16 | 2004-08-11 | Bespak Plc | Dispensing apparatus |
US7504538B2 (en) | 2003-10-16 | 2009-03-17 | Cara Therapeutics, Inc. | Amide or thioamide derivatives and their use in the treatment of pain |
WO2005041022A1 (en) | 2003-10-24 | 2005-05-06 | Judy Singley | Method, system, and computer program for performing carbohydrate/insulin calculation based upon food weight |
USD511208S1 (en) | 2003-10-24 | 2005-11-01 | Valois Sas | Metered dose inhaler |
US7377277B2 (en) | 2003-10-27 | 2008-05-27 | Oriel Therapeutics, Inc. | Blister packages with frames and associated methods of fabricating dry powder drug containment systems |
US7451761B2 (en) | 2003-10-27 | 2008-11-18 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister package indexing and opening mechanisms, and associated methods of dispensing dry powder substances |
US20070277820A1 (en) | 2003-10-27 | 2007-12-06 | Timothy Crowder | Blister packages and associated methods of fabricating dry powder drug containment systems |
US20050147581A1 (en) * | 2003-11-19 | 2005-07-07 | The Board Of Trustees Of The University Of Illinois | Macromolecular drug complexes having improved stability and therapeutic use of the same |
SE0303269L (en) | 2003-12-03 | 2005-06-04 | Microdrug Ag | Medical product |
GB0329884D0 (en) | 2003-12-23 | 2004-01-28 | Glaxo Group Ltd | Method |
EP1701714A2 (en) | 2004-01-07 | 2006-09-20 | Nektar Therapeutics | Improved sustained release compositions for pulmonary administration of insulin |
WO2005067964A1 (en) * | 2004-01-12 | 2005-07-28 | Mannkind Corporation | A method of reducing serum proinsulin levels in type 2 diabetics |
US20070027063A1 (en) | 2004-01-12 | 2007-02-01 | Mannkind Corporation | Method of preserving the function of insulin-producing cells |
US7658721B2 (en) | 2004-01-16 | 2010-02-09 | Biodel Inc. | Sublingual drug delivery device |
DE102004006450B4 (en) | 2004-02-05 | 2012-09-27 | Ing. Erich Pfeiffer Gmbh | metering |
USD512777S1 (en) | 2004-02-19 | 2005-12-13 | Chrysalis Technologies Incorporated | Inhaler |
DE102004008141A1 (en) | 2004-02-19 | 2005-09-01 | Abbott Gmbh & Co. Kg | Guanidine compounds and their use as binding partners for 5-HT5 receptors |
NZ549588A (en) | 2004-02-24 | 2009-03-31 | Microdose Technologies Inc | Directional flow sensor inhaler |
NZ549589A (en) | 2004-02-24 | 2009-10-30 | Microdose Therapeutx Inc | Synthetic jet based medicament delivery method and apparatus |
PL2319500T3 (en) | 2004-03-12 | 2013-05-31 | Biodel Inc | Rapid acting drug delivery compositions |
ITMO20040060A1 (en) | 2004-03-18 | 2004-06-18 | Roberto Oliva | INHALER FOR POWDER PREPARATIONS |
USD515696S1 (en) | 2004-03-19 | 2006-02-21 | Innovata Biomed Limited | Inhaler |
US7625865B2 (en) | 2004-03-26 | 2009-12-01 | Universita Degli Studi Di Parma | Insulin highly respirable microparticles |
DE602005027830D1 (en) | 2004-04-05 | 2011-06-16 | Univ Bordeaux 2 | PEPTIDES AND PEPTIDE MIMETICS BINDING TO CD23 |
USD533268S1 (en) | 2004-04-18 | 2006-12-05 | Bahram Olfati | Inhaler |
WO2005102429A1 (en) | 2004-04-21 | 2005-11-03 | Innovata Biomed Limited | Inhaler |
WO2005102428A1 (en) | 2004-04-23 | 2005-11-03 | The Governors Of The University Of Alberta | Enhanced drug delivery for inhaled aerosols |
CA2564083C (en) | 2004-04-23 | 2014-02-04 | Philip Morris Usa Inc. | Aerosol generators and methods for producing aerosols |
GB0410712D0 (en) | 2004-05-13 | 2004-06-16 | Novartis Ag | Organic compounds |
USD527817S1 (en) | 2004-05-13 | 2006-09-05 | Novartis Ag | Inhaler |
US20050265927A1 (en) | 2004-05-17 | 2005-12-01 | Yale University | Intranasal delivery of nucleic acid molecules |
PA8633401A1 (en) | 2004-05-19 | 2006-09-08 | Cipla Ltd | INHALING DRUG DEVICE |
USD529604S1 (en) | 2004-05-28 | 2006-10-03 | Quadrant Technologies Limited | Dry powder inhaler |
USD548833S1 (en) | 2004-05-28 | 2007-08-14 | Quadrant Technologies Limited | Dry powder inhaler |
MXPA06014265A (en) | 2004-06-07 | 2007-03-12 | Mederio Ag | Securing dose quality of inhalable drug. |
SE528190C2 (en) | 2004-06-07 | 2006-09-19 | Mederio Ag | Inhaler |
BRPI0512397A (en) | 2004-06-25 | 2008-03-04 | Takeda Pharmaceutical | compound, pharmaceutical, methods for suppressing cancer metastasis or cancer growth, for preventing or treating a disease or condition, for controlling placental function, for improving gonadal function, for inducing or stimulating ovulation, for promoting secretion gonadotropic hormone or promote sex hormone secretion, to suppress gonadotropic hormone secretion or suppress sex hormone secretion, to regulate gonadrotopic hormone or sex hormone, and human ot7t175 protein, and to enhance blood stability, compound, and, an agent for suppressing gonadotropic hormone secretion or an agent for suppressing sex hormone secretion |
US20060000469A1 (en) | 2004-07-02 | 2006-01-05 | Tseng Daniel C | Nebulizing apparatus for medical use with improved nozzle positioning structure |
CA2574642A1 (en) | 2004-07-23 | 2006-01-26 | Intercure Ltd. | Apparatus and method for breathing pattern determination using a non-contact microphone |
CA2574398C (en) | 2004-07-26 | 2010-05-18 | 1355540 Ontario Inc. | Powder inhaler featuring reduced compaction |
JP2008509153A (en) | 2004-08-03 | 2008-03-27 | バイオレクシス ファーマシューティカル コーポレイション | Combination therapy using transferrin fusion protein containing GLP-1 |
ES2385934T3 (en) | 2004-08-20 | 2012-08-03 | Mannkind Corporation | CATALYSIS OF THE SYNTHESIS OF DICETOPIPERAZINA. |
EP2314298B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Microparticles comprising diketopiperazine salts for drug delivery |
AU2005277042A1 (en) | 2004-08-23 | 2006-03-02 | Mannkind Corporation | Pulmonary delivery of inhibitors of phosphodiesterase type 5 |
GB0419849D0 (en) | 2004-09-07 | 2004-10-13 | Pfizer Ltd | Pharmaceutical combination |
WO2006031712A2 (en) | 2004-09-13 | 2006-03-23 | Oriel Therapeutics, Inc. | Tubular dry powder drug containment systems, associated inhalers and methods |
US8365725B2 (en) | 2004-09-13 | 2013-02-05 | Oriel Therapeutics, Inc. | Dry powder inhalers that inhibit agglomeration, related devices and methods |
USD537936S1 (en) | 2004-09-15 | 2007-03-06 | Glaxo Group Limited | Cap with an extension, particularly for a dust cap of a metered dose inhaler |
USD537522S1 (en) | 2004-09-15 | 2007-02-27 | Glaxo Group Limited | Telescopic strap, particularly for a dust cap of a metered dose inhaler |
USD518170S1 (en) | 2004-09-28 | 2006-03-28 | Vectura, Ltd. | Inhaler |
EP1819388A2 (en) | 2004-10-06 | 2007-08-22 | Boehringer Ingelheim International GmbH | Dispensing device, storage device and method for dispensing powder |
US7469696B2 (en) | 2004-10-13 | 2008-12-30 | Hewlett-Packard Development Company, L.P. | Thermal drop generator |
USD515924S1 (en) | 2004-11-01 | 2006-02-28 | Warner-Lambert Company Llc | Blister card |
DE102005033398A1 (en) | 2004-11-10 | 2006-05-11 | Alfred Von Schuckmann | Inhale device |
SE0402976L (en) | 2004-12-03 | 2006-06-04 | Mederio Ag | Medical product |
KR20070095927A (en) | 2004-12-03 | 2007-10-01 | 메데리오 에이지 | A medical product comprising a glucagon-like peptide medicament intended for pulmonary inhalation |
GB0427028D0 (en) | 2004-12-09 | 2005-01-12 | Cambridge Consultants | Dry powder inhalers |
US20060130838A1 (en) | 2004-12-20 | 2006-06-22 | Lee Yong Y | Data logger for monitoring asthmatic conditions |
WO2007046834A2 (en) | 2004-12-22 | 2007-04-26 | Centocor, Inc. | Glp-1 agonists, compositions, methods and uses |
CA2592776A1 (en) | 2005-01-10 | 2006-08-17 | Mannkind Corporation | Methods and compositions for minimizing accrual of inhalable insulin in the lungs |
US20060165756A1 (en) | 2005-01-27 | 2006-07-27 | Catani Steven J | Method for weight management |
USD538423S1 (en) | 2005-02-04 | 2007-03-13 | Berube-White | Panda bear inhaler |
GB0503738D0 (en) | 2005-02-23 | 2005-03-30 | Optinose As | Powder delivery devices |
US20060219242A1 (en) | 2005-03-30 | 2006-10-05 | Boehringer Ingelheim International | Method for the Administration of an Anticholinergic by Inhalation |
JP4656397B2 (en) | 2005-03-31 | 2011-03-23 | 株式会社吉野工業所 | Powder container |
CN100431634C (en) | 2005-04-04 | 2008-11-12 | 陈庆堂 | Dry powder aerosolizing inhalator |
US7762953B2 (en) | 2005-04-20 | 2010-07-27 | Adidas Ag | Systems and methods for non-invasive physiological monitoring of non-human animals |
US7694676B2 (en) | 2005-04-22 | 2010-04-13 | Boehringer Ingelheim Gmbh | Dry powder inhaler |
CN101188996B (en) * | 2005-04-27 | 2013-03-27 | 巴克斯特国际公司 | Surface-modified microparticles and methods of forming and using the same |
US7219664B2 (en) | 2005-04-28 | 2007-05-22 | Kos Life Sciences, Inc. | Breath actuated inhaler |
MX2007013272A (en) | 2005-05-02 | 2008-01-22 | Astrazeneca Ab | An arrangement and a method for opening a cavity, a medical package and a dispensing device. |
USD544093S1 (en) | 2005-06-02 | 2007-06-05 | Bang & Olufsen A/S | Inhaler |
EP1890732B1 (en) | 2005-06-17 | 2018-03-28 | Wisconsin Alumni Research Foundation | Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapy |
US20080251072A1 (en) | 2005-07-13 | 2008-10-16 | Amar Lulla | Inhaler Device |
US8763605B2 (en) | 2005-07-20 | 2014-07-01 | Manta Devices, Llc | Inhalation device |
USD550835S1 (en) | 2005-07-22 | 2007-09-11 | Omron Healthcare Co., Ltd. | Atomizer for inhaler |
JP2009503093A (en) | 2005-08-01 | 2009-01-29 | マンカインド コーポレイション | Method for maintaining the function of insulin-producing cells |
WO2007019229A1 (en) | 2005-08-05 | 2007-02-15 | 3M Innovative Properties Company | Compositions exhibiting improved flowability |
EP1934805A4 (en) | 2005-08-25 | 2017-01-11 | Oriel Therapeutics, Inc. | Drug containment systems with sticks, related kits, dry powder inhalers and methods |
US7900625B2 (en) | 2005-08-26 | 2011-03-08 | North Carolina State University | Inhaler system for targeted maximum drug-aerosol delivery |
EP2275095A3 (en) | 2005-08-26 | 2011-08-17 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
JP2007061281A (en) | 2005-08-30 | 2007-03-15 | Hitachi Ltd | Inhalation amount measurement system |
WO2007030706A1 (en) | 2005-09-08 | 2007-03-15 | New England Medical Center Hospitals, Inc. | Fragments of the glucagon-like peptide-i and uses thereof |
KR20160022404A (en) | 2005-09-14 | 2016-02-29 | 맨카인드 코포레이션 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
USD540671S1 (en) | 2005-09-21 | 2007-04-17 | The Procter & Gamble Company | Cap for product dispenser |
WO2007041481A1 (en) | 2005-09-29 | 2007-04-12 | Biodel, Inc. | Rapid acting and prolonged acting insulin preparations |
US20070074989A1 (en) | 2005-09-30 | 2007-04-05 | Musculoskeletal Transplant Foundation | Container for lyophilization and storage of tissue |
GB0520794D0 (en) | 2005-10-12 | 2005-11-23 | Innovata Biomed Ltd | Inhaler |
ITMI20051999A1 (en) | 2005-10-21 | 2007-04-22 | Eratech S R L | INHALATION FORMULATIONS OF DRUGS IN DRY POWDER FOR ADMINISTRATION AS SUCH OR WITH NEBULIZER AND EQUIPPED WITH HIGH EROGABILITY RESPIRABILITY AND STABILITY |
USD566549S1 (en) | 2005-10-26 | 2008-04-15 | Reckitt Benckiser (Uk) Limited | Cap |
WO2007053946A1 (en) | 2005-11-09 | 2007-05-18 | Conjuchem Biotechnologies Inc. | Method of treating diabetes and/or obesity with reduced nausea side effects using an insulinotropic peptide conjugated to albumin |
AR058290A1 (en) | 2005-12-12 | 2008-01-30 | Glaxo Group Ltd | MEDICINAL DISPENSER |
AR058289A1 (en) | 2005-12-12 | 2008-01-30 | Glaxo Group Ltd | COLLECTOR TO BE USED IN MEDICINAL DISPENSER |
US8293869B2 (en) | 2005-12-16 | 2012-10-23 | Nektar Therapeutics | Polymer conjugates of GLP-1 |
EP1981483A1 (en) | 2006-01-24 | 2008-10-22 | Nexbio, Inc. | Technology for preparation of macromolecular microspheres |
USD557798S1 (en) | 2006-01-25 | 2007-12-18 | Valois S.A.S. | Inhaler |
US7390949B2 (en) | 2006-02-01 | 2008-06-24 | Wanne, Inc. | Saxophone and clarinet mouthpiece cap |
GB0602897D0 (en) | 2006-02-13 | 2006-03-22 | Jagotec Ag | Improvements In Or Relating To Dry Powder Inhaler Devices |
EP1991840A1 (en) | 2006-02-14 | 2008-11-19 | Battelle Memorial Institute | Accurate metering system |
CN101389648B (en) | 2006-02-22 | 2013-07-17 | 默沙东公司 | Oxyntomodulin derivatives |
MX2008010721A (en) | 2006-02-22 | 2008-09-01 | Mannkind Corp | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent. |
DE102006010089A1 (en) | 2006-02-24 | 2007-10-18 | Aha-Kunststofftechnik Gmbh | The dry powder inhaler |
USD541151S1 (en) | 2006-03-20 | 2007-04-24 | The Procter & Gamble Company | Cap for product dispenser |
US8037880B2 (en) | 2006-04-07 | 2011-10-18 | The University Of Western Ontario | Dry powder inhaler |
AU2007238114B2 (en) | 2006-04-12 | 2010-10-14 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
EP1844809A1 (en) | 2006-04-13 | 2007-10-17 | Boehringer Ingelheim Pharma GmbH & Co. KG | Container for inhaler, and multidose inhaler |
EP1844806A1 (en) | 2006-04-13 | 2007-10-17 | Boehringer Ingelheim Pharma GmbH | Device for delivery of medicaments, magazine for medicaments, and method for withdrawing medicaments from a medicament chamber |
US20070243216A1 (en) | 2006-04-14 | 2007-10-18 | Stanley Kepka | Stable solutions of prostaglandin and uses of same |
KR101438839B1 (en) | 2006-04-14 | 2014-10-02 | 맨카인드 코포레이션 | Glucagon-like peptide 1 (glp-1)pharmaceutical formulations |
GR1005620B (en) | 2006-05-09 | 2007-09-03 | Improved dry powder inhaler | |
JPWO2007129515A1 (en) | 2006-05-10 | 2009-09-17 | 株式会社スカイネット | Small animal anesthesia system |
DE102006021978A1 (en) | 2006-05-10 | 2007-11-15 | Robert Bosch Gmbh | Apparatus and method for reinforcing a blister |
PT103481B (en) | 2006-05-16 | 2008-08-01 | Hovione Farmaciencia S A | INHALER OF SIMPLE USE AND INHALATION METHOD |
GB0611656D0 (en) | 2006-06-13 | 2006-07-19 | Cambridge Consultants | Dry powder inhalers |
GB0611659D0 (en) | 2006-06-13 | 2006-07-19 | Cambridge Consultants | Dry powder inhalers |
EP2029206A1 (en) | 2006-06-16 | 2009-03-04 | Cipla Limited | Improved dry powder inhaler |
WO2008001744A1 (en) | 2006-06-27 | 2008-01-03 | Otsuka Pharmaceutical Co., Ltd. | Powder inhaler |
EP2035068A1 (en) | 2006-06-27 | 2009-03-18 | Brin Tech International Limited | Inhaler |
GB0613161D0 (en) | 2006-06-30 | 2006-08-09 | Novartis Ag | Organic Compounds |
CN2917673Y (en) | 2006-07-06 | 2007-07-04 | 兴安药业有限公司 | Capsule type dry powder inhaler |
WO2008008021A1 (en) | 2006-07-14 | 2008-01-17 | Astrazeneca Ab | Inhalation system and delivery device for the administration of a drug in the form of dry powder. |
WO2008013938A2 (en) | 2006-07-27 | 2008-01-31 | Nektar Therapeutics | Aerosolizable formulation comprising insulin for pulmonary delivery |
BRPI0714616A2 (en) | 2006-08-04 | 2013-06-11 | Manus Pharmaceuticals Canada Ltd | multifunctional bioactive compound, pharmaceutical composition, and use of a |
GB0616299D0 (en) | 2006-08-16 | 2006-09-27 | Cambridge Consultants | Drug Capsules for dry power inhalers |
US20080066739A1 (en) | 2006-09-20 | 2008-03-20 | Lemahieu Edward | Methods and systems of delivering medication via inhalation |
US20080108574A1 (en) | 2006-09-27 | 2008-05-08 | Braincells, Inc. | Melanocortin receptor mediated modulation of neurogenesis |
JP2010509591A (en) | 2006-11-10 | 2010-03-25 | プロヴェリス・サイエンティフィック・コーポレーション | Automatic nasal spray pump test |
US7842662B2 (en) | 2006-11-10 | 2010-11-30 | Cara Therapeutics, Inc. | Synthetic peptide amide dimers |
US8236766B2 (en) | 2006-11-10 | 2012-08-07 | Cara Therapeutics, Inc. | Uses of synthetic peptide amides |
US7713937B2 (en) | 2006-11-10 | 2010-05-11 | Cara Therapeutics, Inc. | Synthetic peptide amides and dimeric forms thereof |
PT2064228E (en) | 2006-11-10 | 2012-12-10 | Cara Therapeutics Inc | Synthetic peptide amides |
US7824014B2 (en) | 2006-12-05 | 2010-11-02 | Canon Kabushiki Kaisha | Head substrate, printhead, head cartridge, and printing apparatus |
USD548618S1 (en) | 2006-12-06 | 2007-08-14 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
USD548619S1 (en) | 2006-12-06 | 2007-08-14 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
USD549111S1 (en) | 2006-12-06 | 2007-08-21 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
PL2063940T3 (en) | 2006-12-22 | 2012-06-29 | Almirall Sa | Inhalation device for drugs in powder form |
WO2008092864A1 (en) | 2007-01-29 | 2008-08-07 | Novo Nordisk A/S | Method and devices for aerosolizing a drug formulation |
US8172817B2 (en) | 2007-01-31 | 2012-05-08 | Allegiance Corporation | Liquid collection system and related methods |
EP2111414B1 (en) | 2007-02-15 | 2014-07-02 | Indiana University Research and Technology Corporation | Glucagon/glp-1 receptor co-agonists |
US8196576B2 (en) | 2007-02-28 | 2012-06-12 | Microdose Therapeutx, Inc. | Inhaler |
WO2009005546A1 (en) | 2007-03-05 | 2009-01-08 | Board of Governors for Higher Education, State of Rhode Island and the Providence Plantations | High efficiency mouthpiece/adaptor for inhalers |
JP2008212436A (en) | 2007-03-06 | 2008-09-18 | Canon Inc | Inhalation apparatus |
US8146745B2 (en) | 2007-03-09 | 2012-04-03 | Cardpak, Inc. | Environmentally separable packaging device with attaching base |
GB0704928D0 (en) | 2007-03-14 | 2007-04-25 | Cambridge Consultants | Dry powder inhalers |
WO2009076325A2 (en) | 2007-04-11 | 2009-06-18 | Starr Life Sciences Corp. | Noninvasive photoplethysmographic sensor platform for mobile animals |
JP4417400B2 (en) | 2007-04-16 | 2010-02-17 | アンリツ株式会社 | Solder inspection line centralized management system and management device used therefor |
CA2683610C (en) | 2007-04-23 | 2013-01-08 | Intarcia Therapeutics, Inc. | Suspension formulations of insulinotropic peptides and uses thereof |
EP2152316A4 (en) | 2007-04-26 | 2011-03-23 | Quark Pharmaceuticals Inc | Therapeutic delivery of inhibitory nucleic acid molecules to the respiratory system |
USD577815S1 (en) | 2007-04-30 | 2008-09-30 | Sun Pharma Advanced Research Company Limited | Inhaler |
CN101980739B (en) | 2007-04-30 | 2013-06-26 | 太阳医药高级研发有限公司 | Inhalation device |
USD583463S1 (en) | 2007-04-30 | 2008-12-23 | Sun Pharma Advanced Research Company Limited | Inhaler |
EP1992378A1 (en) | 2007-05-16 | 2008-11-19 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device |
CN101715428B (en) | 2007-05-16 | 2016-08-24 | 神秘制药公司 | For carrying the formulation of pharmaceutical compositions and including the dosage band of this formulation |
USD579549S1 (en) | 2007-06-07 | 2008-10-28 | Novartis Ag | Inhaler |
EP2164509A1 (en) | 2007-06-08 | 2010-03-24 | Massachusetts Institute of Technology | Igf for the treatment of rett syndrome and synaptic disorders |
CN101686989B (en) | 2007-06-21 | 2016-10-19 | 卡拉治疗学股份有限公司 | Substituted imidazoheterocycles |
WO2009009013A2 (en) | 2007-07-06 | 2009-01-15 | Manta Devices, Llc | Inhalation devices for storing and delivering medicament |
WO2009046072A1 (en) | 2007-10-02 | 2009-04-09 | Baxter International Inc | Dry powder inhaler |
EP2048112A1 (en) | 2007-10-09 | 2009-04-15 | Kemira Kemi AB | Use of a nozzle for manufacturing sodium percarbonate |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
WO2009055742A2 (en) | 2007-10-24 | 2009-04-30 | Mannkind Corporation | Delivery of active agents |
WO2009055740A2 (en) | 2007-10-24 | 2009-04-30 | Mannkind Corporation | Method of preventing adverse effects by glp-1 |
JP5350388B2 (en) | 2007-10-25 | 2013-11-27 | ノバルティス アーゲー | Powder preparation of unit dose drug package |
GB0721394D0 (en) | 2007-10-31 | 2007-12-12 | Vectura Group Plc | Compositions for trating parkinson's disease |
AU2008323924B2 (en) | 2007-11-06 | 2013-01-17 | 3M Innovative Properties Company | Medicinal inhalation devices and components thereof |
CN101317821B (en) | 2007-11-15 | 2012-01-04 | 陈晓东 | Ultra-fine dry powder particle suitable for drug administration for lung, and preparation method thereof |
EP2060268A1 (en) | 2007-11-15 | 2009-05-20 | Novo Nordisk A/S | Pharmaceutical compositions for pulmonary or nasal delivery of peptides |
CA2709071C (en) | 2007-12-14 | 2016-11-15 | Labogroup S.A.S. | Delivering aerosolizable food products |
USD594753S1 (en) | 2007-12-14 | 2009-06-23 | The Procter & Gamble Company | Blister card |
WO2009082341A1 (en) | 2007-12-20 | 2009-07-02 | Astrazeneca Ab | Device and method for deaggregating powder 854 |
US7584846B2 (en) | 2007-12-21 | 2009-09-08 | S.C. Johnson & Son, Inc. | Shaped packaging for a refill |
EP2252268A1 (en) | 2008-02-01 | 2010-11-24 | Vectura Limited | Pulmonary formulations of triptans |
GB0802028D0 (en) | 2008-02-05 | 2008-03-12 | Dunne Stephen T | Powder inhaler flow regulator |
USD614045S1 (en) | 2008-02-22 | 2010-04-20 | Ima Safe S.R.L. | Blister packaging |
SG192447A1 (en) | 2008-03-27 | 2013-08-30 | Mannkind Corp | A dry powder inhalation system |
CA2720864C (en) | 2008-04-07 | 2017-07-04 | National Institute Of Immunology | Compositions useful for the treatment of diabetes and other chronic disorder |
DE102008023376A1 (en) | 2008-05-13 | 2009-11-19 | Alfred Von Schuckmann | Dispenser for powdery masses contained in a separate packaging |
BRPI0913021A2 (en) | 2008-05-15 | 2015-10-13 | Novartis Ag | pulmonary distribution of a fluoroquinolone |
USD598785S1 (en) | 2008-05-22 | 2009-08-25 | Wm. Wrigley Jr. Company | Blister card |
USD597418S1 (en) | 2008-05-22 | 2009-08-04 | Wm. Wrigley Jr. Company | Blister card |
USD604833S1 (en) | 2008-06-13 | 2009-11-24 | Mannkind Corporation | Dry powder inhaler |
USD597657S1 (en) | 2008-06-13 | 2009-08-04 | Mannkind Corporation | Dry powder inhaler |
USD604832S1 (en) | 2008-06-13 | 2009-11-24 | Mannkind Corporation | Cartridge for a dry powder inhaler |
USD605752S1 (en) | 2008-06-13 | 2009-12-08 | Mannkind Corporation | Dry powder inhaler |
EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
USD614760S1 (en) | 2008-06-13 | 2010-04-27 | Mannkind Corporation | Dry powder inhaler |
USD605753S1 (en) | 2008-06-13 | 2009-12-08 | Mannkind Corporation | Cartridge for a dry powder inhaler |
USD613849S1 (en) | 2008-06-13 | 2010-04-13 | Mannkind Corporation | Cartridge for a dry powder inhaler |
USD635241S1 (en) | 2008-06-13 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
MX2010014240A (en) | 2008-06-20 | 2011-03-25 | Mankind Corp | An interactive apparatus and method for real-time profiling of inhalation efforts. |
TWI614024B (en) | 2008-08-11 | 2018-02-11 | 曼凱公司 | Use of ultrarapid acting insulin |
USD629888S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
USD629886S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
USD635242S1 (en) | 2008-12-01 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
USD635243S1 (en) | 2008-12-01 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
USD629505S1 (en) | 2008-12-01 | 2010-12-21 | Mannkind Corporation | Dry powder inhaler |
USD629506S1 (en) | 2008-12-01 | 2010-12-21 | Mannkind Corporation | Dry powder inhaler |
USD629887S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
JP5788806B2 (en) | 2008-12-29 | 2015-10-07 | マンカインド コーポレイション | Substituted diketopiperazines and salts thereof for drug delivery agents, therapeutic compositions containing them, fine particle compositions and dry powder compositions, and methods for preparing the same |
US8550074B2 (en) | 2009-01-15 | 2013-10-08 | Manta Devices, Llc | Delivery device and related methods |
TWI528982B (en) | 2009-03-04 | 2016-04-11 | 曼凱公司 | An improved dry powder drug delivery system |
CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
MX2011009682A (en) | 2009-03-18 | 2011-10-17 | Mannkind Corp | Inhaler adaptor for a laser diffraction apparatus and method for measuring particle size distribution. |
GB0907425D0 (en) | 2009-04-29 | 2009-06-10 | Glaxo Group Ltd | Compounds |
USD626836S1 (en) | 2009-04-30 | 2010-11-09 | Bryce Lien | Bottle cap |
USD628090S1 (en) | 2009-05-07 | 2010-11-30 | Mccormick & Company, Incorporated | Seasoning package |
USD620375S1 (en) | 2009-05-11 | 2010-07-27 | Mcneil-Ppc, Inc. | Blister |
EP2432536B1 (en) | 2009-05-21 | 2018-07-04 | MicroDose Therapeutx, Inc. | Rotary cassette system for dry powder inhaler |
PL3106149T3 (en) | 2009-05-29 | 2020-06-01 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting beta-2 adrenergic receptor agonists and associated methods and systems |
WO2010144785A2 (en) | 2009-06-12 | 2010-12-16 | Mannkind Corporation | Diketopiperazine microparticles with defined isomer contents |
US8551528B2 (en) | 2009-06-12 | 2013-10-08 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
US9180263B2 (en) | 2009-07-01 | 2015-11-10 | Microdose Therapeutx, Inc. | Laboratory animal pulmonary dosing device |
US8642548B2 (en) | 2009-08-07 | 2014-02-04 | Mannkind Corporation | Val (8) GLP-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome |
CA2770714A1 (en) | 2009-08-27 | 2011-03-17 | Stc.Unm | Methods and systems for dosing and coating inhalation powders onto carrier particles |
IT1395945B1 (en) | 2009-09-30 | 2012-11-02 | Oliva | INHALER PERFECTED FOR POWDER PREPARATIONS |
USD647195S1 (en) | 2009-10-09 | 2011-10-18 | Vectura Delivery Devices Limited | Inhaler having cover |
USD647196S1 (en) | 2009-10-09 | 2011-10-18 | Vectura Delivery Devices Limited | Inhaler having cover |
EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
USD650295S1 (en) | 2009-11-13 | 2011-12-13 | Avidiamed Gmbh | Blister pack for pharmaceuticals |
WO2011079310A1 (en) | 2009-12-23 | 2011-06-30 | Map Pharmaceuticals,Inc. | Enhanced eductor design |
CN102111798A (en) | 2009-12-29 | 2011-06-29 | 中兴通讯股份有限公司 | Method and device for generating TD-SCDMA analog test signal |
EP2915540A1 (en) | 2009-12-31 | 2015-09-09 | Stealth Peptides International, Inc. | Methods for performing a coronary artery bypass graft procedure |
AU332056S (en) | 2010-01-08 | 2010-08-04 | Teva Pharma Ireland | Inhaler |
USD641076S1 (en) | 2010-03-26 | 2011-07-05 | Oriel Therapeutics, Inc. | Dry powder inhaler |
GB201006901D0 (en) | 2010-04-26 | 2010-06-09 | Sagentia Ltd | Device for monitoring status and use of an inhalation or nasal drug delivery device |
PT105065B (en) | 2010-04-26 | 2012-07-31 | Hovione Farmaciencia S A | A SIMPLE INHALER OF CAPSULES |
USD645954S1 (en) | 2010-05-21 | 2011-09-27 | Consort Medical Plc | Mechanical dosage counter apparatus |
USD636868S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
USD636869S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
USD636867S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
BR112012033060A2 (en) | 2010-06-21 | 2018-02-27 | Mannkind Corp | Dry powder drug release system methods |
CN101851213A (en) | 2010-06-21 | 2010-10-06 | 于清 | Synthetic methods of 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine and salt substitute thereof |
CA2808469A1 (en) | 2010-08-19 | 2012-02-23 | Sanofi-Aventis Deutschland Gmbh | Method and system for determining information related to a drug reservoir using an electronic sensor |
USD643308S1 (en) | 2010-09-28 | 2011-08-16 | Mannkind Corporation | Blister packaging |
DK2621488T3 (en) | 2010-09-29 | 2019-03-04 | Pulmatrix Operating Co Inc | CATIONIC DRY POWDER |
MX340112B (en) | 2010-11-09 | 2016-06-27 | Mannkind Corp | Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines. |
CA140810S (en) | 2010-12-01 | 2012-05-23 | Teva Pharma | Inhaler cap |
USD642483S1 (en) | 2010-12-03 | 2011-08-02 | Mccormick & Company, Incorporated | Seasoning package |
SG192708A1 (en) | 2011-02-10 | 2013-09-30 | Mannkind Corp | Formation of n-protected bis-3,6-(4-aminoalkyl) -2,5,diketopiperazine |
KR101940832B1 (en) | 2011-04-01 | 2019-01-21 | 맨카인드 코포레이션 | Blister package for pharmaceutical cartridges |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
LT2739268T (en) | 2011-08-01 | 2019-03-25 | Monash University | Method and formulation for inhalation |
USD674893S1 (en) | 2011-10-20 | 2013-01-22 | Mannkind Corporation | Inhaler device |
EP2776053A1 (en) | 2011-10-24 | 2014-09-17 | MannKind Corporation | Methods and compositions for treating pain |
CN102436238B (en) | 2011-11-03 | 2014-04-16 | 广东轻工职业技术学院 | Acquisition method of data acquisition and information management system for production line |
RU2014143116A (en) | 2012-04-27 | 2016-06-20 | Маннкайнд Корп | METHODS FOR SYNTHESIS OF ETHYLFUMARATES AND THEIR APPLICATION AS INTERMEDIATE COMPOUNDS |
SG11201500218VA (en) | 2012-07-12 | 2015-03-30 | Mannkind Corp | Dry powder drug delivery systems and methods |
KR20150047606A (en) | 2012-08-29 | 2015-05-04 | 맨카인드 코포레이션 | Method and composition for treating hyperglycemia |
EP2911690A1 (en) | 2012-10-26 | 2015-09-02 | MannKind Corporation | Inhalable influenza vaccine compositions and methods |
CN103110611A (en) | 2012-12-11 | 2013-05-22 | 苏州惠仁生物科技有限公司 | Inhalant, preparation method thereof, and application of inhalantas inhalant carrier with pullulan |
USD711740S1 (en) | 2013-01-22 | 2014-08-26 | H204K9, Inc. | Bottle cap |
EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR122019026637B1 (en) | 2013-07-18 | 2023-09-26 | Mannkind Corporation | PHARMACEUTICAL DRY POWDER FORMULATIONS AND METHOD FOR MANUFACTURING A DRY POWDER FORMULATION |
CA2920488C (en) | 2013-08-05 | 2022-04-26 | Mannkind Corporation | Insufflation apparatus and methods |
GB201319265D0 (en) | 2013-10-31 | 2013-12-18 | Norton Waterford Ltd | Medicament inhaler |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
USD771237S1 (en) | 2014-10-02 | 2016-11-08 | Mannkind Corporation | Mouthpiece cover |
WO2017132601A1 (en) | 2016-01-29 | 2017-08-03 | Mannkind Corporation | Dry powder inhaler |
WO2017201463A1 (en) | 2016-05-19 | 2017-11-23 | Mannkind Corporation | Apparatus, system and method for detecting and monitoring inhalations |
-
2006
- 2006-09-14 KR KR1020167004282A patent/KR20160022404A/en not_active Application Discontinuation
- 2006-09-14 WO PCT/US2006/036034 patent/WO2007033372A2/en active Application Filing
- 2006-09-14 KR KR1020087008065A patent/KR101384456B1/en active IP Right Grant
- 2006-09-14 KR KR1020147002141A patent/KR101486829B1/en active IP Right Grant
- 2006-09-14 KR KR1020147001815A patent/KR101486397B1/en active IP Right Grant
- 2006-09-14 ES ES06803680.5T patent/ES2555310T3/en active Active
- 2006-09-14 KR KR1020127011998A patent/KR20120060245A/en active Application Filing
- 2006-09-14 ES ES06803583.1T patent/ES2559677T3/en active Active
- 2006-09-14 IN IN9128DEN2014 patent/IN2014DN09128A/en unknown
- 2006-09-14 BR BRPI0616071A patent/BRPI0616071B8/en active IP Right Grant
- 2006-09-14 DK DK06803583.1T patent/DK1928423T3/en active
- 2006-09-14 CA CA2620758A patent/CA2620758C/en active Active
- 2006-09-14 KR KR1020147002144A patent/KR101643478B1/en active IP Right Grant
- 2006-09-14 CN CN201410508203.1A patent/CN104324366B/en active Active
- 2006-09-14 EP EP06803680.5A patent/EP1937219B1/en active Active
- 2006-09-14 ES ES13176200.7T patent/ES2640282T3/en active Active
- 2006-09-14 RU RU2008114306/15A patent/RU2394550C2/en active
- 2006-09-14 US US11/532,065 patent/US7803404B2/en active Active
- 2006-09-14 HU HUE06803583A patent/HUE028623T2/en unknown
- 2006-09-14 US US11/532,063 patent/US7799344B2/en active Active
- 2006-09-14 CA CA2621806A patent/CA2621806C/en active Active
- 2006-09-14 CN CN2012100686356A patent/CN102614131A/en active Pending
- 2006-09-14 MX MX2013011057A patent/MX358592B/en unknown
- 2006-09-14 AU AU2006290870A patent/AU2006290870B2/en active Active
- 2006-09-14 DK DK13176200.7T patent/DK2656836T3/en active
- 2006-09-14 DK DK06803680.5T patent/DK1937219T3/en active
- 2006-09-14 EP EP13176200.7A patent/EP2656836B1/en active Active
- 2006-09-14 AU AU2006290227A patent/AU2006290227B2/en active Active
- 2006-09-14 JP JP2008531320A patent/JP5167133B2/en active Active
- 2006-09-14 KR KR1020087007326A patent/KR101557502B1/en active IP Right Grant
- 2006-09-14 RU RU2008114361/15A patent/RU2390325C2/en active
- 2006-09-14 JP JP2008531355A patent/JP5465878B2/en active Active
- 2006-09-14 CN CN201410508206.5A patent/CN104324362B/en active Active
- 2006-09-14 HU HUE06803680A patent/HUE028691T2/en unknown
- 2006-09-14 EP EP06803583.1A patent/EP1928423B1/en active Active
- 2006-09-14 WO PCT/US2006/035822 patent/WO2007033316A2/en active Application Filing
- 2006-09-14 BR BRPI0615819A patent/BRPI0615819B8/en active IP Right Grant
-
2008
- 2008-03-14 MX MX2019012598A patent/MX2019012598A/en unknown
- 2008-09-19 HK HK08110376.5A patent/HK1116088A1/en unknown
- 2008-11-05 HK HK08112118.4A patent/HK1117768A1/en unknown
-
2010
- 2010-03-16 RU RU2010109856/15A patent/RU2443414C2/en active
- 2010-06-14 US US12/815,276 patent/US8420604B2/en active Active
- 2010-07-06 US US12/830,557 patent/US8729019B2/en active Active
- 2010-09-16 US US12/883,369 patent/US9089497B2/en active Active
-
2013
- 2013-03-12 US US13/797,657 patent/US9066881B2/en active Active
- 2013-05-08 JP JP2013098881A patent/JP5859481B2/en active Active
-
2014
- 2014-04-10 US US14/249,621 patent/US9283193B2/en active Active
-
2015
- 2015-06-22 US US14/746,656 patent/US9446001B2/en active Active
- 2015-09-16 JP JP2015183478A patent/JP6080926B2/en active Active
-
2016
- 2016-02-05 US US15/017,153 patent/US9717689B2/en active Active
- 2016-08-10 US US15/233,794 patent/US10143655B2/en active Active
-
2017
- 2017-06-21 US US15/629,636 patent/US10357459B2/en active Active
-
2018
- 2018-10-04 US US16/151,736 patent/US11103459B2/en active Active
-
2019
- 2019-06-12 US US16/439,252 patent/US11013692B2/en active Active
-
2021
- 2021-07-26 US US17/443,344 patent/US20210353544A1/en not_active Abandoned
-
2023
- 2023-08-18 US US18/235,592 patent/US20230390206A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230390206A1 (en) | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces | |
AU2013205022B2 (en) | Method of drug formulation based on increasing the affinity of active agents for crystalline microparticle surfaces | |
CN101262849A (en) | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |