CN116603054A - Pharmaceutical composition for repairing cornea endothelium - Google Patents
Pharmaceutical composition for repairing cornea endothelium Download PDFInfo
- Publication number
- CN116603054A CN116603054A CN202310555737.9A CN202310555737A CN116603054A CN 116603054 A CN116603054 A CN 116603054A CN 202310555737 A CN202310555737 A CN 202310555737A CN 116603054 A CN116603054 A CN 116603054A
- Authority
- CN
- China
- Prior art keywords
- corneal endothelial
- pharmaceutical composition
- cornea
- corneal
- fgf10
- 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
- 210000004087 cornea Anatomy 0.000 title claims abstract description 52
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 22
- 210000003038 endothelium Anatomy 0.000 title claims description 7
- 210000000399 corneal endothelial cell Anatomy 0.000 claims abstract description 38
- 102100028412 Fibroblast growth factor 10 Human genes 0.000 claims abstract description 27
- 101000917237 Homo sapiens Fibroblast growth factor 10 Proteins 0.000 claims abstract description 27
- 230000006378 damage Effects 0.000 claims abstract description 15
- 230000001737 promoting effect Effects 0.000 claims abstract description 14
- 230000008439 repair process Effects 0.000 claims abstract description 14
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims abstract description 12
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims abstract description 12
- 229940126864 fibroblast growth factor Drugs 0.000 claims abstract description 12
- 210000002469 basement membrane Anatomy 0.000 claims abstract description 7
- 230000008929 regeneration Effects 0.000 claims abstract description 7
- 238000011069 regeneration method Methods 0.000 claims abstract description 7
- 230000003511 endothelial effect Effects 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 208000014674 injury Diseases 0.000 claims description 11
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 10
- 208000027418 Wounds and injury Diseases 0.000 claims description 10
- 206010011033 Corneal oedema Diseases 0.000 claims description 7
- 241000282414 Homo sapiens Species 0.000 claims description 7
- 201000004778 corneal edema Diseases 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 7
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 6
- 230000008694 endothelial dysfunction Effects 0.000 claims description 6
- 230000008753 endothelial function Effects 0.000 claims description 6
- 206010047513 Vision blurred Diseases 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 230000004083 survival effect Effects 0.000 claims description 4
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 3
- 230000021164 cell adhesion Effects 0.000 claims description 3
- 230000024245 cell differentiation Effects 0.000 claims description 3
- 230000009843 endothelial lesion Effects 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 239000007943 implant Substances 0.000 claims description 3
- 230000035800 maturation Effects 0.000 claims description 3
- 230000005012 migration Effects 0.000 claims description 3
- 238000013508 migration Methods 0.000 claims description 3
- 241000283690 Bos taurus Species 0.000 claims description 2
- 241000282693 Cercopithecidae Species 0.000 claims description 2
- 102000012422 Collagen Type I Human genes 0.000 claims description 2
- 108010022452 Collagen Type I Proteins 0.000 claims description 2
- 102000004266 Collagen Type IV Human genes 0.000 claims description 2
- 108010042086 Collagen Type IV Proteins 0.000 claims description 2
- 102000002734 Collagen Type VI Human genes 0.000 claims description 2
- 108010043741 Collagen Type VI Proteins 0.000 claims description 2
- 102000001191 Collagen Type VIII Human genes 0.000 claims description 2
- 108010069526 Collagen Type VIII Proteins 0.000 claims description 2
- 102000014870 Collagen Type XII Human genes 0.000 claims description 2
- 108010039001 Collagen Type XII Proteins 0.000 claims description 2
- 241000282326 Felis catus Species 0.000 claims description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 claims description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 claims description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 claims description 2
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 claims description 2
- 108010067306 Fibronectins Proteins 0.000 claims description 2
- 101001060274 Homo sapiens Fibroblast growth factor 4 Proteins 0.000 claims description 2
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 2
- 241001494479 Pecora Species 0.000 claims description 2
- 241000009328 Perro Species 0.000 claims description 2
- 241000700159 Rattus Species 0.000 claims description 2
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 241000699800 Cricetinae Species 0.000 claims 1
- 101150021185 FGF gene Proteins 0.000 claims 1
- 102100037362 Fibronectin Human genes 0.000 claims 1
- 230000004663 cell proliferation Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000002045 capillary electrochromatography Methods 0.000 abstract description 7
- 208000015636 celiac disease-epilepsy-cerebral calcification syndrome Diseases 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 abstract description 5
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 230000000877 morphologic effect Effects 0.000 abstract description 2
- 210000002159 anterior chamber Anatomy 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 108010085895 Laminin Proteins 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 210000002889 endothelial cell Anatomy 0.000 description 9
- 201000010099 disease Diseases 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 231100000241 scar Toxicity 0.000 description 7
- 238000002347 injection Methods 0.000 description 5
- 229940090044 injection Drugs 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 206010020718 hyperplasia Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 3
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 2
- 206010056476 Corneal irritation Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 206010015958 Eye pain Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- 102000013814 Wnt Human genes 0.000 description 2
- 108050003627 Wnt Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 230000004453 corneal transparency Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 239000003978 infusion fluid Substances 0.000 description 2
- 108010038862 laminin 10 Proteins 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- IDDDVXIUIXWAGJ-DDSAHXNVSA-N 4-[(1r)-1-aminoethyl]-n-pyridin-4-ylcyclohexane-1-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CC([C@H](N)C)CCC1C(=O)NC1=CC=NC=C1 IDDDVXIUIXWAGJ-DDSAHXNVSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 208000004683 Corneal Endothelial Cell Loss Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010048961 Localised oedema Diseases 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 240000005373 Panax quinquefolius Species 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940010958 carbachol injection Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000000942 confocal micrograph Methods 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000007717 corneal ulcer Diseases 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- 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
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- 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
Abstract
The invention discloses a medicinal composition for eyes, which comprises 5-60 ng/mL of fibroblast growth factor and 5-60 mug/mL of laminin. The coupling of the fibroblast growth factor and laminin is utilized to improve the basal lamina of the posterior elastic layer, promote the adhesion and functional regeneration of the transplanted/autologous CECs, and achieve the effects of treating the damage of the corneal endothelial cells and promoting the repair. Especially, FGF10 coupled LN511 can remarkably promote the restoration of the transparency and thickness of cornea and promote the density, morphological repair and functional reconstruction of corneal endothelial cells.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicinal composition for repairing cornea endothelium.
Background
Corneal endothelial cells (Corneal endothelial cells, CECs) are single-layered hexagonal cells located in the innermost layer of the cornea, whose function is normally a prerequisite for maintaining corneal stromal dehydration to ensure corneal transparency. Human corneal endothelial cells (Human corneal endothelial cells, HCECs) arrest in the G1 phase of the cell cycle with essentially no regenerative capacity. With age, the number of CECs and cell density gradually decrease. Corneal endothelial cell injury may be caused by intraocular inflammation, local trauma, eye surgery or other physical and chemical factors, and when HCECs injury loss exceeds its physiological threshold (< 400/mm 2), corneal endothelial function decompensation occurs, clinical symptoms of corneal irritation are accompanied by blurred vision, epithelial blisters appear in the progressive stage, ocular pain is caused if blisters break, severe cases can be secondary to corneal ulcers and surgical treatment is required. Because of the lack of cornea donor tissue reaching the transplantation level worldwide, the clinical diagnosis and treatment needs cannot be satisfied, so how to maintain the physiological function of the cornea endothelial cells, alleviate the damage caused by various physical and chemical factors, promote the cornea endothelial repair, delay the disease progress and the operation time window are important directions of the current research, but the lower proliferation capacity of the cornea endothelium is a challenge for researchers.
Current strategies for treating corneal endothelial decompensation include methods such as drug therapy, donor cornea transplantation, and tissue engineering cornea endothelial transplantation. For mild corneal endothelial injury, local treatment can play a role. In the aspect of local treatment, the invasiveness of the drug intervention is small, the drug intervention is easier to obtain, a low-traumatic method is provided for treating the corneal endothelial dysfunction, the service life of residual corneal endothelial cells can be prolonged, the disease progress and the operation time window can be delayed, the functional repair of the corneal endothelial cells after the operation can be promoted, and the like. Studies have shown that certain potential pharmaceutical agents can be used to promote the repair of damage to corneal endothelial cells. Hepatocyte growth factors promote the growth and repair of CECs by way of autocrine. We have previously reported that Nicotinamide (NIC) enhances corneal endothelial wound healing by promoting CECs proliferation and inhibiting endothelial-mesenchymal transition (EnMT). Studies have demonstrated the effectiveness of the ROCK inhibitor Y-27632 in endothelial cell regeneration, and can be used to treat corneal endothelial dysfunction by promoting proliferation of CECs and reducing apoptosis. In addition, Y-27632 can treat corneal endothelial dysfunction by improving the adhesion efficiency of cells in combination with cell injection. But the use of drugs has certain limitations.
Disclosure of Invention
The invention provides a medicinal composition for eyes, which comprises 5-60 ng/mL of fibroblast growth factor and 5-60 mug/mL of laminin; the fibroblast growth factor and laminin are used as active substances and have the effects of promoting repairing, growing, migrating, survival, attaching, proliferating and/or differentiating of ocular corneal endothelial cells and/or elastic layer injury after cornea. The pharmaceutical composition can be used for preparing medicines or medical devices for relieving or treating corneal endothelial injury, corneal endothelial lesion, corneal endothelial dysfunction and corneal endothelial cell dysfunction.
Preferably, the laminin is selected from one or more of LN211, LN322, LN 511; the fibroblast growth factor is selected from one or more of FGF1, FGF2 (bFGF), FGF4 and FGF 10.
Preferably, the pharmaceutical composition comprises at least fibroblast growth factor FGF10 and laminin LN511.
Preferably, LN511 is present in a concentration of 10-50. Mu.g/mL and FGF10 is present in a concentration of 10-50ng/mL; more preferably, LN511 is present at a concentration of 10. Mu.g/mL and FGF10 is present at a concentration of 10ng/mL.
In the present invention, the pharmaceutical composition may further comprise one or more of type I collagen fibers, type VIII collagen, type IV collagen, type VI collagen, type XII collagen, fibronectin, nicotinamide, Y-27632.
In another aspect of the invention, the use of the above-described pharmaceutical composition in medicaments or medical devices for repairing corneal endothelial cells against oxidative damage, against apoptosis, against inflammation, reversing corneal endothelial cell-matrix transformation, balancing the homeostasis of the survival microenvironment of the corneal endothelial cells, promoting corneal endothelial cell adhesion, functional regeneration, remodeling and/or maturation is provided.
In another aspect of the invention, the invention provides the use of the above pharmaceutical composition in the preparation of a medicament or medical device for treating or alleviating symptoms such as pain, blurred vision, corneal edema and the like caused by decompensation of corneal endothelial function.
In the present invention, the pharmaceutical composition is administered to the eye of a subject suffering from corneal endothelial cell damage, lesions, dysfunction or functional decompensation in an effective dose.
In the present invention, the term "individual" or "patient" is used interchangeably herein and refers to a vertebrate, preferably a mammal. The mammal may be a human, non-human primate, mouse, rat, rabbit, dog, cat, horse, sheep, monkey, or cow, but is not limited to these examples. Preferably, the patient is a human. Such "individuals" or "patients" typically suffer from or are susceptible to a condition that can be prevented or treated by administration of the above-described pharmaceutical, pharmaceutical combinations of the invention, including, but not limited to, corneal endothelial injury, corneal endothelial lesions, corneal endothelial dysfunction, corneal endothelial cell dysfunction symptoms: abnormal corneal thickness, reduced corneal transparency, corneal edema, reduced or lost vision, dry eyes, pain, etc.
The invention can be mixed by a conventional method by a technician before application, and finally becomes a required pharmaceutical dosage form. Can be in the form of dripping pill, aqueous suspension, aqueous solution, eye drop, injection, colloid, colloidal solution, nanometer preparation or other dosage forms for human, animal or clinic. Preferably, the pharmaceutical composition is administered in the form of an intraocular injection or infusion fluid.
In the present invention, the terms "effective amount", "effective dose" refer to that amount which imparts a therapeutic or inhibitory effect (e.g., controls, relieves, improves, mitigates or slows progression) to "an individual" or "patient"; or the aforementioned drugs, pharmaceutical compositions, medical devices that prevent (e.g., delay onset or reduce risk of developing) a disease, disorder or condition or symptom thereof. The amount effective for this use will depend on, for example, the route of delivery, the concentration or composition of the drug employed, the severity of the corneal endothelial injury, the weight and general health of the individual, and the practitioner's advice on a case-by-case basis. The dose may be administered once a week, or for two days or once a day, or even several times a day. Dosage units may be administered for a short period (e.g., weeks to months) or longer period (months to years). Can be made into any preparation formulation.
In another aspect of the invention, the invention provides the use of the above pharmaceutical composition in the preparation of medicaments or medical devices for corneal endothelial basement membrane, corneal endothelial implant graft carrier, corneal endothelial cell graft carrier, artificial cornea posterior elastic layer, artificial cornea endothelium and artificial whole cornea.
Advantageous effects
1) The extracellular matrix component of the elastic layer after cornea is utilized for the first time to promote the restoration of the elastic layer after cornea, so as to construct the endothelial cell restoration basement membrane.
2) The fibroblast growth factor is coupled with laminin for the first time to improve the basal lamina of the posterior elastic layer, further promote the adhesion and functional regeneration of the transplanted/autologous CECs, and achieve the effects of treating the corneal endothelial cell injury and promoting the repair.
3) The method is characterized in that the fibroblast growth factor is coupled with laminin for the first time and is used for treating serious corneal endothelial diseases, in the stage of disease, the elastic layer behind the cornea is obviously abnormal, the treatment purpose cannot be achieved only by using cell transplantation, and the treatment effect can be achieved only by tearing off the elastic layer behind the abnormal pathological changes and jointly performing corneal endothelial repair promotion treatment or cell transplantation; FGF10 coupled LN511 can remarkably promote the restoration of the transparency and thickness of cornea and promote the density, morphological repair and functional reconstruction of corneal endothelial cells.
Drawings
FIG. 1, effects of different concentrations of drugs on promoting corneal endothelial cell attachment;
FIG. 2. Animal model (A) for removing elastic layer after rabbit cornea establishment, DM with diameter of about 5mm in the center of rabbit cornea is removed by endothelial hook, and the preparation is injected into anterior chamber to form cytokine coating; (B) The extent of the posterior elastic layer tear (circular area) in the center of the cornea;
FIG. 3 shows changes in transparency of rabbit cornea as observed by slit lamp microscopy;
FIG. 4 is a slit lamp microscope view showing cornea transparency, thickness, scar hyperplasia;
FIG. 5 is a confocal microscopy image showing morphological changes in corneal endothelial cells;
FIG. 6F-actin immunofluorescence staining pattern.
Detailed Description
A variety of critical signaling pathways, such as MAPK pathway, TGF-beta pathway, PI3K/AKT pathway, wnt pathway and ROCK pathway, are involved in the process of repairing corneal endothelial injury. The fibroblast growth factor (Fibroblast growth factor) is taken as a polypeptide growth factor with various biological activities, and can regulate and control the signal paths such as PI3K/AKT, wnt and the like to promote the injury repair, cell differentiation and regeneration process of tissues. Laminin (LN), an extracellular matrix glycoprotein, is the major non-collagenous component of the retrocorneal elastic layer.
In the invention, animal models of damage of the elastic layer after cornea with different degrees are built, the effects of adhering the elastic layer after basement membrane repair abnormality by utilizing LN pre-coating and improving cornea endothelial repair (cell growth, migration, survival, attachment, proliferation and differentiation) by coupling FGF are explored, a new thought is provided for treating cornea endothelial function decompensation by tissue engineering technology, and a new scheme is provided for clinical treatment of cornea endothelial diseases.
The corneal endothelium plays an important role in maintaining the transparency of the cornea. When the damage loss degree of HCECs exceeds the physiological critical value, corneal endothelial function decompensation occurs, and the clinical manifestation is corneal irritation symptoms accompanied by blurred vision and edema, epithelial and subcutaneous blisters appear in the progressive stage, and ocular pain is caused if the blisters break. The repair promoting effect of the present invention includes adhesion of corneal endothelial jogging, growth, proliferation and differentiation of cells, migration, inhibition of scar hyperplasia, formation of a corneal endothelial cell layer which makes cells have good morphology and high cell density, and further shows an apoptosis inhibiting effect of corneal endothelial jogging. Therefore, the pharmaceutical composition provided by the invention can be used in medicines or kits for repairing the oxidation injury, apoptosis and inflammation resistance of the corneal endothelial cells, reversing the transformation of the corneal endothelial cells and the matrix, balancing the steady state of the living microenvironment of the corneal endothelial cells, promoting the adhesion, functional regeneration, reconstruction and/or maturation of the corneal endothelial cells; can also be used for treating or relieving symptoms such as pain, blurred vision, corneal edema and the like caused by corneal endothelial function decompensation; can also be used for storing cornea endothelial basement membrane, cornea endothelial implant transplanting carrier, cornea endothelial cell transplanting carrier, artificial cornea back elastic layer, artificial cornea endothelium and artificial whole cornea reagent, improving its preserving effect and promoting its effect after implantation.
The dosage form of the medicament or medical device of the present invention is not particularly limited, and is suitable for topical administration to the eye, but is preferably formulated in the form of an intracameral injection or an intraocular infusion fluid.
The invention is further illustrated by the following examples which illustrate the invention, which are intended to be illustrative only and should not be construed as limiting the scope of the invention. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Preparation of reagents
Preparation of 5-50. Mu.g/mL of a combination preparation of Laminin511 (Biolamina, sundbyberg, sweden), 5-50ng/mL of FGF10 (Wuhan you Sheng commercial Co., ltd.), 5-50. Mu.g/mL of Laminin511 and 5-50ng/mL of FGF10, respectively, placing the above preparations in an ultra clean bench, filtering with a filter with a pore size of 0.22. Mu.m, sub-packaging, mixing the materials in the bench, and storing at a low temperature of 4 ℃.
Example 1 effects of different concentrations of drug combinations on promoting corneal endothelial cell attachment
The prepared LN 511-coated 12-well cell culture plates of 5. Mu.g/mL, 10. Mu.g/mL, 20. Mu.g/mL, and 50. Mu.g/mL of the above split-packs were used, and the control group was coated with DPBS. According to 5X 10 5 Inoculating corneal endothelial cells in each mL, adding DPBS or FGF10 with the concentration of 5ng/mL, 10ng/mL, 20ng/mL and 50ng/mL into the culture solution, observing the adherence condition of the corneal endothelial cells in 30min after inoculation, and photographing by using an inverted microscope; the non-adherent cells were washed off with PBS, and the adherent cells were digested with 0.25% trypsin-EDTA for 5min, and the number of adherent cells was counted using a cytometer, respectively.
As shown in FIG. 1, compared with the control group, LN511 concentration of 10. Mu.g/mL, 20. Mu.g/mL, 50. Mu.g/mL and FGF10 concentration of 10ng/mL, 20ng/mL, 50ng/mL all had the function of promoting endothelial cell adhesion, wherein LN511 and FGF10 concentration of 10. Mu.g/mL and FGF10 concentration of 10ng/mL had the best effect, and the average of 5.09X 10 was reached 5 And (3) per mL, the LN511 and FGF10 drug combination has good function of promoting the adhesion of corneal endothelial cells.
Example 2 animal experiments
Animal model for removing rabbit cornea by flicking
After the new zealand rabbit is anesthetized, a trephine drills a diameter of 5mm on the cornea surface, the bulbar conjunctiva at the position of 11-1 points above the cornea is sheared by corneosclera, a disposable 15-degree puncture knife is used for making an incision with a width of about 2mm at the position of 12 points of the limbus, carbachol injection is injected into the anterior chamber to shrink the pupil, and sodium hyaluronate is injected into the supporting anterior chamber. The cornea posterior elastic layer with the diameter of about 5mm in the center of the cornea of the right eye of the rabbit is torn by an endothelial hook to simulate serious cornea endothelial diseases needing to remove the cornea posterior elastic layer DM, residual sodium hyaluronate and endothelial cell fragments in the anterior chamber are washed by normal saline, and then 250 mu l of gentamicin sulfate and heparin sodium injection are respectively injected into the anterior chamber, so that the gentamicin in the anterior chamber is replaced and exudation in the anterior chamber is prevented. The 10-0 nylon thread is used for intermittently suturing the limbal incision, so that the formation of a good anterior chamber of the rabbit eye is ensured.
After rewarming the preparation stored at low temperature at 4 ℃, 100 μl of the preparation was slowly injected into the anterior chamber using a syringe, the eye pressure Tn of the rabbit eye was measured, the right lateral recumbent position of the rabbit was maintained, the operative eye was kept in the downward position for 1 hour, the preparation was uniformly covered on the surface of the posterior stroma layer of the cornea to form a cytokine coating, and the transparency, thickness, inflammatory reaction in the anterior chamber and recovery of endothelial cell morphology after DM was removed were observed (fig. 2).
The grouping is as follows:
control group: 100 μl DPBS was injected into the anterior chamber
LN511 group: 100 μl LN511 (10 μg/mL) was injected into the anterior chamber;
FGF10 group 100. Mu.l FGF10 (10 ng/mL) was injected into the anterior chamber;
LN511-FGF10 group: mu.l FGF10 (10 ng/mL) coupled LN511 (10. Mu.g/mL) was injected into the anterior chamber.
Experimental results
(1) FGF10 coupled LN511 promotes cornea transparency and thickness recovery and inhibits scar hyperplasia
The slit lamp microscope observation shows that the cornea of the control group still has obvious edema after DM stripping operation for 7 days, the peripheral cornea edema starts to be limited for 10 days, only central area edema is left for 14 days, and large lamellar cornea scars are left in the central area for 30 days. The corneal edema 7 days after the FGF10 alone and LN511 surgery was consistent with the control group, with 10 days of corneal edema significantly localized to the central zone, and 30 days of cornea still had localized edema and left with lamellar pannus. The corneal oedema started to be limited 7 days after FGF10 coupled LN511 surgery, and the cornea restored transparency for 10 days and stabilized for up to 30 days. Cornea OCT shows that the scar is obviously proliferated in the central DM tearing range (about 5 mm) of 30 days after operation of the control group, the scar hyperplasia is only formed in the central tearing area of about 2.5mm in the single FGF10 group and the LN511 group, but the proliferation thickness is reduced compared with that of the control group, the central tearing area of the FGF10 coupled LN511 group is smooth, and no obvious proliferation scar is seen. (FIG. 3, FIG. 4)
(2) FGF10 coupled LN511 for improving corneal endothelial cell morphology
The morphology and density of corneal endothelial cells were observed using a confocal living microscope in the control group, the FGF10 alone group, the LN511 group, and the FGF 10-coupled LN511 group 30 days after DM tear-off. The results showed that the corneal endothelial cell density was increased 30 days after surgery in FGF10 alone and LN511 alone compared with the control group, but the cells were sparse and irregular in morphology and size. The FGF 10-coupled LN511 group had a more uniform corneal endothelial cell density and a regular morphology (fig. 5).
(3) FGF10 coupled LN511 promotes recovery of keratocyte density
F-actin immunofluorescence staining showed morphology of corneal endothelial cells 30 days after DM removal, and the results showed that the endothelial cell skeleton disorder degree of the control group was improved compared with that of the control group in the FGF10 group and LN511 group alone, a small number of cells showed a slightly regular skeleton, and the endothelial cells of the FGF 10-coupled LN511 group showed regular morphology, and a large part showed regular hexagonal morphology (FIG. 6).
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Numerous modifications and substitutions of details are possible in light of all the teachings disclosed, and such modifications are contemplated as falling within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (10)
1. The pharmaceutical composition for eyes is characterized by comprising 5-60 ng/mL of fibroblast growth factor and 5-60 mug/mL of laminin; wherein fibroblast growth factor and laminin are active substances.
2. The pharmaceutical composition of claim 1, wherein said laminin is selected from one or more of LN211, LN322, LN 511; the fibroblast growth factor is selected from one or more of FGF1, FGF2, FGF4 and FGF 10.
3. Pharmaceutical composition according to claim 1 or 2, comprising at least FGF10 and LN511.
4. The pharmaceutical composition of claim 3, wherein said LN511 concentration is 10-50 μg/mL and said FGF10 concentration is 10-50ng/mL.
5. The pharmaceutical composition of any one of claims 1, 2, 4, further comprising one or more of type I collagen fibers, type VIII collagen, type IV collagen, type VI collagen, type XII collagen, fibronectin, nicotinamide, Y-27632.
6. The pharmaceutical composition of any one of claims 1, 2, 4 for use in the eye of a mammal; the mammal includes human, rabbit, mouse, rat, hamster, cat, dog, cow, sheep, monkey.
7. Use of a pharmaceutical composition according to any one of claims 1, 2, 4 for the preparation of a medicament or medical device for promoting repair, growth, migration, survival, cell adhesion, proliferation and/or differentiation, regeneration, reconstruction and/or maturation of corneal endothelial cells and/or post-corneal elastic layer lesions.
8. Use of a pharmaceutical composition according to any one of claims 1, 2, 4 for the preparation of a medicament or medical device for alleviating or treating corneal endothelial injury, corneal endothelial lesions, corneal endothelial dysfunction, corneal endothelial cell dysfunction.
9. Use of a pharmaceutical composition according to any one of claims 1, 2, 4 for the preparation of a medicament or medical device for the treatment or alleviation of symptoms of pain, blurred vision, corneal oedema and the like caused by decompensation of the corneal endothelial function.
10. The use of the pharmaceutical composition according to any one of claims 1, 2, and 4 for the preparation of a medicament or medical device for corneal endothelial basement membrane, corneal endothelial implant graft carrier, corneal endothelial cell graft carrier, post-artificial cornea elastic layer, artificial cornea endothelium and artificial whole cornea.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310555737.9A CN116603054A (en) | 2023-05-17 | 2023-05-17 | Pharmaceutical composition for repairing cornea endothelium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310555737.9A CN116603054A (en) | 2023-05-17 | 2023-05-17 | Pharmaceutical composition for repairing cornea endothelium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116603054A true CN116603054A (en) | 2023-08-18 |
Family
ID=87674056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310555737.9A Pending CN116603054A (en) | 2023-05-17 | 2023-05-17 | Pharmaceutical composition for repairing cornea endothelium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116603054A (en) |
-
2023
- 2023-05-17 CN CN202310555737.9A patent/CN116603054A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Sharma et al. | Treatment of acute ocular chemical burns | |
| Ziaei et al. | Wound healing in the eye: therapeutic prospects | |
| DK171029B1 (en) | Hyaluronic Acid Fraction, Process for Preparation thereof, and Ophthalmic Preparations Containing Hyaluronic Acid Fraction | |
| Shimazaki et al. | Limbal autograft transplantation for recurrent and advanced pterygia | |
| KR101539700B1 (en) | A composition for treating diseases related to angiogenesis and cornea or conjunctiva transplant using chondrocyte-derived extracellular matrix membrane | |
| JPWO2006075602A1 (en) | Sheet-like composition using amniotic membrane and method for producing the same | |
| WO2021244044A1 (en) | Eye drop suitable for limbal stem cell deficiency and preparation | |
| CN1111403C (en) | Secondary cataract inhibitor | |
| CN114425033A (en) | Ophthalmic gel containing mesenchymal stem cell exosomes and preparation method thereof | |
| CN112494729B (en) | Drug-containing tissue graft and preparation method and application thereof | |
| CN113476611A (en) | A composition with skin repairing effect | |
| CN116603054A (en) | Pharmaceutical composition for repairing cornea endothelium | |
| CN111110921A (en) | In-vitro construction method of tissue engineering posterior lamella cornea | |
| KR20130109849A (en) | Composition and kit comprising recombinant human bone morphogenetic protein for gingival regeneration as active ingredient | |
| Chen et al. | Gelatin methacryloyl hydrogel eye pad loaded with amniotic extract prevents symblepharon in rabbit eyes. | |
| JPH08503968A (en) | Composition containing growth factor and antimetabolite | |
| US20220273422A1 (en) | Corneal inlay design and methods of correcting vision | |
| CN114053419A (en) | Application of noradrenaline or beta-adrenergic receptor inhibitor in preparation of medicine for treating diabetic nerve repair | |
| CN111001010B (en) | External eye operation flushing fluid and preparation method thereof | |
| RU2644701C1 (en) | Method of conservative treatment of adapted penetrating wounds of the cornea | |
| Zhang et al. | Use of 5-fluorouracil-soaked bioamniotic membranes in trabeculectomy for primary open-angle glaucoma: a retrospective analysis | |
| Blacharski et al. | Thrombin infusion to control bleeding during vitrectomy for stage V retinopathy of prematurity | |
| Xiao et al. | Effect of Amniotic Membrane Transplantation on Limbal Stem Cells in Alkaline Burn Rats | |
| RU2793525C1 (en) | Method for surgical treatment of corneal defects in limbal cell insufficiency | |
| CN101057823A (en) | Composite biological preparation with antisenility and beautifying function |
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 |