CN1170527C - 含有甲状旁腺激素(pth)的吸入用治疗剂 - Google Patents
含有甲状旁腺激素(pth)的吸入用治疗剂 Download PDFInfo
- Publication number
- CN1170527C CN1170527C CNB951969544A CN95196954A CN1170527C CN 1170527 C CN1170527 C CN 1170527C CN B951969544 A CNB951969544 A CN B951969544A CN 95196954 A CN95196954 A CN 95196954A CN 1170527 C CN1170527 C CN 1170527C
- Authority
- CN
- China
- Prior art keywords
- therapeutic agent
- pth
- parathyroid hormone
- carrier
- diameter
- 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.)
- Expired - Fee Related
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 72
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 67
- 229960001319 parathyroid hormone Drugs 0.000 title claims abstract description 67
- 102100036893 Parathyroid hormone Human genes 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title abstract description 3
- 102000003982 Parathyroid hormone Human genes 0.000 claims abstract description 67
- 239000000843 powder Substances 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 34
- 229940124597 therapeutic agent Drugs 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 20
- 230000002776 aggregation Effects 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 238000005054 agglomeration Methods 0.000 claims description 7
- 235000001014 amino acid Nutrition 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 230000000241 respiratory effect Effects 0.000 claims description 5
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims description 4
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims description 4
- 102000058004 human PTH Human genes 0.000 claims description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 230000001009 osteoporotic effect Effects 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 abstract description 8
- 230000002685 pulmonary effect Effects 0.000 abstract description 7
- 238000004220 aggregation Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000000654 additive Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000011164 ossification Effects 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000029058 respiratory gaseous exchange Effects 0.000 description 4
- 210000002345 respiratory system Anatomy 0.000 description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 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 3
- 239000000243 solution Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 210000002411 hand bone Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- NINQYGGNRIBFSC-CIUDSAMLSA-N Ala-Lys-Ser Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CO)C(O)=O NINQYGGNRIBFSC-CIUDSAMLSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 1
- UYCPJVYQYARFGB-YDHLFZDLSA-N Asn-Phe-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O UYCPJVYQYARFGB-YDHLFZDLSA-N 0.000 description 1
- HPNDBHLITCHRSO-WHFBIAKZSA-N Asp-Ala-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)NCC(O)=O HPNDBHLITCHRSO-WHFBIAKZSA-N 0.000 description 1
- LIVXPXUVXFRWNY-CIUDSAMLSA-N Asp-Lys-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O LIVXPXUVXFRWNY-CIUDSAMLSA-N 0.000 description 1
- PLOKOIJSGCISHE-BYULHYEWSA-N Asp-Val-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PLOKOIJSGCISHE-BYULHYEWSA-N 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 1
- IXFVOPOHSRKJNG-LAEOZQHASA-N Gln-Asp-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IXFVOPOHSRKJNG-LAEOZQHASA-N 0.000 description 1
- NTBDVNJIWCKURJ-ACZMJKKPSA-N Glu-Asp-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NTBDVNJIWCKURJ-ACZMJKKPSA-N 0.000 description 1
- WVYJNPCWJYBHJG-YVNDNENWSA-N Glu-Ile-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O WVYJNPCWJYBHJG-YVNDNENWSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MOJKRXIRAZPZLW-WDSKDSINSA-N Gly-Glu-Ala Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MOJKRXIRAZPZLW-WDSKDSINSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- POMXSEDNUXYPGK-IHRRRGAJSA-N Leu-Met-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N POMXSEDNUXYPGK-IHRRRGAJSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- HZYCAKGEXXKCDM-UHFFFAOYSA-N Methyl 2-(methylthio)acetate Chemical compound COC(=O)CSC HZYCAKGEXXKCDM-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 1
- NIOYDASGXWLHEZ-CIUDSAMLSA-N Ser-Met-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOYDASGXWLHEZ-CIUDSAMLSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- AIISTODACBDQLW-WDSOQIARSA-N Trp-Leu-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 AIISTODACBDQLW-WDSOQIARSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 108010044348 lysyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及给哺乳动物宿主肺部使用全长甲状旁腺激素以治疗骨质疏松的组合物和方法。因此,本发明提供了含有以适于吸入的干粉形式存在的人全长甲状旁腺激素或其类似物的治疗剂,其中所述干粉的至少50%由(a)直径不大于10微米的颗粒;或(b)这种颗粒的聚集物组成。
Description
技术领域
本发明涉及为治疗骨质疏松病给哺乳动物患者肺部施用甲状旁腺激素(甲状旁腺激素,PTH)的组合物和方法。
背景技术
人甲状旁腺激素是含84个氨基酸的蛋白质(SEQ ID NO:1),它参与钙和磷的体内平衡并控制骨生长和密度。可以通过肽合成或由基因工程的酵母、细菌或哺乳动物细胞宿主得到人PTH。人PTH也可购自Bachem Inc.,Bubendorf,Switzer land。重组人甲状旁腺激素的制备公开于EP-B-0383751。
在哺乳动物中,一方面与成骨细胞活性有关的骨形成和另一方面与破骨细胞有关的骨损失之间的平衡在几种受骨影响的疾病(如骨质疏松)中被打破。甲状旁腺激素对骨质疏松具有潜在的治疗作用。Dempster等(1993)内分泌学综述,vol.14,690-709综述了甲状旁腺激素对骨的合成代谢作用。
Reeve等(1980)英国医学杂志,vol.280,1340-1344说明人PTH的N末端片断(PTH1-34)在更年期(involutional)骨质疏松中对骨小梁有合成代谢作用。但是,如果可能,优选使用野生型蛋白,因为这样通过所用化合物就能保证产生天然蛋白的所有生物效用。
多肽药物如PTH不能以有效剂量口服,因为在到达血流前,它们会被胃肠道中的酶及胃中的低pH降解。PTH的给药一般通过皮下注射来完成。但是,每天注射对病人来说是不方便的。由于这些不利因素,需要除注射以外给药形式的PTH。
WO94/07514中公开了对鼠进行甲状旁腺激素及其N末端片断的肺部给药。当给大鼠气管内(IT)使用含氨基酸1-34(PTH34)的N-末端片断时,15分钟后,血清中出现峰值,此后活性迅速消失。相反,IT使用完整PTH(PTH84)后,血清中出现平台现象,在90分钟的实验中未显著消失。由于已知PTH以脉冲形式(即给药后血清浓度应迅速上升而到达峰值后迅速下降)能最有效地给病人使用,文献WO94/07514推断就肺部给药来说PTH的N末端片断优于全长蛋白。
发明概述
按照本发明,表明当全长PTH作为干燥粉末气雾剂通过气管内插管被狗吸入时得到脉冲的血浆图。因此,令人惊奇是,与公开专利申请WO94/07514的结论相反,全长PTH的肺部给药可有效地刺激骨形成并能有效治疗骨质疏松。
附图简述
图1
分别吸入PTH 1-34和PTH 1-84后狗的血浆浓度。(-■-)PTH 1-84(吸入剂量14μg/kg),(…▲…)PTH1-34(吸入剂量4.0μg/kg)。
发明公开
首先,本发明提供了含有PTH的治疗物质,优选是一种治疗剂,它具有全长甲状旁腺激素的基本的生物活性。所述治疗物质是适于吸入的干粉形式,其中活性化合物PTH总量的至少50%由(a)直径小于约10微米,例如在0.01至10微米之间,优选1至6微米间的基本颗粒,或(b)所述颗粒的聚集物组成。
本发明的治疗剂可只含有所述的活性化合物PTH,或者可以含有其它物质,如一种药用载体。此载体可主要由直径小于约10微米的颗粒组成,以便作为整体的所得粉末至少50%由直径小于约10微米,例如在0.01至10微米之间,优选1至6微米间的任意聚集的基本颗粒,或(b)所述颗粒的聚集物组成。
或者,此载体可主要由较大颗粒(“粗颗粒”)组成,以便在该活性化合物和所述载体间形成一种“规则(ordered)的混合物”。在一种规则的混合物(也被称为一种相互作用或粘着混合物)中,细药物颗粒(在本发明中,活性化合物)完全均匀地分布于粗赋形剂颗粒(在本发明中,药用载体)的表面。在此情况下,优选在形成规则混合物前该活性化合物不是聚集物的形式。粗颗粒的直径可超过20微米,例如大于60微米。对于这些下限,粗颗粒的直径并不十分重要,故按照特定制剂的实践需要,如果需要可使用多种粗颗粒粒度。在规则混合物中不需要粗颗粒具有相同的粒度,但在规则混合物中粗颗粒具有相近的粒度是有利的。优选粗颗粒直径为60-800微米。
优选活性化合物PTH总量的至少60%,如至少70%或至少80%,并更优选90%由直径小于约10微米的颗粒,或这种颗粒的聚集物组成。除非需要一种规则的混合物,当干粉制剂含有载体时,优选干粉的至少60%,如至少70%或至少80%,并更优选至少90%(质量)由直径小于约10微米的颗粒或这种颗粒的聚集物组成。
如上所述,作为吸入用干粉,不论含或不含药用载体,其中可含有颗粒的聚集物,而当吸入时任何聚集物应基本解聚为至少50%由直径不大于10微米的颗粒组成的一种粉末。该聚集物可以是受控聚集的产物或它们可以只是粉末颗粒紧密接触的产物。在每种情况中,此聚集物可以解聚(如在吸入器中通过机械手段或其它手段)成上述颗粒是必要的。一般来说,在规则混合物中优选不形成聚集物。在一种规则混合物的情况下,优选吸入时在吸入器中通过机械手段或只是通过吸入作用或通过其它手段,由大颗粒上释放活性化合物,该活性化合物再沉积在下呼吸道而载体留在口中。
当需要时,可以在制剂中含有一种在下呼吸道提高PTH吸收的物质。该物质可以是能提高通过肺泡内上皮细胞层吸收并促进进入邻近的肺脉管***的若干种化合物中的任意一种。促进剂的例子为脂肪酸盐,如癸酸钠,胆汁酸盐及其衍生物、磷脂、螯合剂及环糊精及其衍生物。适宜的促进剂的其它实例可见国际专利申请WO95/00127和WO95/00128。
按照本发明所使用的甲状旁腺激素,虽然可使用具有全长甲状旁腺激素基本生物活性的PTH的任何生物活性形式或衍生物,但是优选人甲状旁腺激素。
按照本发明,所用PTH优选是至少含有序列表中如SEQ ID NO:1所示序列的氨基酸1至34,更优选氨基酸1至84。但是,本发明所用的PTH并不严格限制于具有序列表所示序列的PTH。本发明还包括了使用PTH多肽进行修饰,如进行取代、小缺失、***或倒位,不过该多肽还具有氨基酸序列公开于序列表中的全长PTH的基本生物活性。于是,本发明也包括其氨基酸序列至少90%类似,优选至少95%类似的多肽的用途,其中氨基酸序列见序列表。对全长PTH进行修饰以改善多种性质,如改善稳定性或得到改进的药物动力学性质(即改进的通过上皮细胞膜吸收的性质)。
如上所述,在治疗剂中通常包括其它物质,如药用载体可包含于本发明的治疗剂中。其它物质可以包括如为将粉末稀释至适于由特定粉末吸入器给药的量、为便于制剂制备、为改进制剂的粉末性质、为改进制剂的稳定性(即通过抗氧剂或pH调节化合物)、或为了向制剂中加入某种味道而加入的物质。任何添加剂不能对PTH的稳定性有副作用,或对PTH的吸收有不利干扰。它也应稳定、不吸湿、具有好的粉末性质并对导气管无副作用。
可能的添加剂的例子可以是单、二和多糖、糖醇及其它多元醇,例如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦芽糖醇(maltitol)、海藻糖、蔗糖、甘露糖醇和淀粉。根据所用吸入剂,这种添加剂的总量可以在很宽的范围内变化。
在某些情况中,需要很少或不需要添加剂,而例如对于需要操作大粉末体积的吸入器,添加剂可以占治疗剂的很高百分比。根据特定的情况本领域技术人员可以容易地确定需要的添加剂的量。
按照本发明,将粉末给药至患者肺部的一种可利用的机理是通过适于干粉吸入的便携式吸入器装置。市场上有很多这样的装置,一般设计为向呼吸***转运抗哮喘或抗炎制剂。优选该装置是某种设计的干粉吸入器,它使粉末不受潮并且无过量的危险,即偶然的大剂量。此外,尽可能多地需要如下特性:粉末要避光;在宽的流速范围内具有高的适宜呼吸的部分及高的肺沉积;低偏差的剂量和适宜呼吸的部分;粉末在口中滞留少;吸入器表面吸收低;药物剂量灵活;及低吸入阻力。
虽然也可以使用多剂量吸入器(优选如多剂量、呼吸(breath)启动的、干粉吸入器(多次使用)),但吸入器优选是单剂量的。一种适宜的多剂量吸入器描述于EP-B-0069715和EP-B-0237507。优选所用的吸入器是单剂量的、呼吸(breath)启动的、干粉吸入器(一次性)。优选的单剂量吸入器描述于EP-A-0548166和EP-A-0558879。
于是,本发明的另一方面是本发明的治疗剂在一种吸入装置中的用途。优选所述吸入装置为吸入粉末提供了抗潮湿保护、并且其过量的危险最小。所述吸入装置可以是如单剂量的、呼吸启动的、干粉吸入器(一次性),或多剂量的、呼吸启动的、干粉吸入器(多次使用)。
本发明的另一个方面是含有上述治疗剂的干粉吸入装置。
本发明的另一个重要方面是制备上述治疗剂的方法。所述粉末治疗剂可以用常规技术用几种方法制备。可能需要将活性化合物和合适的情况下(即不考虑规则混合物)载体在适宜的磨(如喷射磨)中在此过程中的适当时候微粒化,以便制备适于在下呼吸道最大沉积的粒度范围(即10μm以下)的基本颗粒。例如,适当的话可以将PTH和载体干混,然后将该物质一起微粒化;或者,可以将该物质分别微粒化,然后混合。当所混合的化合物具有不同物理性质如硬度和脆度时,对微粒化作用的阻力随之变化,于是需要不同的压力将其粉碎至适当的粒度。因此,当一起微粒化时,其中某种组份的所得粒度可能不令人满意。在此情况下,将不同组份分别微粒化然后将其混合将是有利的。
也可能先将活性组份包括任何载体(当不考虑规则混合物时)溶解于适宜的溶剂如水中,得到分子水平的混合。此方法也有可能将pH值调节至所需的水平。必需考虑吸入产品的pH的药用极限:3.0至8.5,因为具有此极限以外pH的产品可能引起刺激和气道狭窄。为了得到一种粉末,必须通过能保持PTH生物活性的方法除去溶剂。适宜的干燥方法包括真空浓缩、露天干燥、喷雾干燥、冻干及使用超临界流体。一般应避免在40℃以上超过几分钟,因为可能发生某种程度的PTH降解。干燥后,如果需要,可以将固体物质研磨得到一种粗粉末,然后如果需要进行微粒化。
如果需要,在掺混入所用吸入装置前可以通过,例如,干制粒形成具有优异处理特性的球形聚集物来处理微粒化的粉末以改善流动性。此时,该装置的构造应保证在流出装置前聚集物基本解聚,以便进入患者呼吸道的颗粒大部分在所需的粒度范围。
当需要规则混合物时,可以通过如微粒化作用处理活性化合物以得到(如果需要)特定粒度范围内的颗粒。载体也被处理,例如得到所需粒度和所需表面性质,如特定的表面积与重量比,或特定的高强度,从而保证规则混合物中的最佳粘着力。规则混合物的这种物理要求是熟知的,获得满足所述要求的规则混合物的方法是多种多样的,根据特定条件本领域技术人员可以容易地确定。
本发明的最后一个方面是治疗骨质疏松的方法,包括给需要此治疗的患者使用有效量的上述治疗剂。适宜的剂量在1至100μg全长PTH/kg,例如,30μg/kg左右。
现在,通过实施例的形式描述本发明,这只是要举例说明而不是限制本发明的范围。
实施例
实施例1
1.1吸入用PTH 1-84的治疗剂
制备如下组份的水溶液:
人PTH 1-84 41mg
枸橼酸,一水合物 57mg
枸橼酸钠 113mg
乳糖 3888mg
水 约53ml
将pH调节至5.0。在37℃,将溶液通过蒸发浓缩约一天。所得固体饼状物被粉碎并过0.5mm筛,通过喷射磨将所得粉末微粒化为直径为2微米的颗粒。
1.2 吸入用PTH 1-34的治疗剂
制备组份如下的水溶液:
人PTH 1-34 11.2mg
枸橼酸,一水合物 66mg
枸橼酸钠 131mg
乳糖 4589mg
水 约52ml
将此溶液按照上述实施例1.1的描述处理。
1.3含有增强剂的治疗用PTH制剂
制备如下组份的水溶液:
人PTH 1-84 50mg
枸橼酸,一水合物 69mg
枸橼酸钠 138mg
牛黄胆酸钠 17mg
乳糖 4726mg
水 约60ml
将pH调节至5.0。在37℃,将溶液通过蒸发浓缩约一天。所得固体饼状物被粉碎并过0.5mm筛,通过喷射磨将所得粉末微粒化为直径为2微米的颗粒。
实施例2
药物动力学实验
2.1粉末制剂和吸入***
分别按照实施例1.1和1.3制备人PTH 1-84或PTH 1-34。在集尘器(dust container)中粉末制剂被压制并通过赖特粉尘供应器(Wright Dust Feed(WDF))以干粉气溶胶形式连续产生。此气溶胶在集尘器中通过刮拭片剂产生。物质流过WDF的速度为8.0升/分钟。
通过检测吸入峰(tidal)体积(ITV)和在吸入期间PTH浓度来测定吸入剂量(ID)。
2.2治疗
在吸入前英国种小猎兔犬(n=5,每种制剂)禁食16小时,实验在早晨进行。用Plegecil和Penthotal将狗麻醉,插管并接触PTH1-34或PTH1-84约10分钟。
测定由颈静脉采集至肝素抗凝的抽真空(Vacutainer)管(2ml)中的静脉血样的PTH浓度。在给药前和吸入开始(t=0)后10、15、20、30、40、60、90、120、240和360分钟采集样品。将全血样品立即离心,或在离心前在冰水中保存最多20分钟,用血浆(1ml)进行PTH分析。用放射免疫实验(RIA)试剂盒分析血浆中PTH。
结果(表1和图1)清楚地表明PTH 1-34和PTH 1-84的吸入与PTH皮下给药相似产生脉冲血浆特性,证明全长PTH或具有全长PTH基本生物活性的PTH片断的肺部给药,对刺激骨形成和治疗骨质疏松是有效的。
实施例3
骨效应
给药4周(卵巢切除6周后开始给药)后,在卵巢切除的骨质疏松(osteopenic)大鼠中以远侧股骨的矿物质密度(重量/体积)来衡量骨效应。所得结果表明全长PTH的吸入对股骨形成具有显著作用。
表1
吸入PTH 1-34或PTH 1-84后,狗PTH的血浆浓度
时间(min) | PTH1-34 | PTH 1-84 | ||
浓度(pM) | S.E. | 浓度(pM) | S.E. | |
0 | 8.0 | 1.82 | 3.4 | 1.02 |
10 | 30.4 | 4.99 | 8.3 | 1.04 |
15 | 47.4 | 5.20 | 11.4 | 1.01 |
20 | 49.6 | 6.81 | 11.6 | 1.11 |
30 | 44.6 | 8.55 | 9.6 | 1.15 |
40 | 36.2 | 6.84 | 7.9 | 1.21 |
60 | 26.0 | 4.90 | 5.8 | 0.84 |
90 | 17.0 | 2.05 | 4.1 | 0.60 |
120 | 12.6 | 2.06 | 3.0 | 0.36 |
240 | 6.0 | 1.76 | 2.2 | 0.40 |
360 | 7.6 | 2.93 | 2.6 | 0.85 |
S.E.=平均值的标准误差
序列表
(1)总信息
(i)申请人:
(A)名称:ASTRA AKTIEVOLAG
(B)街区:Vastra malarehamnen9
(C)城市:Sodertalje
(E)国家:瑞典
(F)邮编(ZIP):S-15185
(G)电话:+46-853326000
(H)传真:+46-853328800
(I)电传:19237 astra s
(ii)发明题目:吸入用治疗剂
(iii)序列数量:1
(iv)计算机可读形式:
(A)介质类型:软盘
(B)计算机:IBM PC兼容机
(C)操作***:PC-DOS/MS-DOS
(D)软件:Patent In Release#1.0,version#1.30(EPO)
(2)SEQ ID NO:1信息:
(i)序列特性:
(A)长度:84氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(vi)来源:
(A)有机体:人
(x)***息:
(H)文献号:EP0383751B
(I)申请日:1987年10月7日
(J)公告日:1994年3月9日
(K)SEQ ID NO:1相关残基:由1至84
(xi)序列描述:SEQ ID NO:1:
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
1 5 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser
35 40 45
Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu
50 55 60
Lys Ser Leu Gly Glu Ala Asp Lys Ala Asp Val Asn Val Leu Thr Lys
65 70 75 80
Ala Lys Ser Gln
Claims (15)
1.一种治疗剂,其中含有一种或多种活性物质(i)具有全长甲状旁腺激素的基本生物活性的甲状旁腺激素,所述甲状旁腺激素具有与序列表中SEQ ID NO:1所示序列至少90%同源的氨基酸序列,(ii)一种药物可接受的载体,及(iii)促进PTH在下消化道吸收的一种物质,所述一种或多种活性物质以适于吸入的干粉形式存在,其中所述干粉的至少50%由(a)直径不大于10微米的颗粒;或(b)这种颗粒的聚集物组成;和其中所述载体由直径不大于10微米的颗粒组成,以便使所述的干粉的至少50%由(a)直径不大于10微米的颗粒;或(b)这种颗粒的聚集物组成。
2.权利要求1的治疗剂,其中干粉的至少50%由(a)直径在1至6微米之间的颗粒;或(b)这种颗粒的聚集物组成。
3.权利要求1的治疗剂,其特征在于所述载体由粗颗粒组成,以便在所述活性化合物和载体之间形成规则混合物。
4.权利要求1的治疗剂,其中甲状旁腺激素的总质量的至少50%由直径在1至6微米之间的颗粒组成。
5.权利要求1的治疗剂,其特征在于所述甲状旁腺激素是含有序列表中SEQ ID NO:1所示序列的氨基酸1-84的人甲状旁腺激素。
6.权利要求1的治疗剂,其特征在于所述载体选自单-、二-及多糖、糖醇及其它多元醇。
7.权利要求1的治疗剂,其特征在于所述载体是乳糖。
8.权利要求1的治疗剂在一种吸入装置中的用途。
9.权利要求8的用途,其特征在于所述吸入装置是单剂量的、呼吸启动的、一次性的干粉吸入器。
10.权利要求8的用途,其特征在于所述吸入装置是多剂量的、呼吸启动的、多次使用的干粉吸入器。
11.一种含有权利要求1的治疗剂的干粉吸入器。
12.一种制备权利要求1的治疗剂的方法,该方法包括形成一种甲状旁腺激素和至少一种药物可接受的载体的溶液,通过蒸发或其它方法除去溶剂以得到一种固体并任选地研磨所述固体。
13.一种制备权利要求1的治疗剂的方法,该方法包括将PTH与一种药物可接受的载体干混,并任选地研磨和/或混合所述固体。
14.权利要求12或13的方法,该方法还包括将制剂微粒化的附加步骤。
15.权利要求1-7的任一项的治疗剂用于制备治疗骨质疏松的药物的用途。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE94044492 | 1994-12-22 | ||
SE9404449A SE9404449D0 (sv) | 1994-12-22 | 1994-12-22 | Therapeutic preparations for inhalation |
SE9404449 | 1994-12-22 | ||
SE9502576A SE9502576D0 (sv) | 1995-07-12 | 1995-07-12 | Therapeutic preparations for inhalation II |
SE95025763 | 1995-07-12 | ||
SE9502576 | 1995-07-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1170361A CN1170361A (zh) | 1998-01-14 |
CN1170527C true CN1170527C (zh) | 2004-10-13 |
Family
ID=26662192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB951969544A Expired - Fee Related CN1170527C (zh) | 1994-12-22 | 1995-12-08 | 含有甲状旁腺激素(pth)的吸入用治疗剂 |
Country Status (27)
Country | Link |
---|---|
US (2) | US6436902B1 (zh) |
EP (2) | EP0806945B1 (zh) |
JP (1) | JPH10511090A (zh) |
KR (1) | KR100389080B1 (zh) |
CN (1) | CN1170527C (zh) |
AR (1) | AR001779A1 (zh) |
AT (1) | ATE238043T1 (zh) |
AU (1) | AU703532B2 (zh) |
BR (1) | BR9510516A (zh) |
CA (1) | CA2206657C (zh) |
CZ (1) | CZ182297A3 (zh) |
DE (1) | DE69530519T2 (zh) |
DK (1) | DK0806945T3 (zh) |
EE (1) | EE9700136A (zh) |
ES (1) | ES2197212T3 (zh) |
FI (1) | FI972652A (zh) |
HU (1) | HU218940B (zh) |
IL (1) | IL116492A (zh) |
IS (1) | IS4502A (zh) |
MX (1) | MX9704544A (zh) |
NO (1) | NO320432B1 (zh) |
NZ (1) | NZ297921A (zh) |
PL (1) | PL321094A1 (zh) |
PT (1) | PT806945E (zh) |
SK (1) | SK76797A3 (zh) |
TR (1) | TR199501635A1 (zh) |
WO (1) | WO1996019206A1 (zh) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US6632456B1 (en) * | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
JP3901738B2 (ja) * | 1997-03-20 | 2007-04-04 | シェーリング コーポレイション | 粉末凝集体の調製 |
US6503537B2 (en) | 1997-03-20 | 2003-01-07 | Schering Corporation | Preparation of powder agglomerates |
US6495167B2 (en) | 1997-03-20 | 2002-12-17 | Schering Corporation | Preparation of powder agglomerates |
DZ2873A1 (fr) * | 1998-08-19 | 2003-12-15 | Lilly Co Eli | Procédé pour augmenter la dureté et la rigidité osseuse. |
WO2000023594A1 (en) | 1998-10-22 | 2000-04-27 | The General Hospital Corporation | BIOACTIVE PEPTIDES AND PEPTIDE DERIVATIVES OF PARATHYROID HORMONE (PTH) AND PARATHYROID HORMONE-RELATED PEPTIDE (PTHrP) |
WO2001077328A1 (en) * | 2000-04-06 | 2001-10-18 | Franco Wayne P | Methods of using growth factors for treating heart disease |
US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
KR20070010115A (ko) * | 2003-11-13 | 2007-01-22 | 알자 코포레이션 | 경피전달용 조성물 및 장치 |
US20070020298A1 (en) * | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid |
US20070020299A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
MX348041B (es) | 2003-12-31 | 2017-05-25 | Cydex Pharmaceuticals Inc | Formulación inhalante que contiene éter sulfoalquilico-ciclodextri na y un corticosteroide. |
JP2007522149A (ja) * | 2004-02-10 | 2007-08-09 | アドバンスト インハレーション リサーチ,インコーポレイテッド | 高速放出特性を有する吸入のための粒子 |
DE602004023765D1 (de) * | 2004-03-12 | 2009-12-03 | Trinity College Dublin | Magnetoresistives medium |
ES2717248T3 (es) | 2004-04-23 | 2019-06-20 | Cydex Pharmaceuticals Inc | Formulación de DPI que contiene sulfoalquil éter ciclodextrina |
US7629331B2 (en) | 2005-10-26 | 2009-12-08 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof |
AU2006315132A1 (en) * | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
US20070185066A1 (en) * | 2005-12-20 | 2007-08-09 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
US20070178049A1 (en) * | 2005-12-20 | 2007-08-02 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
US20070160542A1 (en) * | 2005-12-20 | 2007-07-12 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile |
US20070197486A1 (en) * | 2005-12-20 | 2007-08-23 | Verus Pharmaceuticals, Inc. | Methods and systems for the delivery of corticosteroids |
US20070249572A1 (en) * | 2005-12-20 | 2007-10-25 | Verus Pharmaceuticals, Inc. | Systems and methods for the delivery of corticosteroids |
JP2009526858A (ja) * | 2006-02-15 | 2009-07-23 | ティカ レーケメデル アーベー | コルチコステロイド溶液を製造する方法 |
EP2187902B1 (en) | 2007-08-01 | 2013-04-17 | The General Hospital Corporation | Screening methods using g-protein coupled receptors and related compositions |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
WO2011143406A2 (en) | 2010-05-13 | 2011-11-17 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
WO2012130193A1 (en) | 2011-03-31 | 2012-10-04 | Zentiva, K.S. | Non-covalent soluble complexes of teriparatide with polysaccharides and a dosage form of teriparatide for oral administration |
US10266228B2 (en) | 2016-06-24 | 2019-04-23 | Easy2.Company B.V. | Drive train for a treadle scooter |
EP4110370A4 (en) * | 2020-03-30 | 2023-06-07 | Sichuan Luzhou Buchang Bio-Pharmaceutical Co., Ltd. | FORMULATIONS OF HUMAN PARATHYROID HORMONE (PTH) AND METHODS OF MANUFACTURE THEREOF |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE261096C (zh) | ||||
BE556587A (zh) | 1957-01-31 | 1957-04-11 | ||
US2992645A (en) | 1958-05-06 | 1961-07-18 | Benger Lab Ltd | Disperser for powders |
GB1144905A (en) * | 1965-03-25 | 1969-03-12 | Fisons Pharmaceuticals Ltd | Substituted bis-(2-carboxy-chromonyl-oxy) derivatives and preparation and pharmaceutical compositions thereof |
GB1242211A (en) | 1967-08-08 | 1971-08-11 | Fisons Pharmaceuticals Ltd | Pharmaceutical composition |
GB1520247A (en) | 1974-08-10 | 1978-08-02 | Fisons Ltd | Pelletised medicament formulations |
GB1569611A (en) | 1976-01-23 | 1980-06-18 | Fisons Ltd | Pelletised or granular medicament formulation |
DE2750090A1 (de) * | 1976-11-19 | 1978-06-01 | Sandoz Ag | Neue verabreichungsformen fuer organische verbindungen |
SE7812207L (sv) * | 1977-12-01 | 1979-06-02 | Welsh Nat School Med | Apparat, forfarande och framstellda produkter for anvendning vid administration av antihistaminer |
JPS6034925B2 (ja) | 1979-07-31 | 1985-08-12 | 帝人株式会社 | 持続性鼻腔用製剤およびその製造法 |
US4900730A (en) | 1981-01-14 | 1990-02-13 | Toyo Jozo Co., Ltd. | Preparation which promotes the absorption of peptides |
SE438261B (sv) * | 1981-07-08 | 1985-04-15 | Draco Ab | Anvendning i dosinhalator av ett perforerat membran |
EP0069715B1 (en) * | 1981-07-08 | 1986-11-05 | Aktiebolaget Draco | Powder inhalator |
US5260306A (en) * | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
JPS59163313A (ja) | 1983-03-09 | 1984-09-14 | Teijin Ltd | 経鼻投与用ペプチドホルモン類組成物 |
US4959358A (en) * | 1983-06-06 | 1990-09-25 | Beth Israel Hospital Assn. | Drug administration |
US4746508A (en) * | 1983-06-06 | 1988-05-24 | Beth Israel Hospital Assn. | Drug administration |
US4548922A (en) * | 1983-06-06 | 1985-10-22 | Beth Israel Hospital | Drug administration |
US4963367A (en) | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
US5288498A (en) * | 1985-05-01 | 1994-02-22 | University Of Utah Research Foundation | Compositions of oral nondissolvable matrixes for transmucosal administration of medicaments |
US4537772A (en) * | 1984-05-02 | 1985-08-27 | Merck & Co., Inc. | Enhancing absorption of drugs from gastrointestinal tract using acylcarnitines |
JPS61267528A (ja) | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | 吸収促進剤を含有するカルシトニン経鼻剤 |
SE448277B (sv) * | 1985-04-12 | 1987-02-09 | Draco Ab | Indikeringsanordning vid en doseringsanordning for lekemedel |
US5122127A (en) | 1985-05-01 | 1992-06-16 | University Of Utah | Apparatus and methods for use in administering medicaments by direct medicament contact to mucosal tissues |
JPS63500175A (ja) | 1985-05-22 | 1988-01-21 | リポソ−ム テクノロジ−,インコ−ポレイテツド | リポソ−ム吸入法および吸入システム |
US4731360A (en) * | 1985-08-16 | 1988-03-15 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
US4847298A (en) | 1985-08-16 | 1989-07-11 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
SE453566B (sv) | 1986-03-07 | 1988-02-15 | Draco Ab | Anordning vid pulverinhalatorer |
JPS632932A (ja) | 1986-06-23 | 1988-01-07 | Teijin Ltd | 経鼻投与用粉末状組成物 |
EP0318492A1 (en) | 1986-08-11 | 1989-06-07 | Innovata Biomed Limited | Pharmaceutical formulations comprising microcapsules |
US5179079A (en) | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
GB8712176D0 (en) | 1987-05-22 | 1987-06-24 | Cosmas Damian Ltd | Drug delivery system |
US5059587A (en) * | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
KR890006252A (ko) | 1987-10-15 | 1989-06-12 | 헤르비그 폰 모르체 | 분말형 폴리펩타이드의 비강내 투여용 조성물 및 투여방법 |
JPH01117825A (ja) | 1987-10-28 | 1989-05-10 | Sanwa Kagaku Kenkyusho Co Ltd | 鼻くう、副鼻くう投与用製剤及びその使用方法並びにその形状及び使用器具 |
EP0360340A1 (en) | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
US5997856A (en) | 1988-10-05 | 1999-12-07 | Chiron Corporation | Method and compositions for solubilization and stabilization of polypeptides, especially proteins |
JPH02104531A (ja) | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド組成物 |
US5006343A (en) | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
US4994439A (en) | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
AU639228B2 (en) | 1989-02-17 | 1993-07-22 | Transave, Inc. | Lipid excipient for nasal delivery and topical application |
IT8920486A0 (it) | 1989-05-12 | 1989-05-12 | Isf Spa | Composizioni farmaceutiche. |
US5176132A (en) | 1989-05-31 | 1993-01-05 | Fisons Plc | Medicament inhalation device and formulation |
JP2642486B2 (ja) | 1989-08-04 | 1997-08-20 | 田辺製薬株式会社 | 難溶性薬物の超微粒子化法 |
GB8921222D0 (en) | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
US5707644A (en) | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
GB9001635D0 (en) * | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
US5376386A (en) * | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
US5118494A (en) | 1990-03-23 | 1992-06-02 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
JPH05963A (ja) | 1990-04-13 | 1993-01-08 | Toray Ind Inc | ポリペプチド類組成物 |
US5192548A (en) * | 1990-04-30 | 1993-03-09 | Riker Laboratoires, Inc. | Device |
EP0527940A1 (en) | 1990-05-08 | 1993-02-24 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
JPH0441421A (ja) | 1990-06-07 | 1992-02-12 | Taisho Pharmaceut Co Ltd | 肺吸収組成物 |
SE9002895D0 (sv) | 1990-09-12 | 1990-09-12 | Astra Ab | Inhalation devices for dispensing powders i |
GB9020544D0 (en) * | 1990-09-20 | 1990-10-31 | Sandoz Ltd | Improvements in or relating to organic compounds |
JPH04149126A (ja) | 1990-10-09 | 1992-05-22 | Mitsubishi Kasei Corp | 経粘膜投与用医薬組成物 |
IL99699A (en) * | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
DE4039656A1 (de) * | 1990-12-12 | 1992-06-17 | Bissendorf Peptide Gmbh | Arzneimittel, enthaltend das humane parathormon-fragment (1-37) in der form des amids oder ethylamids als aktiven wirkstoff |
JP3507486B2 (ja) | 1991-03-15 | 2004-03-15 | アムジエン・インコーポレーテツド | 顆粒球コロニー刺激因子の肺内投与 |
US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
DE69306755T2 (de) | 1992-01-21 | 1997-04-10 | Stanford Res Inst Int | Verbessertes verfahren zur herstellung von mikronisierter polypeptidarzneimitteln |
US5482706A (en) | 1992-04-17 | 1996-01-09 | Takeda Chemical Industries, Ltd. | Transmucosal therapeutic composition |
US5376359A (en) * | 1992-07-07 | 1994-12-27 | Glaxo, Inc. | Method of stabilizing aerosol formulations |
CZ286632B6 (cs) * | 1992-09-29 | 2000-05-17 | Inhale Therapeutic Systems | Farmaceutický prostředek |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
ES2154673T3 (es) | 1993-01-29 | 2001-04-16 | Aradigm Corp | Suministro intrapulmonar de hormonas. |
WO1994023772A2 (en) | 1993-04-06 | 1994-10-27 | Minnesota Mining And Manufacturing Company | Deagglomerators for dry powder inhalers |
US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
US5661130A (en) | 1993-06-24 | 1997-08-26 | The Uab Research Foundation | Absorption enhancers for drug administration |
IS1796B (is) * | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
US5747445A (en) | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
US5349947A (en) | 1993-07-15 | 1994-09-27 | Newhouse Michael T | Dry powder inhaler and process that explosively discharges a dose of powder and gas from a soft plastic pillow |
US5514670A (en) | 1993-08-13 | 1996-05-07 | Pharmos Corporation | Submicron emulsions for delivery of peptides |
EP0748213B1 (en) | 1994-03-07 | 2004-04-14 | Nektar Therapeutics | Methods and compositions for pulmonary delivery of insulin |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
US5451569A (en) | 1994-04-19 | 1995-09-19 | Hong Kong University Of Science And Technology R & D Corporation Limited | Pulmonary drug delivery system |
PL326078A1 (en) | 1995-09-21 | 1998-08-17 | Andaris Ltd | Transcytotic carriers and enhancers for delivery of drugs |
-
1995
- 1995-12-08 SK SK767-97A patent/SK76797A3/sk unknown
- 1995-12-08 CN CNB951969544A patent/CN1170527C/zh not_active Expired - Fee Related
- 1995-12-08 ES ES95941953T patent/ES2197212T3/es not_active Expired - Lifetime
- 1995-12-08 HU HU9800553A patent/HU218940B/hu not_active IP Right Cessation
- 1995-12-08 PL PL95321094A patent/PL321094A1/xx unknown
- 1995-12-08 WO PCT/SE1995/001475 patent/WO1996019206A1/en active IP Right Grant
- 1995-12-08 BR BR9510516A patent/BR9510516A/pt not_active Application Discontinuation
- 1995-12-08 EP EP95941953A patent/EP0806945B1/en not_active Expired - Lifetime
- 1995-12-08 JP JP8519713A patent/JPH10511090A/ja active Pending
- 1995-12-08 CZ CZ971822A patent/CZ182297A3/cs unknown
- 1995-12-08 EE EE9700136A patent/EE9700136A/xx unknown
- 1995-12-08 KR KR1019970704255A patent/KR100389080B1/ko not_active IP Right Cessation
- 1995-12-08 PT PT95941953T patent/PT806945E/pt unknown
- 1995-12-08 MX MX9704544A patent/MX9704544A/es unknown
- 1995-12-08 DK DK95941953T patent/DK0806945T3/da active
- 1995-12-08 AU AU43199/96A patent/AU703532B2/en not_active Ceased
- 1995-12-08 CA CA002206657A patent/CA2206657C/en not_active Expired - Fee Related
- 1995-12-08 EP EP02025764A patent/EP1283035A3/en not_active Withdrawn
- 1995-12-08 AT AT95941953T patent/ATE238043T1/de active
- 1995-12-08 DE DE69530519T patent/DE69530519T2/de not_active Expired - Lifetime
- 1995-12-21 AR AR33475995A patent/AR001779A1/es unknown
- 1995-12-21 IL IL11649295A patent/IL116492A/xx not_active IP Right Cessation
- 1995-12-21 TR TR95/01635A patent/TR199501635A1/xx unknown
-
1997
- 1997-06-02 NZ NZ297921A patent/NZ297921A/en not_active IP Right Cessation
- 1997-06-09 IS IS4502A patent/IS4502A/is unknown
- 1997-06-12 NO NO19972715A patent/NO320432B1/no not_active IP Right Cessation
- 1997-06-19 FI FI972652A patent/FI972652A/fi unknown
-
1999
- 1999-08-26 US US09/383,590 patent/US6436902B1/en not_active Expired - Fee Related
-
2002
- 2002-08-19 US US10/224,522 patent/US20030064928A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1170527C (zh) | 含有甲状旁腺激素(pth)的吸入用治疗剂 | |
CN1116030C (zh) | 吸入性组合物 | |
AU688283B2 (en) | Pulmonary delivery of active fragments of parathyroid hormone | |
CN1195543C (zh) | 给予单体胰岛素类似物的方法 | |
CN1073119C (zh) | 干扰素干粉配方的方法及组合物 | |
KR100419037B1 (ko) | 폐를통한인슐린의전달방법및그조성물 | |
CN1314818A (zh) | 服用促胰岛素肽的方法 | |
AU2002218503B2 (en) | Powdery preparations and methods for producing the same | |
KR20160032139A (ko) | 열-안정성 건조 분말 약제학적 조성물 및 방법 | |
CN100349611C (zh) | 鲑降钙素吸入粉雾剂及其制备方法 | |
CN1168496C (zh) | 胰岛素肺部给药的粉雾剂及其制备方法 | |
CN1439360A (zh) | 有效部位药物沉积得到改善的干粉组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20041013 Termination date: 20121208 |