CN87108340A - 鼻用药配方及其制备方法 - Google Patents
鼻用药配方及其制备方法 Download PDFInfo
- Publication number
- CN87108340A CN87108340A CN87108340.XA CN87108340A CN87108340A CN 87108340 A CN87108340 A CN 87108340A CN 87108340 A CN87108340 A CN 87108340A CN 87108340 A CN87108340 A CN 87108340A
- Authority
- CN
- China
- Prior art keywords
- preparation
- carbonyl
- insulin
- oil
- alkyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 52
- 238000009472 formulation Methods 0.000 title claims description 4
- 239000003814 drug Substances 0.000 title abstract description 10
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 15
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 15
- 238000010521 absorption reaction Methods 0.000 claims abstract description 14
- 229920001184 polypeptide Polymers 0.000 claims abstract description 13
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 13
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 6
- 239000008158 vegetable oil Substances 0.000 claims 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 claims description 60
- 102000004877 Insulin Human genes 0.000 claims description 32
- 108090001061 Insulin Proteins 0.000 claims description 32
- 229940125396 insulin Drugs 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 239000010685 fatty oil Substances 0.000 claims description 12
- -1 2-carboxyl-2-amino-ethyl Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000013543 active substance Substances 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 230000002421 anti-septic effect Effects 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 108060003199 Glucagon Proteins 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 5
- 229960004666 glucagon Drugs 0.000 claims description 5
- 150000002333 glycines Chemical class 0.000 claims description 5
- 210000000582 semen Anatomy 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229940002297 nasacort Drugs 0.000 claims description 4
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000003204 osmotic effect Effects 0.000 claims description 3
- 239000006174 pH buffer Substances 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 235000019486 Sunflower oil Nutrition 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 2
- 230000000295 complement effect Effects 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 235000019198 oils Nutrition 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000002600 sunflower oil Substances 0.000 claims description 2
- 150000005671 trienes Chemical class 0.000 claims description 2
- 102400000321 Glucagon Human genes 0.000 claims 1
- 241000894007 species Species 0.000 claims 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000000787 lecithin Substances 0.000 abstract description 5
- 235000010445 lecithin Nutrition 0.000 abstract description 5
- 229940067606 lecithin Drugs 0.000 abstract description 5
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 abstract description 4
- 230000009885 systemic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000008103 glucose Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000000839 emulsion Substances 0.000 description 5
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 210000002850 nasal mucosa Anatomy 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 102000051325 Glucagon Human genes 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000002250 absorbent Substances 0.000 description 3
- 230000002745 absorbent Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 210000003928 nasal cavity Anatomy 0.000 description 3
- 210000001331 nose Anatomy 0.000 description 3
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 102000005548 Hexokinase Human genes 0.000 description 2
- 108700040460 Hexokinases Proteins 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 102000003982 Parathyroid hormone Human genes 0.000 description 2
- 108090000445 Parathyroid hormone Proteins 0.000 description 2
- 240000007711 Peperomia pellucida Species 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 150000004665 fatty acids Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000004026 insulin derivative Substances 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-di-[(9Z,12Z)-octadecadienoyl]-sn-glycero-3-phosphocholine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC FVXDQWZBHIXIEJ-LNDKUQBDSA-N 0.000 description 1
- MLKLDGSYMHFAOC-AREMUKBSSA-N 1,2-dicapryl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCC MLKLDGSYMHFAOC-AREMUKBSSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- IJFVSSZAOYLHEE-UHFFFAOYSA-N 2,3-di(dodecanoyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-UHFFFAOYSA-N 0.000 description 1
- YQAXFVHNHSPUPO-RNJOBUHISA-N 2-[[(2s)-2-[[2-[[(2s,4r)-1-[(2s)-1-(2-aminoacetyl)pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]propanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@H]1N(C(=O)CN)CCC1 YQAXFVHNHSPUPO-RNJOBUHISA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 1
- 206010018873 Haemoconcentration Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 108010073961 Insulin Aspart Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000032420 Latent Infection Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001319148 Pharmacis Species 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100022831 Somatoliberin Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)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=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)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)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)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@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 108010082685 antiarrhythmic peptide Proteins 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)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=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)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)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)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@@H](C)CC)[C@@H](C)O)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)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229940015047 chorionic gonadotropin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](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](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229960004717 insulin aspart Drugs 0.000 description 1
- 229950004152 insulin human Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001592 luteinising effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001272 nitrous oxide Substances 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
- CBFCDTFDPHXCNY-UHFFFAOYSA-N octyldodecane Natural products CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960000874 thyrotropin Drugs 0.000 description 1
- 230000001748 thyrotropin Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
在磷脂如磷脂酰胆碱(卵磷脂)存在下，某些药物，尤其是药用活性多肽，经鼻内给药后可以增加全身吸收，最好将磷脂与植物油相混和。
Description
本发明涉及适用于鼻内给药的新药用制剂和制备该制剂的方法。
虽然那些非侵袭式（non-invasive）给药法如口服法或直肠给药法对病人而言无疑是最方便的，但通常认为胃肠外给药是最有效的。尤其是在胃肠道中失活或吸收很差的药物，以及口服后易进行扩展的首次通过肝代谢效应的药物，通常进行胃肠外给药。
但是胃肠外给药有明显的不便之处，如需要无菌给药器具、反复注射会造成疼痛和刺激，以及潜在感染的危险。因此，人们寻找能阻止首次通过代谢效应而作用相当于胃肠外给药的另一种给药方式。其中，一种有希望的给药方式是通过鼻道给药。但是，正如其它非侵袭式给药法的情况一样，主要由于药物的化学性质，鼻内给药后药物的生物有效度大多无法预测。
例如，已知孕酮和萘心安由鼻腔吸收提供的血液浓度几乎相当于静脉给药。
现已知有分子量高达约1KD的药用活性剂的经鼻给药配方的实例。例如将活性麦角肽（ergopeptide）生物碱溶解到乙醇水溶液中作为气溶胶的配方（瑞士专利NO.636，011）;含有药用活性的胺和脂肪酸形成的盐的配方（加拿大专利NO.988，852）;以及将儿茶酚胺悬浮于脂肪酸（或酯）中并用聚氧乙烯乳化的配方（欧洲专利申请NO.160，501）。
近几十年来，已经研制了各种各样的多肽药物（主要是合成的）。总的来讲，多肽药物因为在消化道中吸收不完全和消化不稳定，所以用胃肠外给药。也许正因如此，近年来多肽经鼻道给药方面的研究加强了。已经发现，虽然一些较小的多肽（至多约10个氨基酸残基）配成简单的水溶液可在鼻内很好地吸收，但是较大的多肽通常的鼻内生物有效度既不完全又不稳定，随着分子量的增大更是如此（综述参见L.Illum：Archiv for Pharmaci Og Chemi 94（1987），127-135）。
为了克服上述缺点（尤其当鼻内用药配方含较大的多肽时），人们设想，可以另外加入各种生物上适用的促进吸收剂或所谓的强化剂（enhancer）。
这方面可参考欧洲专利公告NO.111，841，该专利公开了胆酸的促吸收作用;美国专利NO.4，476，116公开了利用螯合剂（如EDTA）增加吸收的方法。
假如胰岛素经鼻腔吸收适当有效且稳定的话，与目前的肠胃外给药制剂相比，依赖胰岛素的糖尿病患者自然会非常乐于选用胰岛素经鼻用药的合适配方。已发明了许多增加吸收剂（主要是表面活性剂）用于上述配方。
英国专利NO.1，527，605公开了离子型及非离子型的表面活性剂强化剂，如胆汁酸盐和聚氧乙烯高碳醇醚，另一方面，R.Salzman等〔New England J.of Med.312（1985），1078-1084〕叙述了特定的聚氧乙烯高碳醇醚（即聚氧乙烯-9十二烷基醚）的应用。美国专利NO.4，548，922公开了其它一些强化剂，例如牛磺二氢梭链孢酸的盐。
至今已知的强化剂的化学结构与那些已知的细胞膜组分的化学结构（包括鼻腔细胞膜的化学结构）大不相同。这一情况也许可以解释这些药物通常易于引起鼻内刺激，甚至造成鼻粘膜永久损伤（尤其在长期用药的情况下）。在这一背景下，与其它生理上存在的表面活性剂更相类似的强化剂如磷脂，是值得考虑的。然而根据英国专利NO.1，527，605（前已述及）公开的资料，一般长链卵磷脂混合物中的磷脂对于鼻用药配方中的胰岛素看不出有促进吸收的作用。
现已惊奇地发现，中等链长的磷脂酰胆碱和磷脂酰乙醇胺能够显著地促进药用活性化合物鼻内吸收，尤其可促进多肽的吸收，而且对鼻粘膜无刺激或损伤。在配方中将脂油（如植物油）与磷脂混和，则可进一步提高鼻内吸收效果。
首先，本发明提供了由药用活性剂和增加吸收系统所组成的鼻内用药制剂，这种增加吸收系统至少包括一种具有通式Ⅰ的磷脂，
其中R′和R″可以相同或不同，分别选自以下一组基团：氢，烷基，链烯基，烷基羰基，链烯基羰基，链二烯基羰基，链三烯基羰基或链四烯基羰基，这些基团的碳原子总数至多为14，条件是，R′和R″不都是氢，R″′表示亲水基团，可选自2-（三甲铵）乙基，2-氨基乙基，2-羧基-2-氨基乙基，2，3-二羟基丙基和五羟基环己基。这样就分别构成胆碱（卵磷脂）、乙醇胺、甘油、丝氨酸和肌醇的磷脂酰衍生物。在增加吸收系统中可以不加脂油，但是加入脂油和磷脂混合在一起更好。
其次，本发明提供了制备鼻内用药制剂的方法，该方法包括将至少一种具有通式Ⅰ的磷脂（可以不加脂油，但加入脂油更好）和药用活性剂一起，以溶液或粉末状分散在液态或固态的稀释剂中，稀释剂中还可以有选择地加入辅助性的pH缓冲剂，防腐剂和渗透压调节剂。
式Ⅰ化合物中较好的一个亚类是其中的R′和R″都是烷基羰基。其中更好的亚类是R″′为2-（三甲铵）乙基的化合物，这类化合物称为卵磷脂。另一个更为优先的式Ⅰ化合物为，其中的R′和R″都代表烷基羰基并具有约4个碳原子，最好不超过12个碳原子。最优先的式Ⅰ化合物的亚类是其中R′和R″都为壬基羰基。
本发明较好的制剂是含有两种式Ⅰ磷脂的混合物的制剂。两种磷脂中之一，其中的R′和R″都是辛酰基、癸酰基或十二烷酰基，另一磷脂化合物，其中的R′和R″两个取代基之一为氢，另一为辛酰基、癸酰基或十二烷酰基（月桂酰）。
一些较好的式Ⅰ化合物的实例为：
二辛酰基L-α-磷脂酰胆碱
二辛基-O-L-α-磷脂酰胆碱
二癸酰基L-α-磷脂酰胆碱
二癸基-O-L-α-磷脂酰胆碱
癸基-O-L-α-溶血磷脂酰胆碱
二（十二烷酰基）-L-α-磷脂酰胆碱
十二烷酰基L-α-溶血磷脂酰胆碱
式Ⅰ化合物有些是已知的，式Ⅰ化合物可以用实质上已知的方法制备。
本发明中选择性地加到增加吸收系统中的脂油最好是植物油，其中豆油、花生油、椰子油、玉米油、橄榄油、葵花油或它们的混合物更好。
本发明的另一优选的实施方案中，药用活性剂为多肽。多肽中较好的一类是胰岛素和胰岛素衍生物（例如通过化学或酶方法或重组DNA技术修饰过的胰岛素），或这些胰岛素、胰岛素原和胰高血糖素的混合物。其它较好的多肽有甲状旁腺素、甲状旁腺素拮抗物、降钙素、后叶加压素、血管紧张肽原酶、催乳激素、生长激素、促甲状腺激素、促肾上腺皮质素、促肾上腺皮质素释放因子、促卵泡激素、促黄体激素、绒毛膜促性腺激素、前房肽（atrial peptide）、干扰素、组织血纤维蛋白溶酶原激活因子、γ球蛋白、因子Ⅶ、因子Ⅷ、生长激素释放激素、促黄体激素释放激素、生长激素释放抑制因子和胰腺分泌素。
本发明的制剂可以是液体，如适用于喷雾给药，或者是固体，如制成适用于鼻吸的粉剂。液体制剂，例如以水为溶剂的配方，通常包括辅助剂，如pH缓冲系统（最好是磷酸盐，柠檬酸盐或乙酸盐缓冲液），防腐剂和渗透压调节剂（如甘油或氯化钠）。粉剂则含有药用活性剂和增加吸收系统，它们与可鼻用的稀释粉末（或各种稀释粉末的混合物）混合。稀释粉末的例子有纤维素或其衍生物（如纤维素醚或羧甲基纤维素钠）、淀粉或部分降解的淀粉（如糊精）、长链脂肪酸或其盐（如硬脂酸铝）、有机聚合物（如丙烯酸衍生物的聚合物）或无机载体（如滑石或硅藻土）。可以补充加入吸水聚合物，例如聚乙二醇或聚乙烯吡咯烷酮，以便改进粉剂对鼻粘膜的粘附。
液体制剂最好以水作为稀释剂。这样的制剂可以通过将增加吸收系统分散到水介质中来制备。在水介质中含有药用活性剂和辅助剂。分散可以按应用于悬浮剂或乳化剂常用的方法来进行，例如可用超声处理。调水相到中性（即pH在约6.5～约8范围）可以在制备中任何一步进行。最好制备微乳剂，在微乳剂中，分散的颗粒或液滴的直径在10nm数量级，这样易于通过鼻粘膜。这样的微乳剂可以通过过滤灭菌。在本发明的最好配方中，式Ⅰ磷脂和脂油的含量范围分别为该制剂的0.01～10%（W/V）和0.01～50%（W/V）。由于鼻粘膜上有肽酶和蛋白酶（参见R.E.Stratford and V.H.L.Lee：Int.Journ.Pharmaceutics 30（1986），73-82），因此在含有多肽的配方中掺入生物上适用的蛋白酶和肽酶抑制剂是合乎需要的。
本发明制剂中，药用活性剂的浓度显然取决于所选用的具体活化剂、活化剂的功效、鼻内给药和其它途经给药（如胃肠外注射）生物有效度的比较、以及与配方中预定单次剂量相联系的预定给药次数。熟练技术人员通常可从动物实验中获得上述药理数据，例如指标值（index value），如下文实例给出的对胰岛素制剂评价的数据。
以胰岛素为例，本发明制剂中的胰岛素浓度可为每毫升约5-1000国际单位（I.U.）的范围，最好为每毫升50-500I.U.。
本发明的胰岛素制剂最好含有牛、猪或人胰岛素。
制备本发明以水作稀释剂的胰岛素制剂的典型方法为：在酸（如盐酸）存在下，将胰岛素（如锌胰岛素晶体，例如英国专利NO.1，285，023公开的高纯级胰岛素）溶解于水中。再另外制备防腐剂水溶液，如苯酚、烷基苯酚（如甲苯酚）或对羟基苯甲酸甲酯的水溶液，该溶液还可以含有使溶液等渗的物质，如氯化钠或甘油。防腐剂溶液中还可以含有缓冲剂，如磷酸钠、柠檬酸钠、乙酸钠或Tris（三羟甲基氨基甲烷）和蛋白酶抑制剂。而后将所得防腐剂溶液与上述胰岛素酸性溶液混合，接着加入碱（例如氢氧化钠溶液）以调节pH值至中性。将式Ⅰ磷脂（也可以是和脂油的混合物）制成溶液或乳剂（通过将其溶解或悬浮于水中而制得），然后将其加到胰岛素溶液中，如有必要，在与胰岛素溶液混和之前，将所有悬浮液用超声处理。如果需要的话，磷脂溶液或乳剂也可以含有缓冲剂和防腐剂。混合以后，可将胰岛素制剂的pH值再调至中性。最后再加水使所得胰岛素溶液的体积达到计算值。
本发明制剂可以在适用于鼻内给药并能调剂剂量的器具内使用。要求该器具有最佳计量精度并且其部件（如容器，阀门和调节器）适用于鼻给药制剂，且要能藉助于机械泵系统（例如定量喷雾器）或加压气溶胶系统。气溶胶系统要用推进剂，该推进剂应与配方不起化学反应。可以从气体，如碳氟化合物、碳氢化合物、氮气和氧化二氮以及这些气体的混合物中挑选合适的推进剂。
通过下面实例进一步叙述实施本发明的细节。但是，不应认为这些实例给本发明范围强加了各种限制。
实例1-12中使用的胰岛素原料中，每毫克氮约含20～30微克锌。
豆油和花生油纯度分别符合U.S.P XXI和NF.XVI的纯化级。
实例1
将772毫克人胰岛素溶于40ml10.02M盐酸中，并加入1.6g无水甘油。然后加蒸馏水至体积为80ml。用0.2M氢氧化钠溶液调pH值至7.4。再将1.0g二癸酰基L-α-磷脂酰胆碱溶于2ml乙醇（96%）中，并用皮下注射器将其注入10ml蒸馏水中。形成的混浊液用高能超声发生器超声处理10分钟，然后将所得的胶体溶液在搅拌下加到胰岛素溶液中，并加蒸馏水至体积为100ml。将该制剂（每毫升含200国际单位胰岛素）调配到适合鼻内给药的喷雾器中，并向雄性新西兰白兔鼻腔喷入100微升，同时用类似的但不含二癸酰基L-α-磷脂酰胆碱的制剂对兔子进行测试。
每隔一定时间从兔子耳缘静脉采血样，用己糖激酶方法测定葡萄糖浓度。
试验结果如下：
相对于初始水平的血液葡萄糖百分数
给药后时间（分钟） 0 30 60 90 120
不含卵磷脂的胰岛素
制剂 100 100 103 99 100
含二癸酰基L-α-
磷脂酰胆碱的胰岛素
制剂 100 56 65 70 81
实例2
将100mg二癸酰基L-α-磷脂酰胆碱溶解在100mg豆油中，再将该溶液加到5ml0.01MpH7.4的磷酸钠缓冲液中。
将该混合物超声乳化，再向该乳液中加入2ml（每毫升含400单位）胰岛素溶液，调pH值至7.4，并加蒸馏水至体积为10ml。
在对兔子鼻腔给予该制剂后，监测血液葡萄糖浓度120分钟。如果以单次血液葡萄糖值占初始值的血糖百分数表示，则曲线上方的面积可以通过三角形法计算。于是可按下式计算指标：
指标＝0.053×A/D
其中A是试验制剂测得的曲线上方的面积，D是所用试验制剂的剂量，因子0.053是从速效胰岛素制剂经皮下使用推导出的系数。
用这种方法测定，鼻用胰岛素乳剂的指标为24%。
另一种类似的但不含植物油配成的制剂，指标为12-15%。
实例3-12
实例3-6，8和12中的制剂按实例1所述方法类似的方式制备，而实例7和9-11中的制剂则按实例2的方法制备。下表中使用以下缩写符号：
磷脂酰胆碱：PC
二癸酰基磷脂酰胆碱：DDPC
二月桂基磷脂酰胆碱：DLPC
百分含量是指单位体积内的重量。所有制剂每毫升均含80国际单位胰岛素。
表中数据表明，含有中等链长的酰基或烷基磷脂酰胆碱具有良好的增加吸收的效果。
实例13
将100mg二癸酰基L-α-磷脂酰胆碱溶于100mg豆油中，将该溶液加到5ml0.01M含160mg甘油的磷酸钠缓冲液（PH为4）中，混合物经超声乳化后，向该乳剂中加入100mg胰高血糖素，并调pH至7.4，加水至体积为10ml。
该制剂经鼻施用于兔子后，从兔耳缘静脉采血样，用己糖激酶方法监测血样中的葡萄糖浓度。
下面是不同时间所测得的血液葡萄糖浓度：
给药后时间（分钟） 0 15 30 60 120
无强化剂系统的胰
高血糖素 100 107 113 111 107
有强化剂系统的胰
高血糖素 100 144 178 188 163
Claims (15)
1、一种适用于鼻内用药的制剂，其特征在于，它含有一种药用活性剂和一种增加吸收的系统，该系统至少含有一种具有通式I的磷脂
其中R′和R″相同或不同，分别代表氢、不超过14个碳原子的烷基、链烯基、烷基羰基、链烯基羰基、链二烯基羰基、链三烯基羰基或链四烯基羰基，附带条件为：R′和R″不同时为氢，R′″代表亲水基团，选自这样一组基团：2-(三甲铵)乙基、2-氨基乙基、2-羧基-2-氨基乙基、2，3-二羟基丙基或2，3，4，5，6-五羟基环已基。
2、根据权利要求1的制剂，其中R″′为2-（三甲铵）乙基。
3、权利要求2的制剂，其中R′和R″分别为含4-12个碳原子的烷基或烷基羰基，最好是烷基羰基。
4、权利要求3的制剂，其中R′和R″分别代表壬基羰基。
5、权利要求2的制剂，其中R′和R″二者之一为氢。
6、根据权利要求1的制剂，其中增加吸收系统还含有一种脂油。
7、根据权利要求6的制剂，其中的脂油是一种植物油，最好从下列一组植物油中选择：豆油、花生油、椰子油、玉米油、橄榄油和葵花油。
8、根据权利要求1-5的制剂，其中式Ⅰ磷脂的含量范围为该制剂的0.01-10%（W/V），最好是0.5-5%（W/V）。
9、根据权利要求6-7的制剂，其中脂油的含量范围为该制剂的0.01-50%（W/v），最好是0.1-10%（W/V）。
10、根据权利要求1-9的制剂，其中的药用活性剂是一种多肽。
11、根据权利要求10的制剂，其中的多肽是胰岛素或一种胰岛素衍生物，或其混和物。
12、根据权利要求11的制剂，其中每毫升制剂中胰岛素的含量范围为5-1000，最好是50-500国际单位。
13、权利要求10的制剂，其中的多肽是胰高血糖素。
14、一种制备权利要求6的制剂的方法，该方法包括，将至少一种磷脂与一种脂油混和，与药用活性剂一起以溶液或粉末状分散到一种液体或固体稀释剂中，该稀释剂可以有选择地包含辅助性的pH缓冲剂、防腐剂和渗透压调节剂。
15、权利要求6的制剂置于能调剂剂量的适用于鼻内给药的器具内的使用。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK6042/86 | 1986-12-16 | ||
| DK604286A DK604286D0 (da) | 1986-12-16 | 1986-12-16 | Praeparat |
| DK3700/87 | 1987-07-16 | ||
| DK370087A DK370087D0 (da) | 1987-07-16 | 1987-07-16 | Produkt med forbedrede egenskaber |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87108340A true CN87108340A (zh) | 1988-07-13 |
| CN1034105C CN1034105C (zh) | 1997-02-26 |
Family
ID=26067181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87108340A Expired - Fee Related CN1034105C (zh) | 1986-12-16 | 1987-12-16 | 鼻内用药的制剂的制备方法 |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0272097B1 (zh) |
| JP (1) | JPH0768149B2 (zh) |
| KR (1) | KR890700036A (zh) |
| CN (1) | CN1034105C (zh) |
| AT (1) | ATE79039T1 (zh) |
| AU (1) | AU606121B2 (zh) |
| CA (1) | CA1326210C (zh) |
| CS (1) | CS273139B1 (zh) |
| DE (1) | DE3780925T2 (zh) |
| ES (1) | ES2044957T3 (zh) |
| FI (1) | FI94024C (zh) |
| GR (1) | GR3005381T3 (zh) |
| HU (1) | HU209247B (zh) |
| IE (1) | IE61110B1 (zh) |
| IL (1) | IL84835A (zh) |
| MX (1) | MX9203640A (zh) |
| NO (1) | NO175566C (zh) |
| NZ (1) | NZ222907A (zh) |
| PT (1) | PT86370B (zh) |
| RU (1) | RU1837869C (zh) |
| WO (1) | WO1988004556A1 (zh) |
| YU (1) | YU46978B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1299770C (zh) * | 2004-05-31 | 2007-02-14 | 刘近周 | 多功能鼻腔和鼻窦洁疗液 |
Families Citing this family (93)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5690954A (en) * | 1987-05-22 | 1997-11-25 | Danbiosyst Uk Limited | Enhanced uptake drug delivery system having microspheres containing an active drug and a bioavailability improving material |
| US5571500A (en) * | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases through administration by inhalation of autoantigens |
| US5849298A (en) * | 1987-06-24 | 1998-12-15 | Autoimmune Inc. | Treatment of multiple sclerosis by oral administration of bovine myelin |
| US5641474A (en) * | 1987-06-24 | 1997-06-24 | Autoimmune, Inc. | Prevention of autoimmune diseases by aerosol administration of autoantigens |
| US5571499A (en) * | 1987-06-24 | 1996-11-05 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
| US5645820A (en) * | 1987-06-24 | 1997-07-08 | Autoimmune, Inc. | Treatment of autoimmune diseases by aerosol administration of autoantigens |
| EP0308181A1 (en) * | 1987-09-14 | 1989-03-22 | Novo Nordisk A/S | Trans-mucosal delivery formulations and a method for preparation thereof |
| GB8723846D0 (en) * | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
| ES2061688T3 (es) * | 1987-11-13 | 1994-12-16 | Smithkline Beecham Farma | Composiciones farmaceuticas que comprenden una calcitonina y un glicirricinato como mejorador de la absorcion. |
| GB8822857D0 (en) * | 1988-09-29 | 1988-11-02 | Patralan Ltd | Pharmaceutical formulations |
| EP0458894B1 (en) * | 1989-02-17 | 1996-05-15 | The Liposome Company, Inc. | Lipid excipient for nasal delivery and topical application |
| IT8920486A0 (it) * | 1989-05-12 | 1989-05-12 | Isf Spa | Composizioni farmaceutiche. |
| GB8918879D0 (en) * | 1989-08-18 | 1989-09-27 | Danbiosyst Uk | Pharmaceutical compositions |
| US5725871A (en) * | 1989-08-18 | 1998-03-10 | Danbiosyst Uk Limited | Drug delivery compositions comprising lysophosphoglycerolipid |
| GB9007052D0 (en) * | 1990-03-29 | 1990-05-30 | Skua Investments Ltd | Pharmaceutical formulations |
| GB9012663D0 (en) * | 1990-06-07 | 1990-08-01 | Erba Carlo Spa | Galenic formulations containing cyclodextrins |
| 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 |
| IT1250691B (it) | 1991-07-22 | 1995-04-21 | Giancarlo Santus | Composizioni terapeutiche per somministrazione intranasale comprendenti ketorolac. |
| DK36492D0 (da) * | 1992-03-19 | 1992-03-19 | Novo Nordisk As | Praeparat |
| US5482706A (en) * | 1992-04-17 | 1996-01-09 | Takeda Chemical Industries, Ltd. | Transmucosal therapeutic composition |
| DE4214953C2 (de) * | 1992-05-06 | 1995-05-18 | Arrowdean Ltd | Arzneimittel zur Erhöhung des Testosteronspiegels |
| DE4218291A1 (de) * | 1992-06-03 | 1993-12-09 | Mattern Et Partner Pharmazeuti | Dosierspray für pernasale Applikation |
| SI9300468A (en) * | 1992-10-14 | 1994-06-30 | Hoffmann La Roche | Injectable composition for the sustained release of biologically active compounds |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| US5506203C1 (en) * | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| IS1796B (is) * | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
| US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
| DK0748213T3 (da) | 1994-03-07 | 2004-08-02 | Nektar Therapeutics | Fremgangsmåder og sammensætninger til pulmonal indgivelse af insulin |
| US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| ATE223202T1 (de) * | 1994-09-30 | 2002-09-15 | Mika Pharma Ges Fuer Die Entwi | Pharmazeutische zusammensetzung |
| US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
| SE9404468D0 (sv) * | 1994-12-22 | 1994-12-22 | Astra Ab | Powder formulations |
| US5869602A (en) | 1995-03-17 | 1999-02-09 | Novo Nordisk A/S | Peptide derivatives |
| US5780014A (en) * | 1995-04-14 | 1998-07-14 | Inhale Therapeutic Systems | Method and apparatus for pulmonary administration of dry powder alpha 1-antitrypsin |
| US5653987A (en) * | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
| US5856446A (en) * | 1995-07-07 | 1999-01-05 | Autoimmune Inc. | Method of treating rheumatoid arthritis with low dose type II collagen |
| JPH11292787A (ja) * | 1995-08-15 | 1999-10-26 | Asahi Chem Ind Co Ltd | 生理活性ペプチドを含有する経粘膜投与製剤 |
| US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
| US6652837B1 (en) | 1996-05-24 | 2003-11-25 | Massachusetts Institute Of Technology | Preparation of novel particles for inhalation |
| US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
| DE122009000079I2 (de) | 1996-08-30 | 2011-06-16 | Novo Nordisk As Novo Alle | Glp-1 derivate |
| US6017545A (en) * | 1998-02-10 | 2000-01-25 | Modi; Pankaj | Mixed micellar delivery system and method of preparation |
| EP1840134B1 (en) | 1998-02-27 | 2016-04-13 | Novo Nordisk A/S | GLP-1 derivatives |
| EP1062240B1 (en) | 1998-02-27 | 2010-04-28 | Novo Nordisk A/S | N-terminally modified glp-1 derivatives |
| JP2002512175A (ja) | 1998-02-27 | 2002-04-23 | ノボ ノルディスク アクティーゼルスカブ | Ｇｌｐ−１類似体の誘導体類 |
| TWI243687B (en) | 1998-04-21 | 2005-11-21 | Teijin Ltd | Pharmaceutical composition for application to mucosa |
| EP1306091A3 (en) | 1998-07-31 | 2003-05-21 | Novo Nordisk A/S | Stimulation of beta cell proliferation |
| US6290987B1 (en) | 1998-09-27 | 2001-09-18 | Generex Pharmaceuticals, Inc. | Mixed liposome pharmaceutical formulation with amphiphiles and phospholipids |
| US6849263B2 (en) | 1998-12-21 | 2005-02-01 | Generex Pharmaceutical Incorporated | Pharmaceutical compositions for buccal delivery of pain relief medications |
| US6271200B1 (en) | 1998-12-21 | 2001-08-07 | Generex Pharmaceuticals Inc. | Proteinic drug delivery system using aerosolized membrane-mimetic amphiphiles |
| US6436367B1 (en) | 1998-12-21 | 2002-08-20 | Generex Pharmaceuticals Inc. | Aerosol formulations for buccal and pulmonary application |
| US7087215B2 (en) | 1998-12-21 | 2006-08-08 | Generex Pharmaceuticals Incorporated | Methods of administering and enhancing absorption of pharmaceutical agents |
| US6540982B1 (en) * | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
| JP2003525908A (ja) | 2000-03-08 | 2003-09-02 | ノボ ノルディスク アクティーゼルスカブ | 血清脂質の低下 |
| GB0027357D0 (en) | 2000-11-09 | 2000-12-27 | Bradford Particle Design Plc | Particle formation methods and their products |
| US20040176476A1 (en) * | 2001-06-22 | 2004-09-09 | Gyurik Robert J. | Pharmaceutical composition |
| US7244703B2 (en) | 2001-06-22 | 2007-07-17 | Bentley Pharmaceuticals, Inc. | Pharmaceutical compositions and methods for peptide treatment |
| GB0205327D0 (en) * | 2002-03-06 | 2002-04-17 | Glaxo Group Ltd | compounds |
| US9339459B2 (en) | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
| PL2107069T3 (pl) | 2003-08-05 | 2013-06-28 | Novo Nordisk As | Nowe pochodne insuliny |
| PL2275439T3 (pl) | 2003-08-05 | 2014-09-30 | Novo Nordisk As | Nowe pochodne insuliny |
| BRPI0414539B8 (pt) | 2003-09-19 | 2021-05-25 | Novo Nordisk As | composto, composição farmacêutica, e, uso de um composto |
| WO2005092301A1 (en) | 2004-03-26 | 2005-10-06 | Universita' Degli Studi Di Parma | Insulin highly respirable microparticles |
| CN101128487B (zh) | 2004-12-02 | 2012-10-10 | 杜门蒂斯有限公司 | 靶向血清白蛋白和glp-1或pyy的双特异性结构域抗体 |
| JP4933455B2 (ja) | 2005-02-02 | 2012-05-16 | ノヴォ ノルディスク アー／エス | 新規のインスリン誘導体 |
| ES2490243T3 (es) | 2005-02-02 | 2014-09-03 | Novo Nordisk A/S | Derivados de insulina |
| US8722620B2 (en) | 2006-02-27 | 2014-05-13 | Novo Nordisk A/S | Insulin derivatives |
| US8796205B2 (en) | 2006-05-09 | 2014-08-05 | Novo Nordisk A/S | Insulin derivative |
| RU2451029C2 (ru) | 2006-05-09 | 2012-05-20 | Ново Нордиск А/С | Производное инсулина |
| JP5688969B2 (ja) | 2007-07-16 | 2015-03-25 | ノボ・ノルデイスク・エー／エス | プロテアーゼに対して安定しているペグ化インスリンアナログ |
| ES2526924T3 (es) | 2007-08-15 | 2015-01-16 | Novo Nordisk A/S | Insulinas con una fracción acilo que comprende unidades repetitivas de aminoácidos que contienen alquilenglicol |
| EP2178912B1 (en) | 2007-08-15 | 2015-07-08 | Novo Nordisk A/S | Insulin analogues with an acyl and aklylene glycol moiety |
| WO2009115469A1 (en) | 2008-03-18 | 2009-09-24 | Novo Nordisk A/S | Protease stabilized, acylated insulin analogues |
| CA2718480A1 (en) | 2008-03-31 | 2009-10-08 | Glaxo Group Limited | Drug fusions and conjugates |
| WO2009121884A1 (en) | 2008-04-01 | 2009-10-08 | Novo Nordisk A/S | Insulin albumin conjugates |
| US8277781B2 (en) | 2009-03-13 | 2012-10-02 | Luitpold Pharmaceuticals, Inc. | Device for intranasal administration |
| US8551454B2 (en) | 2009-03-13 | 2013-10-08 | Luitpold Pharmaceuticals, Inc. | Device for intranasal administration |
| EP2411054A2 (en) | 2009-03-27 | 2012-02-01 | Glaxo Group Limited | Drug fusions and conjugates |
| MX2012003939A (es) | 2009-09-30 | 2012-07-30 | Glaxo Group Ltd | Fusiones y conjugados de farmaco. |
| US20130261051A1 (en) | 2010-10-27 | 2013-10-03 | Thue Johansen | Treating Diabetes Melitus Using Insulin Injections Administered With Varying Injection Intervals |
| US9808030B2 (en) | 2011-02-11 | 2017-11-07 | Grain Processing Corporation | Salt composition |
| WO2012136792A2 (en) | 2011-04-07 | 2012-10-11 | Glaxo Group Limited | Cck compositions |
| WO2012136790A1 (en) | 2011-04-07 | 2012-10-11 | Glaxo Group Limited | Compositions comprising fusion proteins or conjugates with an improved half -life |
| EP2788027A2 (en) | 2011-12-09 | 2014-10-15 | Novo Nordisk A/S | Glp-1 agonists |
| WO2013164375A1 (en) | 2012-05-01 | 2013-11-07 | Novo Nordisk A/S | Pharmaceutical composition |
| WO2014093688A1 (en) | 2012-12-12 | 2014-06-19 | 1Massachusetts Institute Of Technology | Compositions and methods for functional nucleic acid delivery |
| WO2014093696A2 (en) | 2012-12-12 | 2014-06-19 | Massachusetts Institute Of Technology | Insulin derivatives for diabetes treatment |
| CA2932477C (en) | 2013-12-06 | 2023-10-10 | Baikang (Suzhou) Co., Ltd | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
| EP3258919B2 (en) * | 2015-02-17 | 2022-11-09 | Eli Lilly and Company | Nasal powder formulation for treatment of hypoglycemia |
| EP3873434A1 (en) | 2018-11-04 | 2021-09-08 | Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. | Nasal compositions and methods |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3594476A (en) * | 1969-05-12 | 1971-07-20 | Massachusetts Inst Technology | Submicron aqueous aerosols containing lecithin |
| GB1527605A (en) * | 1975-08-20 | 1978-10-04 | Takeda Chemical Industries Ltd | Insulin preparation for intranasal administration |
| NL193099C (nl) * | 1981-10-30 | 1998-11-03 | Novo Industri As | Gestabiliseerde insuline-oplossing. |
| DE3228629A1 (de) * | 1982-07-31 | 1984-02-02 | Reifenrath, Rainer Richard Otto, Dr., 3104 Unterlüß | Pharmazeutisches erzeugnis zur behandlung der atemwege und verfahren zu seiner herstellung |
| DE3323389A1 (de) * | 1983-06-29 | 1985-01-10 | B. Braun Melsungen Ag, 3508 Melsungen | Auf schleimhaeute des mundes, der nase und/oder des rachens wirkende arzneimittel auf der basis von heparin und tensiden |
| GB8327330D0 (en) * | 1983-10-12 | 1983-11-16 | Parsons W J | Membrane analogue emulsions |
| EP0179904A1 (en) * | 1984-05-09 | 1986-05-07 | Medaphore Inc. | Oral insulin and a method of making the same |
| GB8501015D0 (en) * | 1985-01-16 | 1985-02-20 | Riker Laboratories Inc | Drug |
| CA1274774A (en) * | 1985-04-15 | 1990-10-02 | Kenneth S. Su | Method for administering insulin |
| IT1187743B (it) * | 1985-09-26 | 1987-12-23 | Prodotti Formenti Srl | Composizioni farmaceutiche a base di destrorfano per applicazione instranasale |
-
1987
- 1987-12-14 NZ NZ222907A patent/NZ222907A/xx unknown
- 1987-12-15 DE DE8787311054T patent/DE3780925T2/de not_active Expired - Lifetime
- 1987-12-15 JP JP63501126A patent/JPH0768149B2/ja not_active Expired - Fee Related
- 1987-12-15 EP EP87311054A patent/EP0272097B1/en not_active Expired - Lifetime
- 1987-12-15 PT PT86370A patent/PT86370B/pt not_active IP Right Cessation
- 1987-12-15 AU AU10858/88A patent/AU606121B2/en not_active Ceased
- 1987-12-15 IE IE340887A patent/IE61110B1/en not_active IP Right Cessation
- 1987-12-15 IL IL8483587A patent/IL84835A/en not_active IP Right Cessation
- 1987-12-15 KR KR1019880700999A patent/KR890700036A/ko not_active Application Discontinuation
- 1987-12-15 AT AT87311054T patent/ATE79039T1/de not_active IP Right Cessation
- 1987-12-15 MX MX9203640A patent/MX9203640A/es unknown
- 1987-12-15 WO PCT/DK1987/000158 patent/WO1988004556A1/en active IP Right Grant
- 1987-12-15 HU HU88642A patent/HU209247B/hu not_active IP Right Cessation
- 1987-12-15 ES ES87311054T patent/ES2044957T3/es not_active Expired - Lifetime
- 1987-12-16 CA CA000554555A patent/CA1326210C/en not_active Expired - Fee Related
- 1987-12-16 CS CS930487A patent/CS273139B1/cs unknown
- 1987-12-16 YU YU228487A patent/YU46978B/sh unknown
- 1987-12-16 CN CN87108340A patent/CN1034105C/zh not_active Expired - Fee Related
-
1988
- 1988-08-15 NO NO883627A patent/NO175566C/no not_active IP Right Cessation
- 1988-08-15 FI FI883783A patent/FI94024C/fi not_active IP Right Cessation
- 1988-08-15 RU SU884356382A patent/RU1837869C/ru active
-
1992
- 1992-08-06 GR GR920401718T patent/GR3005381T3/el unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1299770C (zh) * | 2004-05-31 | 2007-02-14 | 刘近周 | 多功能鼻腔和鼻窦洁疗液 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1034105C (zh) | 鼻内用药的制剂的制备方法 | |
| US5179079A (en) | Nasal formulation and intranasal administration therewith | |
| CA1228298A (en) | Compositions and methods for drug delivery involving amphiphilic steroids | |
| KR100217258B1 (ko) | 경비조성물 | |
| US8044020B2 (en) | Pharmaceutical compositions and methods for insulin treatment | |
| US7608608B2 (en) | Pharmaceutical composition | |
| US4153689A (en) | Stable insulin preparation for nasal administration | |
| KR100358373B1 (ko) | 9-하이드록시리스페리돈지방산에스테르의수성현탁액 | |
| KR20060109903A (ko) | 경비투여용 방출 조절 전달 시스템 | |
| JPH02213A (ja) | 生理活性ペプチド持続製剤 | |
| JPH07118166A (ja) | インシュリン組成物 | |
| EP0369437B1 (en) | Motilin preparation | |
| CN1625403A (zh) | 含布那唑嗪和前列腺素的青光眼治疗剂 | |
| JPH0717520B2 (ja) | 鼻腔内投与用薬剤組成物 | |
| SK68799A3 (en) | Topical preparation for introducing peptidaceous pharmacons in living organisms | |
| JP2000044487A (ja) | カルシトニン類のプレフィルドシリンジ製剤 | |
| Erasmus | Evaluation of the oral delivery of goserelin with Pheroid® technology | |
| SI8712284A (sl) | Pripravki za nazalno uporabo in postopki za njihovo pridobivanje | |
| JPH06199681A (ja) | 生理活性ペプチド組成物 |
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 | ||
| C19 | Lapse of patent right due to non-payment of the annual fee |