CN111249470A - PAMAM-Rapa-BODIPY体系、其制备方法与应用 - Google Patents
PAMAM-Rapa-BODIPY体系、其制备方法与应用 Download PDFInfo
- Publication number
- CN111249470A CN111249470A CN201911308509.1A CN201911308509A CN111249470A CN 111249470 A CN111249470 A CN 111249470A CN 201911308509 A CN201911308509 A CN 201911308509A CN 111249470 A CN111249470 A CN 111249470A
- Authority
- CN
- China
- Prior art keywords
- bodipy
- pamam
- rapa
- rapamycin
- preparation
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000003814 drug Substances 0.000 claims abstract description 17
- 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 12
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 36
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 36
- 229960002930 sirolimus Drugs 0.000 claims description 36
- 239000007924 injection Substances 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 239000000412 dendrimer Substances 0.000 claims description 12
- 229920000736 dendritic polymer Polymers 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 230000003213 activating effect Effects 0.000 claims description 9
- 229920000962 poly(amidoamine) Polymers 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- 210000001508 eye Anatomy 0.000 abstract description 12
- 230000002207 retinal effect Effects 0.000 abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- 210000000274 microglia Anatomy 0.000 abstract description 3
- 206010015943 Eye inflammation Diseases 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 238000012377 drug delivery Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 241001506137 Rapa Species 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 210000001232 limbus corneae Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 108010016648 Immunophilins Proteins 0.000 description 1
- 102000000521 Immunophilins Human genes 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- QGNBTYAQAPLTMX-UHFFFAOYSA-L calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 description 1
- 229960005438 calcium dobesilate Drugs 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 210000000887 face Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000010832 independent-sample T-test Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- PRGUDWLMFLCODA-UHFFFAOYSA-N oxybuprocaine hydrochloride Chemical compound [Cl-].CCCCOC1=CC(C(=O)OCC[NH+](CC)CC)=CC=C1N PRGUDWLMFLCODA-UHFFFAOYSA-N 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/595—Polyamides, e.g. nylon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种如式(Ⅰ)所示的PAMAM‑Rapa‑BODIPY体系，其中的M作为载体，R2作为荧光分子指示基团，R3作为药物活性成分，R1使得该体系呈水溶性；因此，本申请提供的PAMAM‑Rapa‑BODIPY体系可主要应用于糖尿病性视网膜病变，靶向至视网膜小胶质细胞释放，在发挥抗炎作用的同时，可以监测药物在眼内的药代动力学特点，在糖尿病眼部炎症的治疗具有重要的学术价值。
Description
技术领域
本发明涉及糖尿病眼部炎症治疗技术领域，尤其涉及一种PAMAM-Rapa-BODIPY体系、其制备方法与应用。
背景技术
糖尿病性视网膜病变是糖尿病在眼部的一类微血管并发症，是西方国家20～74岁人群致盲的首位原因，其防治面临巨大的挑战。视网膜血管渗漏、炎症和新生血管形成是糖尿病视网膜病变的基本病理特征。眼内注射抗VEGF药物可以有效抑制糖尿病性新生血管和血管渗漏，但对于早期糖尿病性视网膜病变，除了控制血压血糖、口服羟笨磺酸钙改善微循环外，眼局部尚无有效的办法。
雷帕霉素最初是在链霉菌中发现，被成功应用于抗真菌治疗。1999年，美国FDA正式批准用于肾移植术后抗排斥治疗。雷帕霉素是一种大环内酯类的免疫抑制剂，可与亲免素蛋白FKBP-12形成复合物，抑制雷帕霉素靶分子信号通路的激活。
雷帕霉素在眼部炎症上也有应用；在雷帕霉素的临床研究上，主要是通过结膜下注射和眼内注射两种方式，应用于非感染性葡萄膜炎的治疗。但雷帕霉素是一种强疏水性药物，有机溶剂对局部组织损伤较大，这些因素限制了雷帕霉素的应用范围。
为雷帕霉素选择合适的载体或对其进行分子修饰增加水溶性，可以在提高眼部药物生物利用度的同时，减轻毒性反应。现有的雷帕霉素的载体多为高分子化合物，例如，公开号为CN108815160A的中国专利公开了一种雷帕霉素脂质体纳米粒及其制备方法，公开号为CN108771656A的中国专利公开了一种雷帕霉素缓释剂型及制备方法、雷帕霉素缓释注射剂及应用。这些给药体系不具备分子探针功能，无法示踪雷帕霉素在细胞、动物体内的动态改变。因此，提供一种新的雷帕霉素的眼部给药体系是十分必要的。
发明内容
本发明解决的技术问题在于提供一种PAMAM-Rapa-BODIPY体系，该体系具有糖尿病性视网膜病变炎症抑制的效果，且可增加药物示踪功能。
有鉴于此，本申请提供了一种如式(Ⅰ)所示的PAMAM-Rapa-BODIPY体系，
其中，m为大于零且小于31的自然数；
n为大于零且小于31的自然数；
R1的结构如式(Ⅱ)所示；
R2的结构如式(Ⅲ)所示；
R3的结构如式(Ⅳ)所示；
M为G3代PAMAM被R1、R2和R3取代后的残基；
优选的，所述m＝1，n＝1。
本申请还提供了所述的PAMAM-Rapa-BODIPY体系的制备方法，包括以下步骤：
将雷帕霉素、氟硼二吡咯、聚酰胺-胺型树枝状高分子和二缩三乙二醇在活化剂和溶剂中反应，得到PAMAM-Rapa-BODIPY体系。
优选的，所述活化剂为N-羟基丁二酰亚胺。
优选的，所述雷帕霉素、活化剂、氟硼二吡咯、聚酰胺-胺类树枝状高分子和OEG的摩尔比为n:30：m：1：(32-m-n)。
优选的，所述PAMAM-Rapa-BODIPY体系的制备方法具体为：
将雷帕霉素、氟硼二吡咯和活化剂溶于有机溶剂中，再在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐活化；然后加入聚酰胺-胺型树枝状高分子和二缩三乙二醇，反应后冷冻干燥。
本申请还提供了所述的PAMAM-Rapa-BODIPY体系或权利要求3～6任一项所述的制备方法所制备的PAMAM-Rapa-BODIPY体系在制备治疗糖尿病性视网膜病变药物上的应用。
优选的，所述药物的剂型为玻璃体腔注射剂。
本申请提供了一种PAMAM-Rapa-BODIPY体系，该体系具有如式(Ⅰ)所示的结构，该体系中M是骨架结构，作为体系的载体，R1提高了大分子体系的水溶性，降低了毒性，R2作为示踪基团，使整个体系发出荧光，而R3发挥药物作用，以抑制糖尿病性视网膜病变炎症反应。因此，本申请提供的PAMAM-Rapa-BODIPY体系具有抑制糖尿病性视网膜病变的效果，且可增加药物示踪功能。
附图说明
图1为本发明实施例1制备的PAMAM-Rapa-BODIPY的核磁共振氢谱图；
图2为本发明实施例1制备的PAMAM-Rapa-BODIPY的紫外吸收光谱图；
图3为本发明实施例1制备的PAMAM-Rapa-BODIPY给药体系对细胞的毒性作用；
图4本发明实施例1制备的PAMAM-Rapa-BODIPY给药体系与细胞共培养，在细胞内的分布情况；
图5为小鼠眼内注射给药体系和溶剂的视网膜组织病理对比照片。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。
针对雷帕霉素在眼局部应用的限制，本申请提供了一种PAMAM-Rapa-BODIPY体系，该体系由聚酰胺-胺型树枝状高分子(PAMAM)、雷帕霉素(Rapa)、氟硼二吡咯(BODIPY)和OEG经过加成反应制备得到，该体系中的各基团相互作用，最终使得疏水性的雷帕霉素变为亲水性，并标记荧光分子，在眼部发挥抗炎作用的同时，还可监测药物的组织细胞分布和代谢动力学。具体的，本申请提供了一种如式(Ⅰ)所示的PAMAM-Rapa-BODIPY体系，
其中，m和n为大于零且小于31的自然数；
n为大于零且小于31的自然数；
R1的结构如式(Ⅱ)所示；
R2的结构如式(Ⅲ)所示；
R3的结构如式(Ⅳ)所示；
M为G3代PAMAM被R1、R2和R3取代后的残基；
本申请中所述PAMAM-Rapa-BODIPY体系的实质是PAMAM中末端氨基中的H被OEG、Rapa和BODIPY分子取代而形成的一个大分子体系。其中的R1、R2和R3的数目可根据实际需要进行调整，即m为大于零且小于31的自然数，n为大于零且小于31的自然数；在具体实施例中，所述m＝n＝1，在该种情况下，所述PAMAM-Rapa-BODIPY体系的结构具体如下所示；下式只是给出了该体系的结构示意图，R1、R2和R3的具体位置是可调整的；
本申请还提供了上述PAMAM-Rapa-BODIPY体系的制备方法，包括以下步骤：
将雷帕霉素、氟硼二吡咯、聚酰胺-胺型树枝状高分子和OEG在活化剂和溶剂中反应，得到PAMAM-Rapa-BODIPY体系。
在制备PAMAM-Rapa-BODIPY体系的过程中，PAMAM、Rapa、BODIPY和OEG发生了亲核加成反应，由此得到了PAMAM-Rapa-BODIPY体系。在上述制备过程中，所述活化剂为N-羟基丁二酰亚胺；所述溶剂为本领域技术人员熟知的有机溶剂，对此本申请不进行特别的限制，在本申请中，所述溶剂为甲醇。为了使得反应更充分，所述PAMAM-Rapa-BODIPY体系的制备方法具体为：
将雷帕霉素、氟硼二吡咯和活化剂溶于有机溶剂中，再在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐活化；然后加入聚酰胺-胺型树枝状高分子和OEG，反应后冷冻干燥。
在制备PAMAM-Rapa-BODIPY体系的过程中，所述雷帕霉素、活化剂、氟硼二吡咯、聚酰胺-胺类树枝状高分子和OEG的摩尔比为n:30：m：1：(32-m-n)；在具体实施例中，所述雷帕霉素、N-羟基丁二酰亚胺、氟硼二吡咯、聚酰胺-胺类树枝状高分子和OEG的摩尔比为1:30:1:1:30，以得到如上式结构示意图所示的大分子体系。
本申请还提供了上述PAMAM-Rapa-BODIPY体系在制备抑制糖尿病性视网膜病变药物上的应用。所述药物剂型为本领域技术人员熟知的剂型，示例的，所述药物的剂型为注射剂；更具体的，所述药物的剂型为玻璃体腔注射剂。
本申请提供的PAMAM-Rapa-BODIPY体系是一种具有在糖尿病性视网膜病变抗炎作用的给药体系，该给药体系以雷帕霉素为运送靶分子，增加雷帕霉素亲水性特点，使其在玻璃体腔缓慢释放，在视网膜组织逐步发挥作用；还可给雷帕霉素增加药物示踪功能，分析其在视网膜组织的分布情况及药物代谢动力学特点。
为了进一步理解本发明，下面结合实施例对本发明提供的PAMAM-Rapa-BODIPY体系、其制备方法与应用进行详细说明，本发明的保护范围不受以下实施例的限制。
实施例1 PAMAM-Rapa-BODIPY纳米给药体系的制备过程
合成方法：将雷帕霉素(Rapa)、N-羟基丁二酰亚胺以及氟硼二吡咯(BODIPY)溶于甲醇溶液中，二缩三乙二醇分子(OEG)，加入EDC·HCl预先活化搅拌1h；再加入聚酰胺-胺类树枝状高分子(PAMAM)的甲醇/水混合溶液，PAMAM：N-羟基丁二酰亚胺：OEG：BODIPY：雷帕霉素摩尔比为1：30：30：1：1；室温磁力搅拌三天后，置于透析袋中，透析两天；透析过程中每两个小时需要更换去离子水，冷冻干燥除去水，得到产物PAMAM-Rapa-BODIPY。
1H NMR核磁分析：精密天平称取PAMAM和PAMAM-Rapa-BODIPY样品5mg，溶于0.5mL重水，在室温下，用核磁共振光谱仪测量其特征基团；积分处理软件为Topspin系统。结果如图1所示。图2为本发明实施例1制备的PAMAM-Rapa-BODIPY的紫外吸收光谱图。
实施例2 PAMAM-Rapa-BODIPY在细胞模型中安全性和有效性评价
1)细胞来源：人视网膜色素上皮细胞系(ARPE-19)；
2)人视网膜色素上皮细胞活性测定(CCK-8法)：收集对数期生长的ARPE-19，含10％FBS的DMEM-F12调整细胞悬液成合适浓度，计数后96孔板接种细胞5000个/孔，置入培养箱继续培养，过夜；96孔加入不同浓度PAMAM-Rapa(0、10-6、10-4、10-2、10-1、1、10、100和500μM)，对照组为药物溶媒无菌双蒸水，同时设调零孔，每组复孔为3个，继续培养24小时；孵育结束前1小时，吸除所有孔内培养基，每孔加入含CCK-8的完全培养基混悬液110μL(CCK-8：培养基体积比为1：10)继续培养1小时；终止培养后，轻轻晃动96孔板，使酶标仪检测各孔在450nm处的吸光度值并计算统计，结果图3所示，由图3可知，该体系浓度高达100μM时对细胞无明显毒性。
3)激光共聚焦显微镜观察人视网膜色素上皮细胞对PAMAM-Rapa-BODIPY的内吞作用：ARPE-19细胞接种于细胞爬片，贴壁过夜；浓度为20μM和50μM的PAMAM-Rapa-BODIPY与细胞37℃共培养40分钟；吸除培养基，PBS清洗三遍后，每孔加入500μL4％多聚甲醛，固定细胞15～20分钟；吸除多聚甲醛，PBS漂洗细胞三次，每次15分钟；PBST通透15分钟；加入DAPI染核，5分钟；PBS清洗细胞两遍；激光共聚焦显微镜拍照；结果如图4所示，由图4可知，该体系可进入细胞内从而发挥生物学效应。
实施例3动物体内观察PAMAM-Rapa-BODIPY的有效性和安全性
1)1型糖尿病小鼠模型的建立
本实验所需C57/BL6雄性小鼠购于江苏常州卡文斯实验动物有限公司，鼠龄6～8周；恒温恒湿房内常规喂养，12小时昼夜交替光照，适应性喂养3天；20只C57/BL6小鼠造模前过夜禁食(不禁水)12小时，临用前配制STZ溶液；正常组单次腹腔注射柠檬酸-柠檬酸钠溶液，实验组单次腹腔注射150mg/Kg的STZ溶液，注射STZ空腹2h后喂食，在水里加1ml 20％高糖，防低血糖致死；注射STZ后第1天(DM 0w)测小鼠尾静脉血糖；隔日更换垫料，每5天注射2U诺和灵30R；血糖高于17.6mmol/L持续3周(DM 3w)的糖尿病小鼠用于玻璃体腔内药物注射；所有程序均按中南大学实验动物福利伦理批准的协议；
2)玻璃体腔内药物注射
麻醉成功后，双眼托吡卡胺散瞳，剪去小鼠胡须，络合碘消毒眼睑皮肤，抗生素滴眼液滴眼，盐酸奥布卡因滴眼液注射前滴眼；纱布垫高小鼠头部，使角膜缘保持水平位；微量注射器在小鼠角膜缘后1mm垂直进针，突破巩膜后，针尖即向后倾斜，确认注射器针头在玻璃体腔后，缓慢推注体积为2μl的液体，实验眼注射1nmol PAMAM-Rapa树状大分子，对照眼注射等量的DMSO+生理盐水混悬液；注射完成后，稍停顿，镊子轻轻钳夹切口周围结膜组织，减少药物因眼内压增高导致的溢出；眼部滴抗生素眼液及抗生素眼膏；每3天注射一次，共注射两次，时间为1周；
3)小鼠视网膜组织病理观察
染色时先将切片放入二甲苯透明20分钟，重复一次后，用100％酒精脱水2次，每次5分钟，再放入75％酒精浸泡5分钟；复水后的切片放入苏木素溶液染色5分钟，自来水洗，盐酸酒精分化15秒，再次自来水洗，氨水返蓝后水洗2min；然后用酒精梯度脱水后，伊红溶液染色5分钟；再次进行脱水：100％酒精每次5分钟、共3次，正丁醇溶液5分钟，最后放入二甲苯透明；将上述处理好的玻片平置，在载玻片组织上滴中性树胶封片，注意避免气泡产生；将切片放于显微镜下观察，采集图像并分析，结果如图5所示，由图5可知，相比溶剂组，该体系有利于保护视网膜外层神经元细胞；采用SPSS 22.0软件进行统计学分析，两组均数比较采用独立样本t检验，多组均数比较采用单因素方差分析(One-Way Anova)。
4)药物在视网膜组织的示踪定位
在正常小鼠和糖尿病小鼠眼内注入PAMAM-Rapa-BODIPY，24小时、72小时、21天处死小鼠，取出眼球，冰冻切片后，在激光共聚焦显微镜下观察BODIPY红色荧光在视网膜组织的分布；对视网膜组织进行Iba-1荧光染色，标记小胶质细胞和Muller细胞，同时在激光共聚焦显微镜下观察PAMAM-Rapa-BODIPY和细胞的关系；IMARIS系统定量计数小胶质细胞、Muller细胞与PAMAM-Rapa-BODIPY共定位的阳性细胞数目。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (8)
1.一种如式(Ⅰ)所示的PAMAM-Rapa-BODIPY体系，
其中，m为大于零且小于31的自然数；
n为大于零且小于31的自然数；
R1的结构如式(Ⅱ)所示；
R2的结构如式(Ⅲ)所示；
R3的结构如式(Ⅳ)所示；
M为G3代PAMAM被R1、R2和R3取代后的残基；
2.根据权利要求1所述的PAMAM-Rapa-BODIPY体系，其特征在于，所述m＝1，n＝1。
3.权利要求1所述的PAMAM-Rapa-BODIPY体系的制备方法，包括以下步骤：
将雷帕霉素、氟硼二吡咯、聚酰胺-胺型树枝状高分子和二缩三乙二醇在活化剂和溶剂中反应，得到PAMAM-Rapa-BODIPY体系。
4.根据权利要求3所述的制备方法，其特征在于，所述活化剂为N-羟基丁二酰亚胺。
5.根据权利要求3所述的制备方法，其特征在于，所述雷帕霉素、活化剂、氟硼二吡咯、聚酰胺-胺类树枝状高分子和OEG的摩尔比为n:30：m：1：(32-m-n)。
6.根据权利要求3所述的制备方法，其特征在于，所述PAMAM-Rapa-BODIPY体系的制备方法具体为：
将雷帕霉素、氟硼二吡咯和活化剂溶于有机溶剂中，再在1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐活化；然后加入聚酰胺-胺型树枝状高分子和二缩三乙二醇，反应后冷冻干燥。
7.权利要求1～2任一项所述的PAMAM-Rapa-BODIPY体系或权利要求3～6任一项所述的制备方法所制备的PAMAM-Rapa-BODIPY体系在制备治疗糖尿病性视网膜病变药物上的应用。
8.根据权利要求7所述的应用，其特征在于，所述药物的剂型为玻璃体腔注射剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911308509.1A CN111249470A (zh) | 2019-12-18 | 2019-12-18 | PAMAM-Rapa-BODIPY体系、其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911308509.1A CN111249470A (zh) | 2019-12-18 | 2019-12-18 | PAMAM-Rapa-BODIPY体系、其制备方法与应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111249470A true CN111249470A (zh) | 2020-06-09 |
Family
ID=70946713
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911308509.1A Pending CN111249470A (zh) | 2019-12-18 | 2019-12-18 | PAMAM-Rapa-BODIPY体系、其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111249470A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022258005A1 (en) * | 2021-06-10 | 2022-12-15 | The University Of Hong Kong | A photoresponsive delivery system based on a modified pamam and methods thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101336886A (zh) * | 2008-07-02 | 2009-01-07 | 中国药科大学 | 一种灯盏花素的可溶制剂 |
| CN109456351A (zh) * | 2018-12-21 | 2019-03-12 | 中南大学 | 一种两亲性氟硼染料有机物及其制备和在抑制眼角膜新生血管生长光敏药物中的应用 |
| CN109776570A (zh) * | 2017-11-14 | 2019-05-21 | 上海医药工业研究院 | 一种依维莫司中间体、其制备方法及其应用 |
| US20190343821A1 (en) * | 2017-01-06 | 2019-11-14 | Santen Pharmaceutical Co., Ltd. | Intratumoral administration of sirolimus for treatment of prostate cancer |
-
2019
- 2019-12-18 CN CN201911308509.1A patent/CN111249470A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101336886A (zh) * | 2008-07-02 | 2009-01-07 | 中国药科大学 | 一种灯盏花素的可溶制剂 |
| US20190343821A1 (en) * | 2017-01-06 | 2019-11-14 | Santen Pharmaceutical Co., Ltd. | Intratumoral administration of sirolimus for treatment of prostate cancer |
| CN109776570A (zh) * | 2017-11-14 | 2019-05-21 | 上海医药工业研究院 | 一种依维莫司中间体、其制备方法及其应用 |
| CN109456351A (zh) * | 2018-12-21 | 2019-03-12 | 中南大学 | 一种两亲性氟硼染料有机物及其制备和在抑制眼角膜新生血管生长光敏药物中的应用 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022258005A1 (en) * | 2021-06-10 | 2022-12-15 | The University Of Hong Kong | A photoresponsive delivery system based on a modified pamam and methods thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bao et al. | Glycol chitosan/oxidized hyaluronic acid hydrogel film for topical ocular delivery of dexamethasone and levofloxacin | |
| Roy et al. | Microneedle scleral patch for minimally invasive delivery of triamcinolone to the posterior segment of eye | |
| Shi et al. | A dual-functional chitosan derivative platform for fungal keratitis | |
| CN1694727A (zh) | 含与聚乙二醇结合的药物的眼组织注射剂 | |
| CN105726484B (zh) | 一种粉防己碱液晶纳米粒眼用制剂及其制备方法 | |
| Guo et al. | Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution | |
| Taich et al. | Sustained-release hydrogels of topotecan for retinoblastoma | |
| CN102697795A (zh) | 一种抗肿瘤联合用药物 | |
| CN109077993A (zh) | 一种泪小管缓释水凝胶植入剂及其制备方法 | |
| CN110693831B (zh) | 一种长眼表停留和高角膜渗透载药纳米胶束制备方法 | |
| CN109481403B (zh) | 一种壳聚糖修饰的醋酸曲安奈德脂质体及制备方法 | |
| CN111249470A (zh) | PAMAM-Rapa-BODIPY体系、其制备方法与应用 | |
| CN112691087B (zh) | 一种那他霉素纳米粒及其制备方法 | |
| Gupta et al. | Enhancement of anti-glaucoma potential by novel ocular drug delivery system | |
| Wang et al. | A preliminary study to treat severe endophthalmitis via a foldable capsular vitreous body with sustained levofloxacin release in rabbits | |
| CN115364091B (zh) | 青蒿素衍生物眼用制剂及其制备方法 | |
| CN111494305A (zh) | 一种叶黄素脂质体眼用温敏型原位凝胶制剂及其制备方法 | |
| CN108309930B (zh) | 一种氧氟沙星液晶凝胶纳米粒滴眼液及其制备方法 | |
| CN105566100A (zh) | 一种苯乙烯酸类化合物，包含其的组合物及其应用 | |
| CN107296808B (zh) | 化合物埃博霉素b在制备修复角膜神经创伤的药物中的应用 | |
| CN110812323B (zh) | 一种眼用组合物、其制备方法及用途 | |
| JP2022545223A (ja) | 末梢神経障害とそれに関連する疾患の予防及び／又は治療に使用する調剤 | |
| CN109172520A (zh) | 一种紫杉烷类衍生物tm-2胶束注射液及其制备方法与应用 | |
| CN115192578B (zh) | 一种载槲皮素和尼达尼布混合胶束的制备 | |
| RU2800382C1 (ru) | Новая лекарственная форма эхинохрома А, способ ее получения и применение |
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 |