MXPA99011675A - Proliposome powders for inhalation stabilised by tocopherol - Google Patents
Proliposome powders for inhalation stabilised by tocopherolInfo
- Publication number
- MXPA99011675A MXPA99011675A MXPA/A/1999/011675A MX9911675A MXPA99011675A MX PA99011675 A MXPA99011675 A MX PA99011675A MX 9911675 A MX9911675 A MX 9911675A MX PA99011675 A MXPA99011675 A MX PA99011675A
- Authority
- MX
- Mexico
- Prior art keywords
- powder
- powder according
- tocopherol
- dmpc
- dppc
- Prior art date
Links
- 239000000843 powder Substances 0.000 title claims abstract description 83
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 title claims abstract description 29
- 229960001295 Tocopherol Drugs 0.000 title claims abstract description 18
- 239000011732 tocopherol Substances 0.000 title claims abstract description 18
- 235000010384 tocopherol Nutrition 0.000 title claims abstract description 18
- 229930003799 tocopherols Natural products 0.000 title claims abstract description 18
- 150000002632 lipids Chemical class 0.000 claims abstract description 48
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 239000002245 particle Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol 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 26
- KILNVBDSWZSGLL-KXQOOQHDSA-N Dipalmitoylphosphatidylcholine 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 20
- 229940107161 Cholesterol Drugs 0.000 claims description 13
- 235000012000 cholesterol Nutrition 0.000 claims description 13
- 239000000969 carrier Substances 0.000 claims description 10
- 239000000787 lecithin Substances 0.000 claims description 10
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 6
- OZSITQMWYBNPMW-GDLZYMKVSA-N 1,2-ditetradecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCC OZSITQMWYBNPMW-GDLZYMKVSA-N 0.000 claims description 5
- 229940112141 Dry Powder Inhaler Drugs 0.000 claims description 5
- 229940087168 alpha Tocopherol Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 claims description 5
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 5
- REYJJPSVUYRZGE-UHFFFAOYSA-N stearylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims description 5
- 229960000984 tocofersolan Drugs 0.000 claims description 5
- 239000002076 α-tocopherol Substances 0.000 claims description 5
- 235000004835 α-tocopherol Nutrition 0.000 claims description 5
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims 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 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 150000003408 sphingolipids Chemical class 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 229960001021 Lactose Monohydrate Drugs 0.000 claims description 3
- IXTCZMJQGGONPY-XJAYAHQCSA-N Rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 claims description 3
- 229950004432 Rofleponide Drugs 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- ZAKBPRIDLSBYQQ-VHSXEESVSA-N 1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OC[C@@H](O)CO ZAKBPRIDLSBYQQ-VHSXEESVSA-N 0.000 claims description 2
- 230000000087 stabilizing Effects 0.000 claims description 2
- GZDFHIJNHHMENY-UHFFFAOYSA-N DMPC Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims 8
- FVXDQWZBHIXIEJ-LNDKUQBDSA-N 1,2-dilinoleoyl-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 claims 4
- 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 claims 3
- 239000003862 glucocorticoid Substances 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 230000003019 stabilising Effects 0.000 abstract 1
- 239000002502 liposome Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 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 13
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 13
- 239000000654 additive Substances 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- -1 myristoyl phosphatidylcholine Chemical compound 0.000 description 7
- IJFVSSZAOYLHEE-SSEXGKCCSA-O 1,2-dilauroyl-sn-glycero-3-phosphocholine(1+) Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-SSEXGKCCSA-O 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 210000002345 respiratory system Anatomy 0.000 description 6
- SNKAWJBJQDLSFF-YEUCEMRASA-N [2-({2,3-bis[(9Z)-octadec-9-enoyloxy]propyl phosphonato}oxy)ethyl]trimethylazanium Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-YEUCEMRASA-N 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- LKQLRGMMMAHREN-YJFXYUILSA-N N-stearoylsphingosine-1-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)[C@H](O)\C=C\CCCCCCCCCCCCC LKQLRGMMMAHREN-YJFXYUILSA-N 0.000 description 4
- 230000000996 additive Effects 0.000 description 4
- 239000000232 Lipid Bilayer Substances 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 150000003431 steroids Chemical group 0.000 description 3
- LDQFLSUQYHBXSX-HPPMYKKZSA-N 1,2-Dioctadecanoyl-3-(galactosyl-B-1-6-galactosyl-B-1)-glycerol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](OC[C@@H](COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC)OC1CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 LDQFLSUQYHBXSX-HPPMYKKZSA-N 0.000 description 2
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N Bricaril Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- 210000002969 Egg Yolk Anatomy 0.000 description 2
- BPZSYCZIITTYBL-YJYMSZOUSA-N Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N Salbutamol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- 229960000195 Terbutaline Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Trimethylglycine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 229960002848 formoterol Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 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 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DXEXNWDGDYUITL-FXSSSKFRSA-N (8S,9R,10S,11S,13S,14S,17R)-17-ethylsulfanyl-9-fluoro-11-hydroxy-10,13-dimethyl-17-methylsulfanyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](SC)(SCC)[C@@]1(C)C[C@@H]2O DXEXNWDGDYUITL-FXSSSKFRSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-Furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- 229940035676 ANALGESICS Drugs 0.000 description 1
- 206010001889 Alveolitis Diseases 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- 229940092705 Beclomethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N Betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- FZGVEKPRDOIXJY-UHFFFAOYSA-N Bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 206010006451 Bronchitis Diseases 0.000 description 1
- CQFNOACVVKSEOJ-VBQPQCOESA-N Bronilide Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O CQFNOACVVKSEOJ-VBQPQCOESA-N 0.000 description 1
- JBRBWHCVRGURBA-UHFFFAOYSA-N Broxaterol Chemical compound CC(C)(C)NCC(O)C1=CC(Br)=NO1 JBRBWHCVRGURBA-UHFFFAOYSA-N 0.000 description 1
- 229950008847 Broxaterol Drugs 0.000 description 1
- 229960004436 Budesonide Drugs 0.000 description 1
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 description 1
- 229940097217 CARDIAC GLYCOSIDES Drugs 0.000 description 1
- 101700068305 COP1 Proteins 0.000 description 1
- 101700037066 COP3 Proteins 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- STJMRWALKKWQGH-UHFFFAOYSA-N Clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 1
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 101700086301 Ear1 Proteins 0.000 description 1
- LSLYOANBFKQKPT-UHFFFAOYSA-N Fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 description 1
- 229940013399 Flumethasone Drugs 0.000 description 1
- UUOUOERPONYGOS-CLCRDYEYSA-N Fluocinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 UUOUOERPONYGOS-CLCRDYEYSA-N 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N Fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 229960000367 Inositol Drugs 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
- 208000007906 Intestinal Disease Diseases 0.000 description 1
- 210000001503 Joints Anatomy 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229960001664 Mometasone Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N Myoinositol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229940105132 Myristate Drugs 0.000 description 1
- VODZWWMEJITOND-OWWNRXNESA-N N-Stearoylsphingosine Chemical compound CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(O)\C=C\CCCCCCCCCCCCC VODZWWMEJITOND-OWWNRXNESA-N 0.000 description 1
- 101700007039 PA21 Proteins 0.000 description 1
- 101700016159 PA22 Proteins 0.000 description 1
- 101700040243 PA23 Proteins 0.000 description 1
- 101700071566 PA2A2 Proteins 0.000 description 1
- 101710031203 PA2CS Proteins 0.000 description 1
- 101700039989 PA2V Proteins 0.000 description 1
- 101700014500 PA2X1 Proteins 0.000 description 1
- 101700036609 PA2X2 Proteins 0.000 description 1
- 101700024882 PLA2 Proteins 0.000 description 1
- 102100001381 PLA2G1B Human genes 0.000 description 1
- 101710029814 PLA2G1B Proteins 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 229960002288 Procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N Procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N Raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 206010039083 Rhinitis Diseases 0.000 description 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N Sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 description 1
- 229940032147 Starch Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 229950001669 Tipredane Drugs 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229960002117 Triamcinolone Acetonide Drugs 0.000 description 1
- 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 description 1
- 229940029983 VITAMINS Drugs 0.000 description 1
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229960002675 Xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 230000003356 anti-rheumatic Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960004620 bitolterol Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000003182 bronchodilatating Effects 0.000 description 1
- 230000003523 bronchorelaxant Effects 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M caprate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 108010015046 cell aggregation factors Proteins 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 229960001117 clenbuterol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 229960003469 flumetasone Drugs 0.000 description 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003126 pregnane derivatives Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000001624 sedative Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 229960005486 vaccines Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 101710033049 xecG Proteins 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
There is described a proliposome powder, said powder comprising discrete particles each comprising in a single phase (1) a biologically active component, (2) a stabilising proportion of tocopherol, and (3) a lipid or mixture of lipids having a phase transition temperature of below 37°C. Also described is a process for the preparation of, and the pharmaceutical use of, the powder.
Description
INHALATION PROLIPOSOME POWDLES, STABILIZED BY TOCOPHEROL Field of the Invention The present invention relates to proliposome powders, particularly for inhalation, a process for producing proliposome powders, compositions containing proliposome powders and methods for their use .
BACKGROUND OF THE ART: Liposomes are vesicles similar to membranes that consist of a series of concentric lipid bilayers alternately with hydrophilic compartments. They can also be made from a variety of natural and synthetic lipids such as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids. One of the main uses of liposomes have been as carriers of different types of pharmaceutically active components, to improve the release of drugs and minimize the side effects of some treatments. The pharmaceutically active compounds can be incorporated into liposomes either by encapsulation in hydrophilic compartments of the liposomes (when the active component is soluble in water), or by encapsulation in the lipid bilayers, when the active component is lipophilic.
REF .: 32252 One of the main problems associated with pharmaceutical liposomal formulations is long-term stability. The dispersions of aqueous liposomes have a limited stability due to aggregation, loss of the active component encapsulated towards the external phase, chemical degradation of the active component or the lipid material, etc. These problems can be overcome to a large extent if a solid composition is used. Such a solid composition may comprise a liposome powder, i.e. a dry liposomal dispersion or a powder of proliposomes. WO 96/19199 describes a variety of literature on liposome and proliposome and describes a proliposome powder. The powder contains, a single phase, discrete particles that contain a biologically active component and a lipid mixing component has a phase transition temperature (Te) of less than 37 ° C. It has now been found that the stability of the proliposome powder of WO 96/19199 can be increased to a considerable degree. Description of the Invention The present invention provides a proliposome powder, the powder contains discrete particles, each of which comprises in a single phase (1) a biologically active component, (2) a stabilizing ratio of tocopherol, and (3) a lipid or lipid mixture having a phase transition temperature of less than 37 ° C. Preferably, tocopherol is α-tocopherol, and more preferably racemic α-tocopherol. The powder is particularly suitable for administration by inhalation. The single-phase powder can alternatively be described as comprising a homogeneous molecular mixture and a biologically active component, a lipid or mixture of lipids having a phase transition temperature lower than 37 ° C, and tocopherol. It should be understood according to the terms "a single phase" and "homogeneous molecular mixture" that there is no non-separated crystalline phase of the active component, the lipid or the tocopherol in the powder of the present invention. The single-phase powder can be inhaled directly, and in situ for examin the upper or lower respiratory system, will form liposomes in which the biologically active component is incorporated. In general, any amphiphatic lipid or lipid mixture known to be suitable for preparing liposomes by known methods could be used in the present invention. The lipid or lipid mixture must have a phase transition temperature lower than the body temperature (37 ° C) so that the product of the proliposome powder is able to hydrate under physiological conditions (i.e. to be able to form liposomes in the body). respiratory system) . The phase transition temperatures for the different lipid mixtures can be easily estimated, using well-established methods, for example DSC methods-see for example J. Suurkuusk et al., Biochemistry, vol. 15, no.7, p. 1393 (1976). In general, any lipid or mixture of natural or synthetic lipids having a phase transition temperature of less than 37 ° C is useful in the present invention. As examples of potentially useful lipids there may be mentioned natural and synthetic lipids as well as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids. Among the natural lipids can be mentioned sphingolipids(SL) such as sphingomyelin (SM), ceramide and cerebroside; galactosylglycerolipids such as digalactosyldiacylglycerol (DGalDG); phosphoglycerolipids such as egg yolk phosphatidylcholine (ePC) and soy phosphatidylcholine (s-PC); and lecithins such as egg yolk lecithin (e-lecithin) and soy lecithin (s-lecithin). Synthetic lipids include dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dilauryl phosphatidylcholine (DLPC), l-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), l-palmitoyl-2 myristoyl phosphatidylcholine (PMPC), and dioleoyl phosphatidylcholine (DOPC). Among the lipid mixtures, the following can be mentioned: SM / PC, SM / Cholesterol, ePC / Cholesterol, sPC / Cholesterol, PC / PS / cholesterol, DMPC / DPPC, DMPC / DPPC / CH, DMPC / CH, DPPC / DOPC, DPPC / DOPC / CH, DLPC / DPPC, DLPC / DPPC / CH, DLPC / DMPC, DLPC / DMPC / CH, DOPC / DSPC, DPSM / DMSM, e-lecithin / Cholesterol and s-lecithin / Cholesterol. In addition, any of the foregoing may include a charged lipid such as dimyristoyl phosphatidylglycerol (DMPG), diphospalmitoyl phosphatidylglycerol (DPPG), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA) or stearylamine (SA). Lipids of particular interest in the present invention are DPPC and / or DMPC. The mixture of DPPC and DMPC containing at least 10% (/) of DMPC, for example 10-50% of DMPC is preferred. Especially preferred is a mixture of DPPC and DMPC containing at least one charged lipid such as DMPG, DPPG, DMPA or SA, for example in an amount of up to 5% (w / w). Other preferred mixtures include DPSM and DMSM optionally containing at least one charged lipid, and mixtures of cholesterol or e-lecithin or s-lecithin, optionally containing at least one charged lipid, and having a Tc of less than 37 ° C. Other mixtures can be easily selected by one skilled in the art with reference to the example of Gregor Cevc, Phospholipids Handbook, Marcel Dekker, New York (1993) pp 427-435. The tocopherol is preferably present in a proportion of 0.05 to 1.0%, more preferably of O.lal to 0.6%, by weight of the total single phase containing the lipids and the biologically active component. The active component preferably has a molecular structure which can be incorporated into the lipid bilayers, to aid in the encapsulation in the liposomes during hydration. An example of such a molecular structure is a fatty acid ester having a long hydrocarbon chain sufficient to act as a hydrophobic anchor. Suitable active components can be readily identified by a person skilled in the art and can include, for example, anti-inflammatory and broncho-relaxant drugs, antihistamines, cyclooxygenase inhibitors, leukotrin synthesis inhibitors, leukotriene antagonists, phospholipase A2 inhibitors ( PLA2), antagonists of platelet aggregation factor
(PAF) and asthma prophylactics. Antiarrhythmic drugs, tranquillizers, cardiac glycosides, hormones, antihypertensive drugs, antidiabetic, antiparasitic and anti-cancer drugs, sedative drugs, analgesics, antibiotics, antirheumatics, immunotherapies, antifungal drugs, antiphypotensive drugs, vaccines, antiviral drugs, proteins, peptides and vitamins, may also be of interest. Specifically, glucocorticosteroids such as budesonide, fluticasone propionate, ciclesonide, rofleponide, for example, as their palmitate, mometasone, for example as their furoate, tipredane, RPR 106541, dexamethasone, betamethasone, fluocinolone, flumethasone, triamcinolone acetonide, flunisolide , Beclomethasone and Acétals 16,17 of pregnane derivatives and compound derivatives thereof and β-2 agonists such as terbutaline, salmeterol, salbutamol, formoterol, fenoterol, clenbuterol, procaterol, bitolterol, and broxaterol, may be useful in present invention. The active component can also be a mixture of pharmaceutically active substances; for example a mixture of glucocorticosteroids with a bronchodilator such as formoterol, salmeterol, terbutaline or salbutamol, may be useful. For the avoidance of doubt, where reference is made here to any active component, the reference is intended to include a reference to pharmaceutically acceptable esters, salts and hydrates thereof. I Where the active component is a steroid this is preferably a steroid ester. The active component is preferably a steroid, preferably a steroid which is Iβ esterified at position 21 with a saturated or unsaturated fatty acid of at least 8, for example and / or at least 10 or at least 12 carbon atoms . The fatty acid can have, for example, up to 24 carbon atoms, for example up to 20 carbon atoms or up to 18 carbon atoms. More preferably, the active component is steroid-21-palmitate, myristate, laurate, caprate, caprylate or stearate. The most preferred active component according to the invention is the compound (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11β-hydroxy-21-palmitoyloxypregn-4-en-3,20-dione, i.e. Rylleponide palmitate. When the active component is an ester this must be able to be hydrolyzed the main active component. Surprisingly, the single-phase proliposome powder of the present invention facilitates the necessary hydrolysis in itself, although such crystalline state esters are generally not hydrolyzed. Where release by inhalation is desired, as much as possible the proliposome powder of the present invention should consist of particles having a diameter of less than 10 microns, for example 0.01-10 microns or 0.1-6 microns, for example 0.1- 5 microns, or agglomerates of such particles. Preferably at least 50% of the powder consists of particles within the range of the desired size. For example at least 60%, preferably at least 70%, more preferably at least 80% and more preferably at least 90% of the powder consists of any particles within the desired size range. or of agglomerates of such particles. The proliposome powders of the present invention need not contain other ingredients. However, pharmaceutical compositions comprising the powders of the present invention can also include other pharmaceutically acceptable additives such as a pharmaceutically acceptable adjuvant, diluent or carrier. These can be added to the proliposome composition after any micronization, or before any micronization, provided that the solvent has been completely removed. Any carrier is preferably a hydrophilic, crystalline substance. A preferred carrier is crystalline lactose monohydrate. Other suitable carriers include glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, estoquiosa, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine and betaine. The amount of additive present in the formulation can vary over a wide range. In some circumstances little or no additive may be required, although for example it is often preferable to dilute a powder with additive, to improve the properties of the powder for use in an inhaler. In the latter case, for example, at least 50%, for example at least 70%, or at least 80% of the formulation may constitute additives, the remainder being the polyphosoma powder. The percentage of additives may also depend on the potency of the biologically active compound and the optimum amount of powder for inhalation. Where an additive, for example a carrier, is present, the entire composition may be in the form of a particle within the range of respirable particle size. Alternatively the carrier may comprise larger particles for example with a mass median diameter greater than 20 microns, or may comprise agglomerates of smaller particles, the agglomerates have a mass average diameter of for example greater than 20 microns, so that in any case an ordered mixture of proliposome and carrier is formed. A further object of the present invention is to provide a process for the preparation of the proliposome powder of the present invention, that is, a process that produces the proliposome powder in a single phase. Accordingly, the present invention also provides a process for the preparation of a proliposome powder for inhalation, which comprises dissolving a lipid or mixture of lipids, tocopherol and a lipophilically active component in a solvent, the lipid or lipid mixture has a phase transition temperature less than 37 ° C; obtaining a crystalline solvent matrix and a single lipid phase in its vitreous state to freeze the solution, the freezing is carried out at a temperature lower than the phase transition temperature of the lipid phase; and evaporating the frozen solvent at a temperature lower than the phase transition temperature of the lipid phase. The freezing of the solution and the evaporation of the solvent can be carried out by conventional methods, for example in a conventional lyophilizer. For example, the solution of lipids, tocopherol and biologically active component can be poured into the shelves of a lyophilizer and the temperature can be lowered to freeze the solution. The evaporation of the solvent can then be achieved, for example, by lowering the pressure in the lyophilization chamber; the resulting powder can be detached from the chamber shelves and optionally passed through a sieve. "If necessary, the lyophilized powder can be subjected to further processing to obtain particles within the range of respirable particle size, for example the lyophilized powder can be micronized to give respirable particles, for example using an air jet mill. Freezing of the solution of the biologically active component, tocopherol and lipid is carried out in such a way that it produces a single lipid phase in the frozen solvent matrix.The production of a single lipid phase is controlled by the final temperature and the freezing speed of the solution, the optimal freezing speed of any particular solution will be somewhere between the time needed for the crystallization of the solvent in question and the time necessary for the crystallization of the lipids, tocopherol and the active component and can be determined by a skilled in the art, simply by trial and error. The optimum final temperature should be 10-20 ° C lower than the vitreous transition temperature of the lipid phase. For example, a powder X-ray method can be used to verify the crystallinity and differential scanning calorimetry can be used to verify the degree of incorporation of the biologically active component into the liposomes after hydration. The solvent must have the capacity to dissolve the lipids, tocopherol and the biologically active component completely, since it is essential that all the components are in solution before freezing to avoid precipitation or separation of phases, which will give rise to dust with more of a phase. In addition, the solvent must be toxicologically acceptable, have an appropriate freezing point and preferably a high vapor pressure. The solvent may be, for example, an organic solvent, for example an alcohol, a mixture of aqueous and organic solvents. The preferred solvent for use in the present invention is tertiary butanol. The powder can be agglomerated optionally in small spheres, to control the cohesiveness of the powder. The spheres should preferably not be larger than 1 mm in diameter; the larger spheres of this can be removed, for example, by sieving. Any agglomerates should be friable, so that they can be easily de-agglomerated, for example in the air flow generated in a powder inhaler. The proliposome powder of the present invention is useful for the local or systemic treatment of diseases and can be administered for example via the upper and lower respiratory tract, including through the nasal route. Therefore, the present invention also provides the proliposome powder for use in therapy; the use of proliposome powder in the manufacture of a medicament for the treatment of diseases via the respiratory tract; and a method for treating a patient in need of therapy, which comprises administering to the patient a therapeutically effective amount of the proliposome powder of the present invention. For example, the proliposome powder of the present invention can be used in the treatment of inflammatory diseases in the respiratory tract, for example asthma, rhinitis, alveolitis, bronchiolitis and bronchitis. Administration to the respiratory tract can be effected for example using a dry powder inhaler or a pressurized aerosol inhaler. Suitable dry powder inhalers include those inhalers, for example the single-dose inhaler known by the trademark Monohaler® and multi-dose inhalers, for example, a multi-dose, respiratory-powered dry powder inhaler, such as the inhaler known by the Turbuhaler brand. Although the proliposome powder of the present invention is particularly adapted to be administered by inhalation, it may also be included in formulations adapted for other forms of delivery. For example, oral, topical and injectable formulations can be prepared for use in the treatment of, for example, inflammatory diseases of the joints, for example arthritis, skin diseases and intestinal diseases.
The following Examples are intended to illustrate, but not limit, the scope of the present invention. The parts are in weight.
Example 1 Rofleponide palmitate (10 parts), DPPC (63 parts), DMPC (24 parts), NaDPPG (3 parts), and racemic α-tocopherol (0.1 parts) in tertiary butanol (1300 parts) at 80 ° C were dissolved. . The solution was poured onto the shelves of a lyophilizer cooled to -35 ° C. The solution reached this temperature after about 30 minutes; then the pressure of the lyophilizer was reduced to induce the sublimation of the solvent. Although the sublimation speed could be adjusted by lowering the pressure and increasing the temperature, the temperature through the process was allowed to exceed -10 ° C. The lyophilization continued until all the solvent had been removed. The resulting powder was detached from the freeze dryer shelves and passed through a screen. This powder was micronized in an air jet mill at a particle size of the powder of less than 5 μm. The micronized powder was mixed with a lactose hydrate (20 parts of powder: 80 parts of lactose monohydrate) by a sieving process and the mixture was further homogenized by micronising at low pressure, in an air jet mill.
The powder mixture was agglomerated into spheres no larger than 1 mm, using standard techniques. The large spheres were removed by sieving. The agglomerated powder was filled in a Turbuhaler® dry powder inhaler. In separate experiments the amount of a-tocopherol in the previous formulation was changed to 0.06 parts and 0.6 parts, respectively. Surprisingly it was found that the proliposome formulations of Example 1 are more stable than equivalent formulations containing other antioxidants.
Dust Analysis The X-ray diffraction of the powder carried out on the powder mixture of Example 1 showed that it was not present in the crystalline state in the powder.
Incorporation of the active component in the liposomes The proliposome powders of Example 1. they were hydrated and the degree of incorporation of the active component was measured using differential scanning calorimetry methods. The DSC showed that the active component was completely incorporated into the liposomes.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (27)
1. A powder of proliposome, the powder is characterized in that it comprises discrete particles, each of which comprises. in a single phase (1) a biologically active component, (2) a stabilizing ratio of tocopherol, and (3) a lipid or lipid mixture having a phase transition temperature of less than 37 ° C.
2. The powder in accordance with the claim 1, characterized in that the tocopherol is α-tocopherol.
3. The powder in accordance with the claim 2, characterized in that the tocopherol is the racemic α-tocopherol.
4. The powder according to any of the preceding claims, characterized in that the tocopherol is present in a proportion of 0.05 to 1.0% by weight of the single phase.
5. The powder according to claim 4, characterized in that the tocopherol is present in a proportion of 0.1 to 0.6% by weight.
6. The powder according to any of the preceding claims, characterized in that it comprises one or more lipids selected from the group consisting of natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids.
The powder according to any of the preceding claims, characterized in that it comprises a mixture of lipids selected from the group consisting of SM / PC, SM / Cholesterol, ePC / Cholesterol, sPC / Cholesterol, PC / PS / Cholesterol, DMPC / DPPC, DMPC / DPPC / CH, DMPC / CH, DPPC / DOPC, DPPC / DOPC / CH, DLPC / DPPC, DLPC / DPPC / CH, DLPC / DMPC, DLPC / DMPC / CH, DOPC / DSPC, DPSM / DMSM, e-lecithin / Cholesterol and s-lecithin / Cholesterol.
8. The powder according to any of the preceding claims, characterized in that it comprises DPPC or DMPC, or a mixture of DPPC and DMPC.
9. The powder according to claim 8, characterized in that the mixture comprises at least 10% of DMPC.
The powder according to any of the preceding claims, characterized in that it additionally includes a charged lipid.
The powder according to claim 10, characterized in that the charged lipid is selected from the group consisting of dimyristoyl phosphatidylglycerol (DMPG), diphospalmitoyl phosphatidylglycerol (DPPG), dimyristoyl phosphatidic acid (DPPA) and stearylamine (SA).
The powder according to any of the preceding claims, characterized in that the active component comprises a glucocorticosteroid.
13. The powder in accordance with the claim 12, characterized in that the active component comprises a glucocorticosteroid which is esterified at position 21 with a fatty acid of at least 8 carbon atoms.
14. The powder in accordance with the claim 13, characterized in that the active component comprises a glucocorticosteroid which is esterified at position 21 with a fatty acid of at least 10 carbon atoms.
15. The powder according to claim 14, characterized in that the active component comprises a glucocorticosteroid-21-palmitate.
16. The powder according to claim 15, characterized in that the active component comprises rofleponide palmitate.
17. The powder according to any of the preceding claims, characterized in that at least 50% of the powder consists of particles having a diameter less than 10 microns.
18. The powder according to claim 17, characterized in that at least 50% of the powder consists of particles having a diameter of O.Ol-10 microns.
19. The powder according to claim 18, characterized in that at least 50% of the powder consists of particles having a diameter smaller than 0.1-6 microns.
20. The powder according to any of claims 17-19, characterized in that it comprises agglomerated particles.
21. A pharmaceutical composition, characterized in that it comprises a powder according to any of the preceding claims and a pharmaceutically acceptable carrier.
22. The pharmaceutical composition according to claim 21, characterized in that the carrier is crystalline lactose monohydrate.
23. The pharmaceutical composition according to any of claims 21 or 22, characterized in that the carrier comprises particles with an average mass diameter of less than 10 microns or agglomerates of such particles.
24. A dry powder inhaler device, characterized in that it contains a proliposome powder according to any one of the preceding claims.
25. The dry powder inhaler device according to claim 24, characterized in that the inhaler is a single dose inhaler.
26. A method for treating a patient in need of therapy with a given biologically active compound, characterized in that it comprises administering to the patient a therapeutically effective amount of a powder according to any one of claims 1 to 20 or a composition in accordance with any of claims 21 to 23.
27. The use of a powder according to any of claims 1-20 in the preparation of a formulation for use in therapy.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US884419 | 1997-06-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99011675A true MXPA99011675A (en) | 2000-05-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6045828A (en) | Powders for inhalation | |
CA1256798A (en) | System for administration of liposomes to mammals | |
EP0223831B1 (en) | Liposome inhalation method and system | |
AU729100B2 (en) | Proliposome powders for inhalation stabilised by tocopherol | |
CZ288146B6 (en) | Pharmaceutical aerosol preparation, process of its preparation and use | |
US20100119587A1 (en) | Solid lipidic particles as pharmaceutically acceptable fillers or carriers for inhalation | |
DE10043509A1 (en) | Solid peptide preparations for inhalation and their manufacture | |
MXPA99011675A (en) | Proliposome powders for inhalation stabilised by tocopherol | |
CZ466799A3 (en) | Proliposome powders stabilized by tocopherol for inhalation purposes | |
MXPA97004406A (en) | Proliposomas powders for inhalac | |
MXPA98004357A (en) | New combination | |
MXPA99011676A (en) | New combination of antiasthma medicaments |