JP7477844B2 - 免疫調節剤を含む徐放性医薬組成物およびその使用 - Google Patents
免疫調節剤を含む徐放性医薬組成物およびその使用 Download PDFInfo
- Publication number
- JP7477844B2 JP7477844B2 JP2021521380A JP2021521380A JP7477844B2 JP 7477844 B2 JP7477844 B2 JP 7477844B2 JP 2021521380 A JP2021521380 A JP 2021521380A JP 2021521380 A JP2021521380 A JP 2021521380A JP 7477844 B2 JP7477844 B2 JP 7477844B2
- Authority
- JP
- Japan
- Prior art keywords
- lipid
- pharmaceutical composition
- fingolimod
- phosphate
- liposomal
- 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.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 36
- 238000013268 sustained release Methods 0.000 title description 15
- 239000012730 sustained-release form Substances 0.000 title description 15
- 239000002955 immunomodulating agent Substances 0.000 title description 8
- 229940121354 immunomodulator Drugs 0.000 title description 4
- 150000002632 lipids Chemical class 0.000 claims description 59
- 229960000556 fingolimod Drugs 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 50
- 239000002502 liposome Substances 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 34
- 208000023275 Autoimmune disease Diseases 0.000 claims description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 16
- 239000003012 bilayer membrane Substances 0.000 claims description 15
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 13
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 claims description 12
- XRVDGNKRPOAQTN-FQEVSTJZSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 XRVDGNKRPOAQTN-FQEVSTJZSA-N 0.000 claims description 11
- 229950008141 ozanimod Drugs 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 10
- 229930006000 Sucrose Natural products 0.000 claims description 10
- 239000005720 sucrose Substances 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 235000012000 cholesterol Nutrition 0.000 claims description 8
- 239000000018 receptor agonist Substances 0.000 claims description 8
- 229940044601 receptor agonist Drugs 0.000 claims description 8
- 238000007920 subcutaneous administration Methods 0.000 claims description 8
- 239000003352 sequestering agent Substances 0.000 claims description 7
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 6
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims description 6
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 5
- 239000004254 Ammonium phosphate Substances 0.000 claims description 5
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 5
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 5
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 5
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 4
- LREILSUKWDDXJX-UHFFFAOYSA-N S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC Chemical compound S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].S(=O)(=O)([O-])[O-].C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC.C(C)[NH+](CC)CC LREILSUKWDDXJX-UHFFFAOYSA-N 0.000 claims description 3
- KIHYPELVXPAIDH-HNSNBQBZSA-N 1-[[4-[(e)-n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid Chemical compound CCC1=CC(C(\C)=N\OCC=2C=C(C(C3CCCCC3)=CC=2)C(F)(F)F)=CC=C1CN1CC(C(O)=O)C1 KIHYPELVXPAIDH-HNSNBQBZSA-N 0.000 claims description 2
- MVGWUTBTXDYMND-QGZVFWFLSA-N 2-[(3r)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid Chemical compound C([C@@H]1CC(=O)O)CC(C2=C3)=C1NC2=CC=C3OCC(C=C1C(F)(F)F)=CC=C1C1CCCC1 MVGWUTBTXDYMND-QGZVFWFLSA-N 0.000 claims description 2
- LPAUOXUZGSBGDU-STDDISTJSA-N chembl1096146 Chemical compound O=C1N(C=2C(=CC=CC=2)C)C(=N/CCC)/S\C1=C/C1=CC=C(OC[C@H](O)CO)C(Cl)=C1 LPAUOXUZGSBGDU-STDDISTJSA-N 0.000 claims description 2
- 229940069604 etrasimod Drugs 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- GKWPCEFFIHSJOE-UHFFFAOYSA-N laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 claims description 2
- 229960004577 laquinimod Drugs 0.000 claims description 2
- 229950009275 ponesimod Drugs 0.000 claims description 2
- 229950005693 siponimod Drugs 0.000 claims description 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 claims 2
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 claims 2
- 230000002500 effect on skin Effects 0.000 claims 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 claims 1
- SWZTYAVBMYWFGS-UHFFFAOYSA-N fingolimod hydrochloride Chemical compound Cl.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 SWZTYAVBMYWFGS-UHFFFAOYSA-N 0.000 description 62
- 238000009472 formulation Methods 0.000 description 40
- 229940079593 drug Drugs 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 18
- 238000005538 encapsulation Methods 0.000 description 12
- 238000000502 dialysis Methods 0.000 description 11
- 230000002519 immonomodulatory effect Effects 0.000 description 10
- 238000011068 loading method Methods 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 9
- 241000700159 Rattus Species 0.000 description 7
- 229960004967 fingolimod hydrochloride Drugs 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 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 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 150000001793 charged compounds Polymers 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- -1 triglycerides Chemical class 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 3
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960000633 dextran sulfate Drugs 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- WEPNHBQBLCNOBB-FZJVNAOYSA-N sucrose octasulfate Chemical compound OS(=O)(=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@H](COS(=O)(=O)O)O[C@]1(COS(O)(=O)=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](COS(O)(=O)=O)O1 WEPNHBQBLCNOBB-FZJVNAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 208000033921 delayed sleep phase type circadian rhythm sleep disease Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000002584 immunomodulator Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-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
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 description 1
- KLFKZIQAIPDJCW-GPOMZPHUSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-GPOMZPHUSA-N 0.000 description 1
- IJFVSSZAOYLHEE-SSEXGKCCSA-N 1,2-dilauroyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-SSEXGKCCSA-N 0.000 description 1
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 description 1
- DSNRWDQKZIEDDB-SQYFZQSCSA-N 1,2-dioleoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-SQYFZQSCSA-N 0.000 description 1
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 1
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 1
- MWRBNPKJOOWZPW-NYVOMTAGSA-N 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-NYVOMTAGSA-N 0.000 description 1
- MHUWZNTUIIFHAS-DSSVUWSHSA-N 1,2-dioleoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-DSSVUWSHSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 1
- 101710087078 Dipeptidyl peptidase 1 Proteins 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- FVJZSBGHRPJMMA-DHPKCYQYSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-DHPKCYQYSA-N 0.000 description 1
- LALGUHSIWLNTNW-HBQZPISHSA-N [(2r)-3-[hydroxy-[(3r)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)COP(O)(=O)OC1C(O)C(O)C(O)[C@@H](O)C1O LALGUHSIWLNTNW-HBQZPISHSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003460 anti-nuclear Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- MRDHBHKPDFRCJQ-HUKLJVEISA-N azane [(2R)-2-hexadecanoyloxy-3-[hydroxy-[(2R,3S,5R,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxypropyl] hexadecanoate Chemical compound [NH4+].CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OC1[C@H](O)[C@@H](O)C(O)[C@@H](O)[C@H]1O)OC(=O)CCCCCCCCCCCCCCC MRDHBHKPDFRCJQ-HUKLJVEISA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- KPHZNDUWYZIXFY-YORIBCANSA-M sodium;(2s)-2-azaniumyl-3-[[(2r)-2,3-bis[[(z)-octadec-9-enoyl]oxy]propoxy]-oxidophosphoryl]oxypropanoate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OC[C@H]([NH3+])C([O-])=O)OC(=O)CCCCCCC\C=C/CCCCCCCC KPHZNDUWYZIXFY-YORIBCANSA-M 0.000 description 1
- QSHQBWBFNCFHLO-MFABWLECSA-M sodium;(2s)-2-azaniumyl-3-[[(2r)-2,3-di(tetradecanoyloxy)propoxy]-oxidophosphoryl]oxypropanoate Chemical compound [Na+].CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OC[C@H]([NH3+])C([O-])=O)OC(=O)CCCCCCCCCCCCC QSHQBWBFNCFHLO-MFABWLECSA-M 0.000 description 1
- FGGPAWQCCGEWTJ-UHFFFAOYSA-M sodium;2,3-bis(sulfanyl)propane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)CC(S)CS FGGPAWQCCGEWTJ-UHFFFAOYSA-M 0.000 description 1
- QLNOOKSBAYIHQI-SKZICHJRSA-M sodium;2,3-dihydroxypropyl [(2r)-2,3-di(tetradecanoyloxy)propyl] phosphate Chemical compound [Na+].CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC QLNOOKSBAYIHQI-SKZICHJRSA-M 0.000 description 1
- BMBWFDPPCSTUSZ-MGDILKBHSA-M sodium;[(2r)-2,3-di(hexadecanoyloxy)propyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)([O-])=O)OC(=O)CCCCCCCCCCCCCCC BMBWFDPPCSTUSZ-MGDILKBHSA-M 0.000 description 1
- ALPWRKFXEOAUDR-GKEJWYBXSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)([O-])=O)OC(=O)CCCCCCCCCCCCCCCCC ALPWRKFXEOAUDR-GKEJWYBXSA-M 0.000 description 1
- UBSPGYHFNIKQIP-XXIQNXCHSA-M sodium;[(2r)-2,3-di(tetradecanoyloxy)propyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)([O-])=O)OC(=O)CCCCCCCCCCCCC UBSPGYHFNIKQIP-XXIQNXCHSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- FHQVHHIBKUMWTI-OTMQOFQLSA-N {1-hexadecanoyl-2-[(Z)-octadec-9-enoyl]-sn-glycero-3-phospho}ethanolamine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC FHQVHHIBKUMWTI-OTMQOFQLSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本出願は、2018年10月17日に出願された、米国特許出願第62/746,810号の利益を主張し、その開示全体は参照により本明細書に組み込まれる。
本発明は、少なくとも1つの捕捉剤を使用して、高い薬物対脂質比(drug to lipid ratio)および高いカプセル化効率を有する免疫調節剤を含む徐放性医薬組成物に関する。請求項に規定される医薬組成物の高い薬物対脂質比、高いカプセル化効率および徐放性プロファイルは、薬物投与の頻度を減少させ、患者のコンプライアンスを増加させ、治療結果を改善する。
一実施形態では、(a)二重層膜を含む少なくとも1つのリポソーム;(b)捕捉剤;および(c)免疫調節剤を含み、二重層膜が少なくとも1つの脂質を含み、免疫調節剤対脂質のモル比(molar ratio of the immunomodulating agent to the lipid)が約0.2以上である、徐放性医薬組成物が提供される。
上記および本開示全体を通して使用される、下記用語は、本明細書中で特記しない限り、単数形「a」、「an」および「the」は、文脈で明確に示されない限り、複数形を含む。
本明細書中で使用される用語「リポソーム(liposome)」、「リポソームの(liposomal)」および関連する用語は、小胞を形成する1つ以上の二重層膜によって外部媒体から隔離された内部水性空間を特徴とする。特定の実施形態において、リポソームの内部水性空間は、トリグリセリド、非水相(油相)、水-油エマルジョンまたは非水相を含む他の混合物などの、中性脂質を実質的に含まない。リポソームの非限定的な例には、50~20μm、50~450nm、50~400nm、50~350nm、50~300nm、50~250nm、50~200nm、100~500nm、100~450nm、100~400nm、100~350nm、100~300nm、100~250nmまたは100~200nmの平均直径範囲を有する小さな単ラメラ小胞(SUV)、大きな単ラメラ小胞(LUV)、および多ラメラ小胞(MLV)が含まれる。
本明細書で使用される「リモート充填(remote loading)」という用語は、多原子イオン勾配(polyatomic ion-gradient)によって、治療薬を外部媒体からリポソームの二重層膜を横切って内部水性空間に移動させる手順を含む薬物充填方法である。このような勾配は、少なくとも1つの多原子イオンを捕捉剤としてリポソームの内部水性空間にカプセル化し、カラム分離、透析または遠心分離などの公知の技術によって、リポソームの外部媒体をより低い多原子イオン濃度の外部媒体、例えば、純水、スクロース溶液および生理食塩水などに置き換えることによって生成される。多原子イオン勾配は、リポソームの内部水性空間と外部媒体との間に生成され、治療薬をリポソームの内部水性空間に捕捉する。捕捉剤としての具体的な多原子イオンとしては、硫酸塩、亜硫酸塩、リン酸塩、リン酸水素塩、モリブデン酸塩、炭酸塩および硝酸塩が挙げられるが、これらに限定されない。具体的な捕捉剤としては、硫酸アンモニウム、リン酸アンモニウム、モリブデン酸アンモニウム、スクロースオクタ硫酸アンモニウム(ammonium sucrose octasulfate)、スクロースオクタ硫酸トリエチルアンモニウム(triethylammonium sucrose octasulfate)、および硫酸デキストランが挙げられるが、これらに限定されない。
本発明は(a)二重層膜を含む少なくとも1つのリポソーム;(b)捕捉剤;および(c)免疫調節剤を含み、二重層膜が少なくとも1つの脂質を含み、免疫調節剤対脂質のモル比(molar ratio of the immunomodulating agent to the lipid)が約0.2以上である徐放性医薬組成物に関する。いくつかの実施形態では、治療薬対脂質のモル比(molar ratio of the therapeutic agent to the lipid)が約0.2以上約20未満、約15未満、約10未満、約5未満、約4未満、約3未満または約2未満である。
本発明の実施形態を以下の実施例によって説明するが、下記実施例はその範囲に限定を課すものとして決して解釈されるべきではない。それどころか、本明細書の説明を読んだ後、本発明の概念から逸脱することなく当業者にそれ自体を示唆し得る、様々な他の実施形態、修飾、およびそれらの同等物の対象となり得ることが明確に理解されるべきである。以下の実施例に記載される研究の間、特記しない限り、従来の手順に従った。
空のリポソームを、脂質フィルム水和-押出法(lipid film hydration-extrusion method)によって調製した。HSPC、コレステロール、およびDSPE-PEG2000(モルパーセント 59.5/39.6/0.9)をクロロホルムに溶解し、ロータリーエバポレーター中で真空下で有機溶媒を除去することによって、薄い脂質フィルムを形成した。乾燥脂質フィルムを300mM 硫酸アンモニウム中、60℃で30分間水和し、硫酸アンモニウムが水性コアにカプセル化された空のリポソームを形成した。液体窒素と60℃の水との間の6回の凍結融解サイクルの後、空のリポソームを、続いて、0.2μmの孔径を有するポリカーボネートフィルター膜を通して10回押し出した。カプセル化されていない硫酸アンモニウムを、9.4%スクロース溶液に対する透析によって除去した。
空のリポソームを、脂質フィルム水和-押出法によって調製した。HSPC、コレステロール、およびDPPG(モルパーセント 59.5/39.6/0.9)をクロロホルムに溶解し、有機溶媒をロータリーエバポレーター中で真空下で除去することによって、薄い脂質フィルムを形成した。乾燥脂質フィルムを300mM 硫酸アンモニウム中、60℃で30分間水和し、硫酸アンモニウムが水性コアにカプセル化された空のリポソームを形成した。液体窒素と60℃の水との間の6回の凍結融解サイクルの後、空のリポソームを、続いて、0.2μmの孔径を有するポリカーボネートフィルター膜を通して10回押し出した。カプセル化されていない硫酸アンモニウムを、9.4%スクロース溶液に対する透析によって除去した。
リポソーム製剤を、以下の捕捉剤:(1)75mMのスクロースオクタ硫酸トリエチルアンモニウム、(2)300mMの硫酸アンモニウム、(3)200mMのリン酸アンモニウム、および(4)7.0mMの硫酸デキストランを用いて、実施例1に従って調製した。表1は、薬物充填(drug loading)に対する種々の捕捉剤の効果を示す。
インビトロ放出システムを準備するために、実施例1に従って調製した0.5mLのリポソームフィンゴリモド製剤(liposomal fingolimod formulation)および0.5mLの遊離フィンゴリモド塩酸塩(free fingolimod hydrochloride)を、それぞれ、0.5mLのウシ胎仔血清と混合した。遊離フィンゴリモド/血清混合物およびリポソームフィンゴリモド/血清混合物を別々の透析バッグ(Spectra/Pro(登録商標)6 dialysis membrane、MWCO 50kDa、Spectrum Labs)に入れ、透析バッグの両端を密封した。各透析バッグを、50mLの遠心分離管内で0.06N HClを含有するpH 7.4の15mL PBSに浸漬し、37±1℃の水浴でインキュベートした。インキュベーションしてから所定の時点(1、2、4、8および24時間)で、15mLのPBSからの0.5mLのアリコートをサンプリングし、毎回0.5mLの新鮮なPBSを添加して、サンプリングアリコートを補充した。各時点でのサンプリングアリコートの薬物濃度を、HPLCを使用して分析して、試験した製剤のインビトロ放出プロファイルを作成した。
7~8週齢の雌Sprague-Dawleyラットを用いて、リポソームフィンゴリモド製剤のインビボPK評価を行った。ラットを、12時間の明/12時間の暗の概日周期で操作した保持室に収容し、水および食物を自由に摂取させた。
Claims (13)
- (a)二重層膜を含む少なくとも1つのリポソームであって、前記二重層膜が約45~約79.9モルパーセントの第1の脂質と、約20~約25モルパーセントのコレステロールと、必要に応じて約0.1~約10モルパーセントの第2の脂質と、の混合物を含む、リポソーム、
(b)スクロースオクタ硫酸トリエチルアンモニウム、硫酸アンモニウム、リン酸アンモニウムおよびそれらの組み合わせからなる群から選択される捕捉剤、および
(c)エトラシモド、フィンゴリモド、ラキニモド、オザニモド、ポネシモド、シポニモドおよびそれらの組み合わせからなる群より選択されるスフィンゴシン-1-リン酸(S1P)受容体アゴニスト
を含み、前記第1の脂質および必要に応じて前記第2の脂質に対するスフィンゴシン-1-リン酸(S1P)受容体アゴニストのモル比が約0.49より高く、
前記第1の脂質がHSPC、DPPC、DMPCまたはそれらの組み合わせであり、前記第2の脂質がPEG-DSPE、DPPGまたはそれらの組み合わせである、医薬組成物。 - 前記リポソームの平均粒径が約50nm~20μmである、請求項1に記載の医薬組成物。
- 前記スクロースオクタ硫酸トリエチルアンモニウムの濃度が約10~200mMである、請求項1に記載の医薬組成物。
- 前記硫酸アンモニウムの濃度が約100~600mMである、請求項1に記載の医薬組成物。
- 前記リン酸アンモニウムの濃度が約100~600mMである、請求項1に記載の医薬組成物。
- 前記第1の脂質がDMPCであり、前記第2の脂質がPEG-DSPEである、請求項1に記載の医薬組成物。
- 前記第1の脂質がDPPCであり、前記第2の脂質がPEG-DSPEである、請求項1に記載の医薬組成物。
- 前記第1の脂質がHSPCであり、前記第2の脂質がPEG-DSPEまたはDPPGである、請求項1に記載の医薬組成物。
- 請求項1~8のいずれか1項に記載の医薬組成物の治療有効量を含む、自己免疫疾患を治療するための治療薬。
- 前記医薬組成物中のスフィンゴシン-1-リン酸(S1P)受容体アゴニストの半減期が、遊離のスフィンゴシン-1-リン酸(S1P)受容体アゴニストの半減期と比較して、少なくとも約2倍延長される、請求項9に記載の治療薬。
- 前記医薬組成物が、少なくとも1週間に1回、2週間に1回、または1ヶ月に1回投与される、請求項9に記載の治療薬。
- 前記医薬組成物が、皮膚注射によって投与される、請求項9に記載の治療薬。
- 前記皮膚注射が、皮内(intracutaneous)、皮下(subcutaneous)、真皮下(subdermal)、皮内(intradermal)または筋肉内経路を含む、請求項12に記載の治療薬。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862746810P | 2018-10-17 | 2018-10-17 | |
US62/746,810 | 2018-10-17 | ||
PCT/US2019/056186 WO2020081485A1 (en) | 2018-10-17 | 2019-10-15 | Sustained-release pharmaceutical compositions comprising an immunomodulating agent and uses thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2022505378A JP2022505378A (ja) | 2022-01-14 |
JPWO2020081485A5 JPWO2020081485A5 (ja) | 2022-09-12 |
JP7477844B2 true JP7477844B2 (ja) | 2024-05-02 |
Family
ID=70284157
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021521380A Active JP7477844B2 (ja) | 2018-10-17 | 2019-10-15 | 免疫調節剤を含む徐放性医薬組成物およびその使用 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20210393524A1 (ja) |
EP (1) | EP3866764A4 (ja) |
JP (1) | JP7477844B2 (ja) |
CN (1) | CN113015520A (ja) |
TW (1) | TWI767149B (ja) |
WO (1) | WO2020081485A1 (ja) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016513655A (ja) | 2013-03-13 | 2016-05-16 | マリンクロッド エルエルシー | 修飾されたドセタキセルリポソーム製剤 |
JP2016518340A (ja) | 2013-03-15 | 2016-06-23 | タイワン リポソーム カンパニー リミテッド | 水性及び非水性区画の両方におけるリポソーム組成物による制御薬物放出プロファイルの操作 |
WO2017123588A1 (en) | 2016-01-11 | 2017-07-20 | Merrimack Pharmaceuticals, Inc. | Inhibiting ataxia telangiectasia and rad3-related protein (atr) |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL91664A (en) * | 1988-09-28 | 1993-05-13 | Yissum Res Dev Co | Ammonium transmembrane gradient system for efficient loading of liposomes with amphipathic drugs and their controlled release |
CN1980637B (zh) * | 2004-05-03 | 2014-02-19 | 赫尔姆生物科学公司 | 用于药物输送的脂质体 |
CN101199505B (zh) * | 2007-12-20 | 2012-05-23 | 沈阳药科大学 | 维拉帕米脂质体及其制备方法 |
CN101756902B (zh) * | 2008-12-23 | 2011-10-05 | 上海医药工业研究院 | 一种可乐定多囊脂质体及其制备方法 |
CN101601654B (zh) * | 2009-07-03 | 2010-08-18 | 王明 | 盐酸法舒地尔脂质体注射剂及其新应用 |
CN102406606B (zh) * | 2011-11-29 | 2013-01-23 | 海南美大制药有限公司 | 富马酸喹硫平脂质体固体制剂 |
US20150157610A1 (en) * | 2012-05-23 | 2015-06-11 | Osaka University | Pharmaceutical composition for treating inflammatory disease |
AU2015301234A1 (en) * | 2014-08-04 | 2017-06-15 | Zoneone Pharma, Inc. | Remote loading of sparingly water-soluble drugs into lipid vesicles |
EP3302435B1 (en) * | 2015-05-26 | 2023-03-08 | Plumb Pharmaceuticals, Inc. | Liposome loading |
JP7068173B2 (ja) * | 2016-01-08 | 2022-05-16 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | カーゴ送達のための、脂質二重層コーティングを備えたメソ多孔性シリカナノ粒子 |
WO2019082139A1 (en) * | 2017-10-27 | 2019-05-02 | Shilpa Medicare Limited | LIPOSOMAL FINGOLIMOD HYDROCHLORIDE INJECTION |
CN108354904A (zh) * | 2018-05-21 | 2018-08-03 | 天津双硕医药科技有限公司 | 一种含有盐酸金刚烷胺的口服药物组合物 |
CN112512508A (zh) * | 2018-07-24 | 2021-03-16 | 台湾微脂体股份有限公司 | 含有治疗失智症的治疗剂的缓释药物组合物及其用途 |
-
2019
- 2019-10-15 US US17/285,623 patent/US20210393524A1/en active Pending
- 2019-10-15 CN CN201980061938.5A patent/CN113015520A/zh active Pending
- 2019-10-15 TW TW108136993A patent/TWI767149B/zh active
- 2019-10-15 WO PCT/US2019/056186 patent/WO2020081485A1/en unknown
- 2019-10-15 JP JP2021521380A patent/JP7477844B2/ja active Active
- 2019-10-15 EP EP19873971.6A patent/EP3866764A4/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016513655A (ja) | 2013-03-13 | 2016-05-16 | マリンクロッド エルエルシー | 修飾されたドセタキセルリポソーム製剤 |
JP2016518340A (ja) | 2013-03-15 | 2016-06-23 | タイワン リポソーム カンパニー リミテッド | 水性及び非水性区画の両方におけるリポソーム組成物による制御薬物放出プロファイルの操作 |
WO2017123588A1 (en) | 2016-01-11 | 2017-07-20 | Merrimack Pharmaceuticals, Inc. | Inhibiting ataxia telangiectasia and rad3-related protein (atr) |
Non-Patent Citations (1)
Title |
---|
MAO Y. et al.,A novel liposomal formulation of FTY720 (Fingolimod) for promising enhanced targeted delivery,Nanomedicine. Author Manuscript, NIH Public Access,2014年08月16日,pp.1-19 |
Also Published As
Publication number | Publication date |
---|---|
EP3866764A1 (en) | 2021-08-25 |
EP3866764A4 (en) | 2022-07-13 |
TWI767149B (zh) | 2022-06-11 |
US20210393524A1 (en) | 2021-12-23 |
WO2020081485A1 (en) | 2020-04-23 |
TW202033184A (zh) | 2020-09-16 |
CN113015520A (zh) | 2021-06-22 |
JP2022505378A (ja) | 2022-01-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI776076B (zh) | 含有治療失智症之治療劑的緩釋藥物組合物及其用途 | |
TWI767133B (zh) | 含有治療憂鬱症或焦慮症之治療劑的緩釋組合物及其用途 | |
JP7482487B2 (ja) | 鎮静薬を含む徐放性医薬組成物およびその使用 | |
TWI772664B (zh) | 含有抗精神病藥物的緩釋藥物組合物及其用途 | |
JP7477844B2 (ja) | 免疫調節剤を含む徐放性医薬組成物およびその使用 | |
TWI729562B (zh) | 包含用於治療因骨密度降低或軟骨損失導致之疾病的治療劑的緩釋藥物組合物及其用途 | |
TWI850208B (zh) | 緩釋型翠普登組成物及其經皮下或類似途徑使用之方法 | |
US20210275447A1 (en) | Sustained-release ophthalmic pharmaceutical compositions and uses thereof | |
EP3727333A1 (en) | Sustained-release triptan compositions and method of use the same through subdermal route or the like |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220902 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220902 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230810 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231003 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20231222 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240322 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240402 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20240322 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240411 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7477844 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |