CN110384681B - Nanometer preparation for pulmonary fibrosis and preparation method thereof - Google Patents
Nanometer preparation for pulmonary fibrosis and preparation method thereof Download PDFInfo
- Publication number
- CN110384681B CN110384681B CN201910688203.7A CN201910688203A CN110384681B CN 110384681 B CN110384681 B CN 110384681B CN 201910688203 A CN201910688203 A CN 201910688203A CN 110384681 B CN110384681 B CN 110384681B
- Authority
- CN
- China
- Prior art keywords
- mal
- drug
- peg
- pulmonary fibrosis
- protease
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 99
- 208000005069 pulmonary fibrosis Diseases 0.000 title claims abstract description 94
- 239000003814 drug Substances 0.000 claims abstract description 154
- 239000004365 Protease Substances 0.000 claims abstract description 150
- 229940079593 drug Drugs 0.000 claims abstract description 140
- 108091005804 Peptidases Proteins 0.000 claims abstract description 54
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 51
- 210000003097 mucus Anatomy 0.000 claims abstract description 33
- 230000028327 secretion Effects 0.000 claims abstract description 18
- 230000015556 catabolic process Effects 0.000 claims abstract description 10
- 238000006731 degradation reaction Methods 0.000 claims abstract description 10
- 210000002175 goblet cell Anatomy 0.000 claims abstract description 9
- 210000003437 trachea Anatomy 0.000 claims abstract description 9
- 239000002105 nanoparticle Substances 0.000 claims description 133
- 108090000526 Papain Proteins 0.000 claims description 86
- 230000001404 mediated effect Effects 0.000 claims description 86
- 229940055729 papain Drugs 0.000 claims description 86
- 235000019834 papain Nutrition 0.000 claims description 86
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 84
- 229960003073 pirfenidone Drugs 0.000 claims description 84
- 235000019419 proteases Nutrition 0.000 claims description 49
- 229910021645 metal ion Inorganic materials 0.000 claims description 42
- 239000002245 particle Substances 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 32
- 230000002209 hydrophobic effect Effects 0.000 claims description 25
- 238000011068 loading method Methods 0.000 claims description 22
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 20
- 229960003105 metformin Drugs 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 108010004032 Bromelains Proteins 0.000 claims description 10
- 235000019835 bromelain Nutrition 0.000 claims description 10
- 230000002300 anti-fibrosis Effects 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 230000036542 oxidative stress Effects 0.000 claims description 8
- 230000002441 reversible effect Effects 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 7
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 7
- 230000000975 bioactive effect Effects 0.000 claims description 7
- 229960001680 ibuprofen Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 238000004448 titration Methods 0.000 claims description 7
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 claims description 6
- 230000004761 fibrosis Effects 0.000 claims description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical group OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 6
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 5
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 4
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 4
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 4
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 4
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 4
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 4
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 4
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 4
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 4
- 229960000590 celecoxib Drugs 0.000 claims description 4
- 210000004027 cell Anatomy 0.000 claims description 4
- 230000008809 cell oxidative stress Effects 0.000 claims description 4
- 229960004544 cortisone Drugs 0.000 claims description 4
- 229960002448 dasatinib Drugs 0.000 claims description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001259 diclofenac Drugs 0.000 claims description 4
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002584 gefitinib Drugs 0.000 claims description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 4
- 229960002411 imatinib Drugs 0.000 claims description 4
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical group OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001346 nilotinib Drugs 0.000 claims description 4
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 4
- 229960000965 nimesulide Drugs 0.000 claims description 4
- 229960004378 nintedanib Drugs 0.000 claims description 4
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 4
- 229960004618 prednisone Drugs 0.000 claims description 4
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 4
- 229960000371 rofecoxib Drugs 0.000 claims description 4
- 229960003787 sorafenib Drugs 0.000 claims description 4
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 4
- 229960001796 sunitinib Drugs 0.000 claims description 4
- 239000010409 thin film Substances 0.000 claims description 4
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004066 trametinib Drugs 0.000 claims description 4
- 108010024636 Glutathione Chemical group 0.000 claims description 3
- SSISHJJTAXXQAX-ZETCQYMHSA-N L-ergothioneine Chemical group C[N+](C)(C)[C@H](C([O-])=O)CC1=CNC(=S)N1 SSISHJJTAXXQAX-ZETCQYMHSA-N 0.000 claims description 3
- 235000021466 carotenoid Nutrition 0.000 claims description 3
- 150000001747 carotenoids Chemical group 0.000 claims description 3
- 230000001413 cellular effect Effects 0.000 claims description 3
- 229940093497 ergothioneine Drugs 0.000 claims description 3
- 229960003180 glutathione Drugs 0.000 claims description 3
- 235000003969 glutathione Nutrition 0.000 claims description 3
- 235000019136 lipoic acid Nutrition 0.000 claims description 3
- -1 neproxen Chemical compound 0.000 claims description 3
- 229960002663 thioctic acid Drugs 0.000 claims description 3
- 108091005658 Basic proteases Proteins 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 3
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 claims 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims 2
- 108091005508 Acid proteases Proteins 0.000 claims 1
- 230000037319 collagen production Effects 0.000 claims 1
- 229950007440 icotinib Drugs 0.000 claims 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 235000008160 pyridoxine Nutrition 0.000 claims 1
- 239000011677 pyridoxine Substances 0.000 claims 1
- 229940011671 vitamin b6 Drugs 0.000 claims 1
- 230000004044 response Effects 0.000 abstract description 15
- 210000003456 pulmonary alveoli Anatomy 0.000 abstract description 6
- 230000004888 barrier function Effects 0.000 abstract description 5
- 229940126585 therapeutic drug Drugs 0.000 abstract description 5
- 230000008859 change Effects 0.000 abstract description 4
- 230000006378 damage Effects 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 239000002552 dosage form Substances 0.000 abstract 1
- 238000002156 mixing Methods 0.000 description 36
- 229920000642 polymer Polymers 0.000 description 25
- 102000015728 Mucins Human genes 0.000 description 17
- 108010063954 Mucins Proteins 0.000 description 17
- 210000004072 lung Anatomy 0.000 description 15
- 239000012153 distilled water Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 229940086436 papain 30 mg Drugs 0.000 description 10
- 108090000746 Chymosin Proteins 0.000 description 9
- 229920000954 Polyglycolide Polymers 0.000 description 9
- 230000003078 antioxidant effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 7
- 229920000747 poly(lactic acid) Polymers 0.000 description 7
- 229920001610 polycaprolactone Polymers 0.000 description 7
- 239000004632 polycaprolactone Substances 0.000 description 7
- 239000004626 polylactic acid Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 5
- 229940080701 chymosin Drugs 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- GNOLWGAJQVLBSM-UHFFFAOYSA-N n,n,5,7-tetramethyl-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=C(C)C=C2C(N(C)C)CCCC2=C1C GNOLWGAJQVLBSM-UHFFFAOYSA-N 0.000 description 5
- 229960002009 naproxen Drugs 0.000 description 5
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000029523 Interstitial Lung disease Diseases 0.000 description 3
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000003367 anti-collagen effect Effects 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 229960001433 erlotinib Drugs 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000004043 responsiveness Effects 0.000 description 3
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000008369 airway response Effects 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 210000002588 alveolar type II cell Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000012904 visual particle Substances 0.000 description 1
Images
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
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a nano preparation for pulmonary fibrosis and a preparation method thereof, namely a protease modified nano preparation with mucin degradation and a carrier thereof. The nanometer preparation is released in a response manner by means of the characteristic that the protease degrades the mucin, so that the therapeutic drug is delivered to the damaged part of the pulmonary fibrosis efficiently, the anti-pulmonary fibrosis drug is delivered in a highly efficient targeted manner, and the aim of highly efficiently treating the pulmonary fibrosis is fulfilled. Aiming at the problem that the deep delivery is difficult in the trachea and inhalation administration dosage forms on the basis of the market at present, namely, mucus is excessively secreted by goblet cells in the airways to cause that a large amount of medicaments are difficult to deliver to the deep part of the alveolus to play a role, the change of the excessive secretion of the mucus in the microenvironment of the pulmonary fibrosis airways is provided, the nano preparation which is released in a response mode and can efficiently pass through the airway barrier is constructed, the therapeutic medicaments are efficiently delivered to the pulmonary fibrosis damage part in the deep part of the alveolus, and the efficiency of the nano preparation reaching the deep part of the alveolu.
Description
Technical Field
The invention discloses a nano preparation for pulmonary fibrosis and a preparation method thereof, belonging to the technical field of medicines.
Background
Idiopathic Pulmonary Fibrosis (IPF) is one of the severe and common forms of Interstitial Lung Disease (ILD). ILD is a progressive lung disease that causes pulmonary fibrosis as the disease progresses to a terminal stage. During the course of the disease, damaged alveolar epithelial cells secrete a large amount of inflammatory factors, which activate fibroblast hyperproliferation and transformation to myofibroblasts, resulting in excessive deposition of extracellular matrix (ECM), destruction of lung parenchyma, and finally death of patients due to respiratory failure. Although the novel anti-fibrotic drug Pirfenidone (PFD) has been approved for clinical treatment in countries such as europe, certain problems still remain. Since pirfenidone is commonly used as an oral formulation for treating IPF, its bioavailability is low and its administration in large amounts may cause side effects and even toxicity to other organs. Therefore, the proposed strategy of delivering drugs to the lungs by inhalation to achieve efficient delivery of the drugs to the lungs provides new ideas and methods for IPF treatment.
In the form of inhaled administration, the efficiency of drug delivery is generally low due to the limitation of the physiological structure of the airways. The mucus layer in the airways is the first barrier that must be overcome for tracheal or inhalational administration. The mucus layer is mainly composed of dense reticular mucin fibers, and mucin is a negatively charged biomacromolecule containing high-density glycan. In patients with advanced obstructive pulmonary disease and fibrosis, mucus secreted by airway goblet cells serves as part of the clearance system, trapping drugs that reach the airway by steric hindrance or adhesion and subsequently clearing them from the mucus, resulting in a reduction in the amount of drug reaching the deep lung, resulting in a reduction in the therapeutic effect of the drug on the disease. Even though the drug may pass through the mucus layer, the alveoli still present another barrier, the macrophage phagocytic system in the lipid layer, which is a protective defense barrier for type II alveolar epithelial cells (AT II). A large number of drugs are engulfed by macrophages in the lipid layer and are not therapeutically effective.
Therefore, for drugs to be effective deep in the lung, these obstacles must be effectively overcome during delivery to achieve the desired therapeutic effect.
Disclosure of Invention
The purpose is as follows: in order to overcome the defects in the prior art, the invention provides an anti-fibrosis drug nano preparation and a preparation method thereof, and the efficiency of the nano preparation reaching the deep part of alveolus is improved.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a nanometer preparation carrier comprises Y-PEG-MAL and protease X modified with mucin degradation, wherein the protease X modified with mucin degradation is connected with the hydrophilic end of the Y-PEG-MAL to form Y-PEG-MAL-X;
wherein Y is selected from one or more of PLGA, PLA, PGA, PCL, PC and PS; the protease X is selected from one or more of bromelain, papain, acidic or alkaline protease, and chymosin.
Furthermore, the nano preparation carrier also comprises a medicine V coordinated with the metal ion W to form Y-PEG-MAL-X-W-V (PPV), and the Y-PEG-MAL, the protease X modified with mucin degradation and the medicine V coordinated with the metal ion W form the nano preparation carrier;
wherein W is a metal ion selected from Mn2+, Zn2+, Fe2+, Fe3+, Cu2+, Mg2+，Ti4+, Zr4+, Co2+,Al3+，Ca2+One or more of them. More preferably, Fe is used as the metal ion W3+As a coordinating metal ion.
On the other hand, the invention also provides a nano preparation, and the nano preparation carrier is adopted to load the hydrophobic anti-pulmonary fibrosis drug Z. More specifically, the nano preparation comprises:
Z-Y-PEG-MAL-X (PPZ) is formed by Y-PEG-MAL and a medicament Z coated by a modified mucin-degraded protease X carrier;
Z-Y-PEG-MAL-X-W-V (PPZV) is formed by encapsulating a drug Z by Y-PEG-MAL, a medicament V modified with mucin degradation protease X and coordinated with metal ions W.
The hydrophobic anti-pulmonary fibrosis drug Z is one or more of anti-inflammatory factor secretion or anti-fibrosis drugs/drugs for relieving cell oxidative stress, the anti-inflammatory factor is a drug or bioactive molecule for reducing cell secretion inflammatory factors and inhibiting collagen generation, and the drug for relieving cell oxidative stress is a drug or bioactive molecule for reducing cell singlet oxygen, superoxide, peroxide and the like. The hydrophobic anti-pulmonary fibrosis drug Z is selected from one or more of imatinib, gefitinib, erlotinib, dasatinib, sunitinib, sorafenib, nilotinib, trametinib, ibuprofen, naproxen, diclofenac, naproxone, ibuprofen, nimesulide, rofecoxib, celecoxib, nintedanib, pirfenidone, cortisone, prednisone and cyclosporine.
The loaded anti-pulmonary fibrosis drug can simultaneously comprise more than one or one of anti-collagen generation and inflammatory factor secretion reduction, and the anti-oxidation drug in the complex can simultaneously comprise more than one or one antioxidant for reducing singlet oxygen and superoxide secretion. The loaded anti-pulmonary fibrosis drug has certain hydrophobicity, the anti-pulmonary fibrosis drug with certain hydrophobicity is loaded through the hydrophobic section Y in the amphiphilic block copolymer, and long circulation of the polymer micelle in vivo is realized through PEG; the antioxidant medicine in the complex has certain hydrophilicity, and the purpose of reducing mucus secretion is achieved by inhibiting oxidative stress of goblet cells, so that the effective delivery of the nanoparticles is improved. The modified protease X has the function of degrading mucin, and the aim of efficiently delivering the mucin in the lung is fulfilled by avoiding being cleared by mucus. The anti-pulmonary fibrosis drug achieves the purpose of treating pulmonary fibrosis by inhibiting the expression of collagen and/or inhibiting the secretion of inflammatory factors at the damaged part of the lung through the deep lung delivery of the anti-oxidative drug.
More preferably, the drug V is metformin and the hydrophobic anti-pulmonary fibrosis drug Z is pirfenidone. The anti-pulmonary fibrosis nano preparation is loaded with pirfenidone through a hydrophobic block and is loaded with Fe3+The coordination adsorption of metformin is used as a therapeutic system for pulmonary fibrosis. By adopting double drugs to synergistically regulate and control pulmonary fibrosis microenvironment, a new treatment strategy is provided for efficient delivery of anti-pulmonary fibrosis drugs.
Wherein, the loaded hydrophobic anti-pulmonary fibrosis drug can simultaneously comprise a plurality of or one selected from drugs or active molecules for reducing the expression of inflammatory factors or resisting the generation of collagen. Antioxidants are drugs or bioactive molecules that reduce singlet oxygen and superoxide in response to oxidative stress at the cellular level.
1) Antioxidant, including active components of metformin, glutathione, α -lipoic acid, carotenoid and ergothioneine;
2) anti-collagen or inflammatory factor producing drugs: imatinib, gefitinib, erlotinib, dasatinib, sunitinib, sorafenib, nilotinib, trametinib, ibuprofen, naproxen, diclofenac, naproxen, ibuprofen, nimesulide, rofecoxib, celecoxib, nintedanib, pirfenidone, cortisone and prednisone, cyclosporine.
The anti-pulmonary fibrosis drug comprises a drug or a bioactive molecule for relieving oxidative stress at a cellular level and reducing intracellular singlet oxygen or superoxide, and a drug or a bioactive molecule for inhibiting the expression of inflammatory factors or collagen.
Specifically, the preparation method of Z-Y-PEG-MAL-X-W-V (PPZV) comprises the following steps:
mixing hydrophobic anti-pulmonary fibrosis drug Z and Y-PEG-MAL, and preparing nano-particle Z-Y-PEG-MAL (PPZ) loaded with anti-pulmonary fibrosis drug by a film dispersion method, a direct titration method or a reverse solvent method;
mixing metal ions W, a drug V and a protease X according to a certain proportion to form a metal ion W-mediated complex X-W-V, reacting nanoparticles Z-Y-PEG-MAL (PPZ) loaded with anti-pulmonary fibrosis drugs with the metal ion W-mediated complex X-W-V through sulfydryl on the protease X and MAL exposed from a nanoparticle shell, and covalently modifying a coordination compound containing metal ions W at the outer ends of the nanoparticles to form Z-Y-PEG-MAL-X-W-V; the mucus layer excessively secreted in the air permeability tube can be efficiently penetrated by the nanoparticles; the drug V released in a responsive manner can relieve the oxidative stress of goblet cells, reduce the secretion of mucus and improve the delivery efficiency of nanoparticles; the medicine delivered to the deep layer can play the role of anti-fibrosis so as to achieve the aim of treating fibrosis.
In the reaction, the mass ratio of the added Y-PEG-MAL polymer nanoparticles to the protease X is 5: 1-10: 1; more preferably 5: 1.
In the reaction, the mass ratio of the added Y-PEG-MAL polymer nanoparticles to the anti-pulmonary fibrosis drug Z is 20: 1-5: 1; more preferably 10: 1.
In the reaction, Fe is added3+The mass ratio of the medicine V is 40: 1-10: 1; more preferably 30: 1.
Specifically, the preparation method of Z-Y-PEG-MAL-X (PPZ) is as follows:
mixing hydrophobic anti-pulmonary fibrosis drug Z and Y-PEG-MAL, and preparing nano-particle Z-Y-PEG-MAL (PPZ) loaded with anti-pulmonary fibrosis drug by a film dispersion method, a direct titration method or a reverse solvent method;
step (2), carrying out grafting reaction on a nanoparticle Z-Y-PEG-MAL (PPZ) loaded with an anti-pulmonary fibrosis drug and a protease X, and covalently modifying the protease X at the outer end of the nanoparticle through the reaction of a sulfydryl on the protease X and the MAL exposed on the nanoparticle shell; the covalent modification of protease X by the nanoparticles is beneficial to the nanoparticles to efficiently penetrate through mucus layers excessively secreted in the trachea; the medicine delivered to the deep layer can play the role of anti-fibrosis so as to achieve the aim of treating fibrosis.
In the reaction, the mass ratio of the added Y-PEG-MAL polymer nanoparticles to the protease X is 5: 1-10: 1; more preferably 5: 1.
In the reaction, the mass ratio of the added Y-PEG-MAL polymer nanoparticles to the anti-pulmonary fibrosis drug Z is 20: 1-5: 1; more preferably 10: 1.
The preparation method of Y-PEG-MAL-X-W-V (PPV) is as follows:
firstly, preparing nano PP particles from Y-PEG-MAL by a film dispersion method, a direct titration method or a reverse solvent method;
mixing metal ions W, a drug V and a protease X according to a certain proportion to form a metal ion W-mediated complex X-W-V, reacting nanoparticles PP and the metal ion W-mediated complex X-W-V with MAL exposed from a nanoparticle shell through sulfydryl on the protease X, and covalently modifying a coordination compound containing the metal ions W at the outer ends of the nanoparticles to form Y-PEG-MAL-X-W-V; the mucus layer excessively secreted in the air permeability tube can be efficiently penetrated by the nanoparticles; the drug V released in a responsive manner can relieve the oxidative stress of goblet cells, reduce the secretion of mucus and improve the delivery efficiency of nanoparticles.
In the reaction, the mass ratio of the added Y-PEG-MAL polymer nanoparticles to the protease X is 5: 1-10: 1; more preferably 5: 1.
In the reaction, the mass ratio of the added metal ions W to the added medicine V is 40: 1-10: 1; more preferably 30: 1.
As a control, PP/drug was prepared as follows:
firstly, dissolving an anti-pulmonary fibrosis drug (pirfenidone) in DMSO, wherein the ratio of Y-PEG-MAL to the drug is 100: 1-5: 1, the scheme is 10:1 is more preferable, the encapsulation rate is 71.6%, and the drug loading rate is 5.4%.
And (3) mixing the product obtained in the step (2) with Y-PEG-MAL, and preparing the nanoparticles loaded with the anti-pulmonary fibrosis drug by a thin film dispersion method, a direct titration method or a reverse solvent method.
Preferably, in the anti-pulmonary fibrosis drug nano preparation, Y-PEG-MAL, the molecular weight range of Y is 1000-50000, and the molecular weight range of PEG is 200-10000. More preferably, PEG with a molecular weight of 2000 is used.
Preferably, the anti-pulmonary fibrosis drug nano preparation has 5-25% of drug-loading rate and 20-500 nm of particle size.
The invention requires the application of the nanometer preparation carrier and the anti-pulmonary fibrosis drug nanometer preparation in preparing drugs for treating pulmonary fibrosis diseases.
The invention provides an enzyme-mediated response type high-efficiency delivery therapeutic drug to achieve the purpose of treating pulmonary fibrosis. Is characterized in that the carrier comprises chemical drug loading components and airway response type degradation and effective delivery components. The chemical drug loading component is an amphiphilic polymer with maleimide modification at the tail end, and the response type degraded mucin component is sulfhydrylation polypeptide.
The invention relates to a mucin-degrading protease-modified nano preparation Y-PEG-MAL, wherein Y is selected from PLGA, PLA, PGA, PCL, PC and PS. The hydrophobic segment in the amphiphilic block copolymer is used for realizing the loading of the anti-fibrosis drug with certain hydrophobicity, and the coordination is used for realizing the loading of the anti-oxidation drug. The efficiency of the nanometer preparation reaching the deep part of the pulmonary alveoli is further improved by overcoming the mucus layer barrier in the air passage through the protease degraded by the mucin, and a new treatment strategy is provided for the efficient delivery of the anti-pulmonary fibrosis drug.
Has the advantages that: the invention provides an enzyme-mediated response type high-efficiency delivery therapeutic drug to achieve the purpose of treating pulmonary fibrosis, and compared with the prior art, the invention has the following advantages: the Y-PEG-MAL in the carrier, wherein Y is a hydrophobic segment, can well realize the entrapment of fat-soluble drugs, the PEG in the carrier can prolong the circulation time of the carrier in blood, metal ions W in the modified carrier in the carrier can responsively release drugs V under the condition that mucus subacid protease X is highly expressed in mucin, the mucus secretion is reduced by regulating and controlling the oxidative stress of goblet cells, so that the delivery efficiency of the nano preparation is improved, and the drugs expressed by anti-fibrosis or anti-inflammatory factors reaching the deep part of the lung can achieve the purpose of treating pulmonary fibrosis by reducing the expression of inflammatory factors or inhibiting the secretion of collagen. The carrier can realize the high-efficiency lung delivery of nano-drugs, the dual responsiveness of enzyme response and acid response realizes the high-efficiency release of anti-oxidative stress drugs, and the nanoparticles reaching the deep part of the alveolus can effectively play a role in resisting the development of pulmonary fibrosis. The invention utilizes microenvironment with high mucin secretion in pulmonary fibrosis trachea to efficiently deliver therapeutic drugs to pulmonary fibrosis injury parts through response type release nano preparations, and simultaneously utilizes anti-pulmonary fibrosis drug Z to inhibit fibrosis progress, thereby providing a new approach and strategy for efficient delivery of anti-pulmonary fibrosis drugs and drug design for effectively treating pulmonary fibrosis. According to the invention, the protease X is used for modifying the nano-carrier Y-PEG-MAL to encapsulate the drug Z, the metal ion W coordinates the nano-preparation of the drug V and the carrier thereof, firstly, during the occurrence process of pulmonary fibrosis, mucus secretions in the trachea are obviously increased, the nano-preparation reaches a mucus layer through trachea administration, and the therapeutic drug is efficiently delivered to the pulmonary fibrosis injury part through the response type release nano-preparation, so that the removal of mucus in the trachea is avoided. The metal ions WV are dissociated from the nano preparation PPZ under the slightly acidic condition of mucus to release the medicine V, mucus secretion is reduced by regulating and controlling oxidative stress of goblet cells to improve the delivery efficiency of the nano preparation, the nano preparation PPZ exposing protease X is released, and the nano preparation PPZ rapidly penetrates through the mucus layer of the airway to reach the deep part of the lung under the condition of high expression of mucin in the mucus layer of the airway to improve the treatment effect of the anti-fibrosis medicine. At present, the delivery by using the hydrophobic block loaded with the hydrophobic drug in the amphiphilic block copolymer is one of common methods, PLGA (polylactic acid-polyglycolic acid), PLA (polylactic acid), PGA (polyglycolide), and PCL (polycaprolactone) are common hydrophobic blocks with good biocompatibility, are often used as hydrophobic cores in the amphiphilic block copolymer, and have good affinity for most hydrophobic drugs. Meanwhile, the antioxidant is encapsulated in a coordination mode, and the complex has good stability under normal physiological conditions, so that the aim of response type release can be fulfilled under the condition of slightly acid in a mucus layer.
In the invention, protease X modified Y-PEG (X is a hydrophobic segment, and X is PLGA, PLA, PGA, PCL) nanoparticles are used, the loading of double drugs/single drugs with certain hydrophobicity is realized through the hydrophobic segment in an amphiphilic block copolymer, the long circulation of a polymer micelle in a body is realized through PEG, and/or the nano preparation of a metal ion W coordination drug V and a carrier thereof can be released in a response mode in a mucus layer, so that the efficient delivery of the lung is realized.
Drawings
FIG. 1 is a schematic flow diagram of the preparation of an example nano-formulation;
FIG. 2 is the optimum ratio of each component of the nano-formulation prepared in the example;
FIG. 3 is a graph of the particle size of the nanoformulation for each of the formulations of the examples;
FIG. 4 is a potential diagram of the nanoformulation of each of the formulations of the examples;
FIG. 5 is a transmission electron micrograph of mucin (papain) according to the example;
FIG. 6 is a transmission electron micrograph of papain specifically degraded by the protease in the example formulation;
FIG. 7 is a graph of the nanoparticle size of the nanoformulations prepared in the examples after their release in response to various time points under enzyme-sensitive conditions;
FIG. 8 is a graph of the nanoparticle size of the nano-formulations prepared in the example after response-type release at different time points under acid-sensitive conditions;
FIG. 9 is a graph of the nanoparticle size of the nanoformulations prepared in the examples after their response-type release at different time points in the presence of both acid and enzyme;
fig. 10 is an analysis of the effect of different nano-preparations in reversing pulmonary fibrosis, which is examined at the in vivo level by the nano-carriers prepared in the examples.
Detailed Description
The invention will be further described with reference to the following drawings and specific embodiments.
Example 1 synthesis and preparation of nano-formulation ingredients, as shown in fig. 1, fig. 2:
preparation of PLGA-PEG-MAL nanoparticles entrapping double drugs/single drug
The invention preferably adopts a film dispersion method to prepare PLGA-PEG-MAL nanoparticles coated with anti-pulmonary fibrosis drug Z. The preparation method comprises the following steps:
100 mg of PLGA-PEG-MAL and 10 mg of anti-pulmonary fibrosis drug Z are weighed and respectively dissolved in 2 mL of ethyl acetate solution and are ultrasonically dissolved. While stirring, the ethyl acetate solution drops were spun dry by a rotary evaporator, then dissolved by adding 3mL of distilled water with ultrasound for 30 min, and centrifuged at 2500 rpm/min for 20 min to remove the unbound free drug. The nanoparticles were concentrated to a volume of 500 μ L using an ultrafiltration tube of molecular weight 10000.
Antioxidant anti-fibrotic drugs:
1) antioxidant, including active components of metformin, glutathione, α -lipoic acid, carotenoid and ergothioneine;
2) anti-collagen or inflammatory factor producing drugs: imatinib, gefitinib, erlotinib, dasatinib, sunitinib, sorafenib, nilotinib, trametinib, ibuprofen, naproxen, diclofenac, naproxen, ibuprofen, nimesulide, rofecoxib, celecoxib, nintedanib, pirfenidone, cortisone and prednisone, cyclosporine.
Preparation of polymer nanoparticles modified by papain and metal ion W-mediated complex
1. Has papain and Fe3+Mediated byPreparation of polymer nanoparticles modified by complex
Metal ion Fe3+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to form enzyme and Fe at the outer end of the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated protease Z.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Fe) prepared by the method3+Mediated complex) and PPZV/(containing pirfenidone, papain and Fe simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Fe at the same time)3+Mediated complex), as shown in fig. 3 and 4, the nano preparation has uniform particle size distribution, uniform shape and obvious core-shell structure.
2. Has papain and Mn2+Mediated complex modified polymer nanoparticle preparation
Metal ions Mn2+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Mn2+The mediated complex is covalently combined with a coordination compound of Mn2+ in the covalent bonding of the papain of the nanoparticles through the reaction of sulfydryl and the MAL exposed from the nanoparticle shell; and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Mn) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Mn simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The formulation of this example(PPZV/(containing pirfenidone, papain and Mn at the same time)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
3. Has papain and Zn2+Mediated complex modified polymer nanoparticle preparation
Metal ion Zn2+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Zn2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to form papain and Zn in the nanoparticle2+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone containing) and PPV/(papain and Zn containing) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Zn simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Zn at the same time)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
4. Has papain and Fe3+Mediated complex modified polymer nanoparticle preparation
Metal ion Fe3+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain papain and Fe in the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(containing papain and pirfenidone) prepared by the methodNicotine), PPV/(containing papain and Fe)3+Mediated complex) and PPZV/(containing pirfenidone, papain and Fe simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Fe at the same time)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
5. Has papain and Cu2+Mediated complex modified polymer nanoparticle preparation
Metal ion Cu2+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, mixing the nanoparticles loaded with anti-pulmonary fibrosis drug pirfenidone with Cu2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to form papain and Cu in the nanoparticle2+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Cu) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Cu simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Cu simultaneously)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
6. Has papain and Mg2+Mediated complex modified polymer nanoparticle preparation
Metal ion Mg2+Mixing 30Mg, metformin 2 Mg and papain 30Mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Mg2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to form papain and Mg in the nanoparticle2+Covalently bonding the coordination compound of (a);and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Mg) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Mg simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Mg at the same time)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
7. Has papain and Si2+Mediated complex modified polymer nanoparticle preparation
Metal ion Si2+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Si2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to form papain and Si in the nanoparticle2+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Si) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Si simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Si simultaneously)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
8. Has papain and Co2+Mediated complex modified polymer nanoparticle preparation
Metal ion Co2+30mg of the mixture, 2 mg of metformin and 30mg of papain are filled in distilled waterMixing the mixture overnight, and mixing the nanoparticles loaded with the anti-pulmonary fibrosis drug pirfenidone with Co2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain papain and Co in the nanoparticle2+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Co) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Co simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Co at the same time)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
9. Has papain and Al3+Mediated complex modified polymer nanoparticle preparation
Metal ion Al3+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with anti-pulmonary fibrosis drug pirfenidone with Al3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain papain and Al on the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Al) prepared by the method3+Mediated complex) and PPZV/(containing pirfenidone, papain and Al simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Al simultaneously)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
10. Has papain and Ca2+Mediated complex modified polymer nanoparticle preparation
Metal ion Ca2+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Ca2+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to generate papain and Ca in the nanoparticle2+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone containing) and PPV/(papain and Ca containing) prepared by the method2+Mediated complex) and PPZV/(containing pirfenidone, papain and Ca simultaneously)2+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Ca simultaneously)2+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
(II) having proteases X and Fe3+Mediated complex modified polymer nanoparticle preparation
1. Has papain and Fe3+Mediated complex modified polymer nanoparticle preparation
Mixing Fe3+Mixing 30mg, metformin 2 mg and papain 30mg in distilled water overnight, and mixing the nanoparticles loaded with pirfenidone for resisting pulmonary fibrosis with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain papain and Fe in the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated papain.
PP/(pirfenidone), PPZ/(papain and pirfenidone) and PPV/(papain and Fe) prepared by the method3+Mediated complexesAnd PPZV/(containing pirfenidone, papain and Fe at the same time)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, papain and Fe at the same time)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
2. Having acid/base proteases and Fe3+Mediated complex modified polymer nanoparticle preparation
Mixing Fe3+Mixing 30mg, metformin 2 mg and acid/alkali protease 30mg in distilled water thoroughly overnight, mixing the nanoparticles loaded with anti-pulmonary fibrosis drug pirfenidone with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain acid/alkali protease and Fe in the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending the mixture for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated acid/alkali protease.
PP/(pirfenidone), PPZ/(acid/alkali protease and pirfenidone), PPV/(acid/alkali protease and Fe prepared by the method3+Mediated complex) and PPZV/(containing pirfenidone, acid/alkali protease and Fe simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. This example formulation (PPZV/(containing pirfenidone, acid/base protease and Fe at the same time)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
3. Has bromelain and Fe3+Mediated complex modified polymer nanoparticle preparation
Mixing Fe3+Mixing 30mg, metformin 2 mg and bromelain 30mg in distilled water overnight, and mixing the nanoparticles loaded with anti-pulmonary fibrosis drug pirfenidone with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to generate bromelain and Fe in the nanoparticle3+Covalently bonding the coordination compound of (a); centrifuging and resuspending for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted sulfydrylA basified bromelain.
PP/(pirfenidone), PPZ/(bromelain and pirfenidone) and PPV/(bromelain and Fe) prepared by the method3+Mediated complex) and PPZV/(containing pirfenidone, bromelain and Fe simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. This example formulation (PPZV/(containing pirfenidone, bromelain and Fe at the same time)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
4. Has rennin and Fe3+Mediated complex modified polymer nanoparticle preparation
Mixing Fe3+Mixing 30mg, metformin 2 mg and chymosin 30mg in distilled water thoroughly overnight, mixing the nanoparticles loaded with anti-pulmonary fibrosis drug pirfenidone with Fe3+The mediated complex reacts with MAL exposed by sulfydryl and the shell of the nanoparticle to obtain chymosin and Fe in the nanoparticle3+Covalently bonding the coordination compound of (a); and centrifuging and resuspending for three times at 10000 rpm/min, collecting the prepared nanoparticles, and removing unreacted thiolated chymosin.
PP/(pirfenidone), PPZ/(containing rennin and pirfenidone), PPV/(containing rennin and Fe) prepared by the method3+Mediated complex) and PPZV/(containing pirfenidone, rennin and Fe simultaneously)3+Mediated complex) with drug loading of 5-25% and particle size of 50-500 nm. The preparation of this example (PPZV/(containing pirfenidone, chymosin and Fe at the same time)3+Mediated complex), the particle size distribution of the nano preparation is uniform, and the shape is uniform.
Example 2 papain can specifically degrade papain
Papain, an analogue of mucin in the mucus layer, was taken as a study object as described in example 1, and added with proteases at different concentrations for 24 h, and morphological changes of papain under a Transmission Electron Microscope (TEM) were photographed. The results of transmission electron microscopy show that the papain and the mucin can be degraded by the mucin after 24 hours of interaction, as shown in fig. 5 and fig. 6.
Example 3 assay of the responsive Release of Nanoparticulates under slightly acid and enzyme sensitive conditions
PP/(pirfenidone), PPZ/(protease X and pirfenidone) and PPV/(protease X and Fe) were prepared as described in example 13+Mediated complex) and PPZV/(containing pirfenidone, protease X and Fe simultaneously)3+Mediated complex). After concentrating the nano preparation to 200 mu L, adding 1mL of PBS with pH 6.8, placing the mixture at 4 ℃ for 24 h, and characterizing the particle size and the potential of the nano particles in different environments by using a particle size meter.
(1) After the particle size is measured by a Malverapaceae visual particle size analyzer, the particle size is inspected again after the action of the micro-acid and the enzyme, and the change condition of the particle size is observed;
the particle size data obtained in this example are shown in fig. 7, 8 and 9, and the change in particle size of the nanoparticles before and after the stimulation was examined. Before the micro-acid environment and the enzyme response type stimulation do not exist, the particle size distribution of the nanoparticles is approximately similar, after the micro-acid environment and the enzyme response type stimulation, the nanoparticles release smaller nanoparticles through micro-environment responsiveness, and meanwhile, Fe3+The mediated complex is released responsively to the mucus layer, while smaller nanoparticles can reach the deep lung by osmosis.
And detecting the potential change condition of the nanoparticles before and after stimulation. Fe before no slightly acidic environment and enzyme response type stimulation3+The potential of the mediated complex nano-particle is positive or low, after the micro-acidity and enzyme stimulation, the nano-particle releases smaller nano-particles through micro-environment responsiveness, and simultaneously Fe3+The mediated complex is released to a mucus layer in a responsive manner, while smaller nanoparticles are mainly electronegative, and other researches prove that the nanoparticles formed by PLGA-PEG self-assembly are mainly electronegative, further showing that the constructed system can achieve the purpose of releasing in a responsive manner under the dual conditions of high expression of micro-acid and enzyme.
Example 4 the effect of the nanopreparative formulations PP, PPZ, PPV, PPZV on the treatment of over-reversed pulmonary fibrosis was analyzed.
The nanoformulations PP, PPZ, PPV, PPZV were prepared as described in example 1. Z is pirfenidone and V is metformin.
Firstly, a molding test of a pulmonary fibrosis model is carried out by adopting male C57BL/6 mice with the age of 6-8 weeks, and the lungs of the mice are directly molded by using a tracheal intubation method during molding. And (3) when the model is made, bleomycin hydrochloride is used as a mouse pulmonary fibrosis inducer, the concentration is 2 USP/Kg, and after three weeks, the effect analysis of the nanometer preparations PP, PPZ, PPV and PPZV in the treatment of over-reversed pulmonary fibrosis is continuously carried out. Mice molded for three weeks were randomly assigned to 5 groups of 5 mice each, and the nanopreparations PP, PPZ, PPV, PPZV and physiological saline were injected through the tail vein, respectively, with the injected drug Z being 2 μ g/g mouse body weight as a standard. Reversal of pulmonary fibrosis effect for different nanopreparations after 4 weeks of treatment the effect of different dosing groups against pulmonary fibrosis was analyzed by H & E staining. From the H & E staining results, it can be seen that the final preparation PPZV group has a significantly reduced alveolar space, a uniform alveolar wall thickness, and a significantly reduced degree of pulmonary fibrosis, as compared to the BLM group, and can achieve the purpose of treating pulmonary fibrosis, indicating that efficient lung targeting and dual drug combination treatment can be achieved by mediating the circulating fiber cell nano-formulation delivery system to effectively reverse pulmonary fibrosis, and the anti-fibrosis effects of the preparation groups are compared with PPZV > PPZ > PPV > PP, with the results shown in fig. 10.
PLGA (polylactic-polyglycolic acid), PLA (polylactic acid), PGA (polyglycolide), PCL (polycaprolactone) are common hydrophobic blocks with good biocompatibility, are often used as hydrophobic cores in amphiphilic block copolymers, and have good affinity for most drugs with certain hydrophobicity. In the above embodiments, PLA-PEG-MAL, PGA-PEG-MAL, PCL-PEG-MAL block copolymers are used instead of PLGA-PEG-MAL block copolymers, and drugs with certain hydrophobicity can be loaded to form polymer micelles, which will be clear to those skilled in the art.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910688203.7A CN110384681B (en) | 2019-07-29 | 2019-07-29 | Nanometer preparation for pulmonary fibrosis and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910688203.7A CN110384681B (en) | 2019-07-29 | 2019-07-29 | Nanometer preparation for pulmonary fibrosis and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110384681A CN110384681A (en) | 2019-10-29 |
| CN110384681B true CN110384681B (en) | 2020-04-28 |
Family
ID=68287789
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910688203.7A Active CN110384681B (en) | 2019-07-29 | 2019-07-29 | Nanometer preparation for pulmonary fibrosis and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110384681B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113694213A (en) * | 2021-08-20 | 2021-11-26 | 锦州医科大学 | Nanometer preparation loaded with gene diagnosis probe and/or anti-pulmonary fibrosis drug and preparation method thereof |
| CN115429898B (en) * | 2022-09-29 | 2024-05-28 | 中国药科大学 | A stem cell preparation for treating pulmonary fibrosis and preparation method thereof |
| CN115414492B (en) * | 2022-09-29 | 2024-05-28 | 中国药科大学 | A nano preparation for treating pancreatic fibrosis and a preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536930A (en) * | 2013-09-24 | 2014-01-29 | 上海纳米技术及应用国家工程研究中心有限公司 | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof |
| CN107789632A (en) * | 2017-09-06 | 2018-03-13 | 哈尔滨理工大学 | A kind of active Brain targeting nanoscale medicine delivery system of T7 peptides modification and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1332715C (en) * | 2003-09-09 | 2007-08-22 | 王继峰 | Novel medicinal use of proteinase inhibior for preventing and curing lang disease |
| CN108273061B (en) * | 2018-03-02 | 2021-04-30 | 中国药科大学 | Anti-fibrosis medicine nano preparation and preparation method thereof |
| CN109432047B (en) * | 2018-10-29 | 2021-07-20 | 中国药科大学 | A kind of nano preparation for reversing pulmonary fibrosis and preparation method thereof |
-
2019
- 2019-07-29 CN CN201910688203.7A patent/CN110384681B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536930A (en) * | 2013-09-24 | 2014-01-29 | 上海纳米技术及应用国家工程研究中心有限公司 | Polylactic acid-polyethylene glycol-tumor penetrating peptide compound, preparation and application thereof |
| CN107789632A (en) * | 2017-09-06 | 2018-03-13 | 哈尔滨理工大学 | A kind of active Brain targeting nanoscale medicine delivery system of T7 peptides modification and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110384681A (en) | 2019-10-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Youssef et al. | Application of some nanoparticles in the field of veterinary medicine | |
| Park et al. | PEGylated PLGA nanoparticles for the improved delivery of doxorubicin | |
| Menon et al. | Polymeric nanoparticles for pulmonary protein and DNA delivery | |
| Hidalgo et al. | Barrier or carrier? Pulmonary surfactant and drug delivery | |
| Dong et al. | Comparative study of mucoadhesive and mucus-penetrative nanoparticles based on phospholipid complex to overcome the mucus barrier for inhaled delivery of baicalein | |
| Shalaby et al. | Bioadhesive chitosan-coated cationic nanoliposomes with improved insulin encapsulation and prolonged oral hypoglycemic effect in diabetic mice | |
| Pandey et al. | Nanomedicine and experimental tuberculosis: facts, flaws, and future | |
| CN101474155B (en) | Lung-targeted medicine carrying precursor liposome for injection and method of use thereof | |
| US11471422B2 (en) | Stealth, targeted nanoparticles (STN) for oral drug delivery | |
| CN110384681B (en) | Nanometer preparation for pulmonary fibrosis and preparation method thereof | |
| KR20140138639A (en) | Nanoparticles formulations with enhanced mucosal penetration | |
| Amararathna et al. | Pulmonary nano-drug delivery systems for lung cancer: current knowledge and prospects | |
| CN112716915A (en) | Bionic nano-carrier and application thereof in preparing medicament for treating brain glioma | |
| CN104888235A (en) | pH sensitive nanoparticles prodrug with capacity of co-delivering multiple drugs, preparation method and application thereof | |
| WO2021057007A1 (en) | Rapamycin nanoscale sustained-release agent and preparation method thereof | |
| CN107441492A (en) | The medical composition and its use of Cyclooxygenase-2 Inhibitor and Nano medication delivery system | |
| Jin et al. | RETRACTED: Pulmonary route of administration is instrumental in developing therapeutic interventions against respiratory diseases | |
| Nguyen | Targeted delivery of surface-modified nanoparticles: modulation of inflammation for acute lung injury | |
| Guliy et al. | Polymeric micelles for targeted drug delivery systems | |
| Resnier et al. | Challenges and successes using nanomedicines for aerosol delivery to the airways | |
| Xu et al. | A polymer-free, biomimicry drug self-delivery system fabricated via a synergistic combination of bottom-up and top-down approaches | |
| Scialabba et al. | Exploiting inhalable microparticles incorporating hybrid polymer-lipid nanoparticles loaded with Iloprost manages lung hyper-inflammation | |
| CN115569115B (en) | A lipid nanoformulation simultaneously encapsulating perfluorocarbon and metformin, and its preparation method and application | |
| CN111557926A (en) | Targeted phase-change nano-drug system and its preparation method and application | |
| Mutreja et al. | Lipid nanoparticle-based formulations for high-performance dentistry applications |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |