CN114225016A - 一种用于抑制近视及圆锥角膜进展的方法 - Google Patents
一种用于抑制近视及圆锥角膜进展的方法 Download PDFInfo
- Publication number
- CN114225016A CN114225016A CN202111461971.2A CN202111461971A CN114225016A CN 114225016 A CN114225016 A CN 114225016A CN 202111461971 A CN202111461971 A CN 202111461971A CN 114225016 A CN114225016 A CN 114225016A
- Authority
- CN
- China
- Prior art keywords
- ophthalmic
- ophthalmic preparation
- preparation
- product
- specifically
- 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.)
- Granted
Links
- 230000004379 myopia Effects 0.000 title claims abstract description 19
- 208000001491 myopia Diseases 0.000 title claims abstract description 19
- 201000002287 Keratoconus Diseases 0.000 title abstract description 12
- 238000000034 method Methods 0.000 title abstract description 9
- 230000002401 inhibitory effect Effects 0.000 title abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 22
- 238000009472 formulation Methods 0.000 claims abstract description 15
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 14
- 108060008539 Transglutaminase Proteins 0.000 claims abstract description 13
- 102000003601 transglutaminase Human genes 0.000 claims abstract description 13
- 230000003204 osmotic effect Effects 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 11
- 102000004190 Enzymes Human genes 0.000 claims abstract description 10
- 108090000790 Enzymes Proteins 0.000 claims abstract description 10
- 102000004669 Protein-Lysine 6-Oxidase Human genes 0.000 claims abstract description 10
- 108010003894 Protein-Lysine 6-Oxidase Proteins 0.000 claims abstract description 10
- 229940088598 enzyme Drugs 0.000 claims abstract description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 7
- 239000001110 calcium chloride Substances 0.000 claims abstract description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 7
- 239000001103 potassium chloride Substances 0.000 claims abstract description 7
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 7
- 239000003381 stabilizer Substances 0.000 claims abstract description 7
- YRQNKMKHABXEJZ-UVQQGXFZSA-N chembl176323 Chemical compound C1C[C@]2(C)[C@@]3(C)CC(N=C4C[C@]5(C)CCC6[C@]7(C)CC[C@@H]([C@]7(CC[C@]6(C)[C@@]5(C)CC4=N4)C)CCCCCCCC)=C4C[C@]3(C)CCC2[C@]2(C)CC[C@H](CCCCCCCC)[C@]21C YRQNKMKHABXEJZ-UVQQGXFZSA-N 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 58
- 239000000022 bacteriostatic agent Substances 0.000 claims description 18
- 239000003889 eye drop Substances 0.000 claims description 17
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 14
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- -1 quaternary ammonium salt compounds Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 3
- 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 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 102000004316 Oxidoreductases Human genes 0.000 claims description 2
- 108090000854 Oxidoreductases Proteins 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 210000000981 epithelium Anatomy 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical class COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004087 cornea Anatomy 0.000 abstract description 24
- 230000004342 moderate myopia Effects 0.000 abstract description 3
- 235000004252 protein component Nutrition 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 12
- 238000011587 new zealand white rabbit Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 229940012356 eye drops Drugs 0.000 description 5
- 108700039882 Protein Glutamine gamma Glutamyltransferase 2 Proteins 0.000 description 4
- 102100038095 Protein-glutamine gamma-glutamyltransferase 2 Human genes 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 239000003855 balanced salt solution Substances 0.000 description 4
- 239000013068 control sample Substances 0.000 description 4
- 210000003683 corneal stroma Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 102100026858 Protein-lysine 6-oxidase Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001054867 Homo sapiens Protein-lysine 6-oxidase Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000009310 astigmatism Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 102000051318 human LOX Human genes 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 201000000766 irregular astigmatism Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 208000014733 refractive error Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 230000004393 visual impairment 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/08—Solutions
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y104/00—Oxidoreductases acting on the CH-NH2 group of donors (1.4)
- C12Y104/03—Oxidoreductases acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
- C12Y104/03013—Protein-lysine 6-oxidase (1.4.3.13), i.e. lysyl-oxidase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y203/00—Acyltransferases (2.3)
- C12Y203/02—Aminoacyltransferases (2.3.2)
- C12Y203/02013—Protein-glutamine gamma-glutamyltransferase (2.3.2.13), i.e. transglutaminase or factor XIII
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24003—Microbial collagenase (3.4.24.3)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种用于抑制近视及圆锥角膜进展的方法。本发明要求保护的组合的眼用制剂,其有效成分包括酶、眼表稳定剂和渗透压调节剂;所述酶选自转谷氨酰胺酶、赖氨酰氧化酶和II型胶原酶中至少一种;所述渗透压调节剂选自氯化钠、氯化钙和氯化钾中至少一种。本发明能够在微观层面改变角膜组织蛋白成分的内部连接、选择性增加/减弱角膜生物力学性质,产生角膜曲率梯度变化,实现角膜屈光度的改变。利用角膜屈光度的变化,进而用于降低眼屈光力,达到实现治疗轻中度近视、预防亚临床型圆锥角膜和抑制圆锥角膜进展的目的。
Description
技术领域
本发明属于医药领域,涉及一种用于抑制近视及圆锥角膜进展的方法。
背景技术
近视是人类发病率最高的疾病之一。我国是近视人口大国,有数据显示,我国青少年近视发病率可达50%-70%之多,按我国总人口估计,近视人口至少在6亿左右。定义上,近视是指物体经眼屈光系统后,物象落在视网膜前,不能在视网膜中央形成清晰的影像,而导致视物模糊的一种疾病。如对眼屈光力进行干预,则可以矫正轻中度的近视。圆锥角膜是一种以角膜基质变薄、角膜进行性前突、角膜不规则散光、矫正视力下降为特征的眼病。早期圆锥角膜特征性地表现为不断增长的近视,其本质也是一种屈光异常。
人眼中的主要屈光力来自于角膜,其屈光能力占到了全眼屈光力的70%,因此目前的近视矫正方式主要为改变角膜曲率。现有的主流方式为角膜屈光手术。该术式的总的思路是程序化去除一部分角膜基质,使得角膜中央基质变薄变凹,改变角膜曲率,降低角膜的屈光力,从而改善近视。从原理可以看出,角膜屈光手术本质是一种减法手术。存在以下不足,包括角膜的创伤和角膜基质的丢失、薄角膜的手术风险较高以及有形成医源性圆锥角膜的风险。
目前尚未出现以滴眼液眼局部应用为治疗手段的、能确切改变角膜曲率且机制合理的治疗方式。
发明内容
本发明的目的是提供一种用于抑制近视及圆锥角膜进展的方法。该方法使用复合制剂,可使得复合制剂在短暂停留眼表的停留期间产生药理学作用,在微观层面改变角膜组织蛋白成分的内部连接、选择性增加/减弱角膜生物力学性质,产生角膜曲率梯度变化,实现角膜屈光度的改变。利用角膜屈光度的变化,进而用于降低眼屈光力,达到实现治疗轻中度近视、预防亚临床型圆锥角膜和抑制圆锥角膜进展的目的。
本发明要求保护的组合的眼用制剂,其有效成分包括酶、眼表稳定剂和渗透压调节剂;
所述酶选自转谷氨酰胺酶、赖氨酰氧化酶和II型胶原酶中至少一种;
所述渗透压调节剂选自氯化钠、氯化钙和氯化钾中至少一种。
上述眼用制剂中,所述转谷氨酰胺酶为微生物型转谷氨酰胺酶2(mTgase-2)或组织型转谷氨酰胺酶2(tTgase-2);赖氨酰氧化酶的亚型不限。转谷氨酰胺酶的浓度为0.1U/mL到2U/mL,赖氨酰氧化酶的浓度为1ug/mL到10ug/mL,Ca2+的浓度为0.1到1mmol/L,Cu2+的浓度为0.02到0.1mmol/L。II型胶原酶1mg/mL到20mg/mL。疾病的严重程度不同,或者治疗流程的不同,其主要成分浓度需要有差别。
所述眼表稳定剂选自玻璃酸钠、海藻酸钠、卡波姆和羧甲基纤维素钠中至少一种;
所述转谷氨酰胺酶、赖酰胺氧化酶和眼表稳定剂的用量比为100U:5-10ug:0.1-0.3g;具体为100U:5-10ug:0.2g;
所述氯化钠、氯化钾和氯化钙同时使用时,所述氯化钠、氯化钾和氯化钙的质量比具体为0.8:0.02:0.01;
所述渗透压调节剂与所述转谷氨酰胺酶的用量比为0.8-0.9g:100U;具体为0.82g:100U或0.83g:100U;
所述渗透压调节剂与所述赖氨酰氧化酶的用量比为0.8-0.9g:5-10ug;具体为0.82g:5ug或0.83g:5ug。
所述眼用制剂的pH值为5.5-7.5;具体为7.4;
所述眼用制剂中还包括水、抑菌剂、pH调节剂和渗透压调节剂;
所述酶与所述水的用量比为0.1U-2U:0.01-0.1ug:1mL;
具体的,所述转谷氨酰胺酶、赖氨酰氧化酶与所述水的用量比为0.1U-2U:0.01-0.1ug:1mL;更具体为0.5U:0.01ug:1mL、2U:0.01ug:1mL、1U:0.01ug:1mL或0.25U:0.01ug:1mL;0.5U:0.1ug:1mL、2U:0.1ug:1mL、1U:0.1ug:1mL或0.25U:0.1ug:1mL;
所述抑菌剂具体选自硫柳汞、季铵盐类化合物和尼泊金类化合物中至少一种;所述季铵盐类化合物具体选自苯扎氯铵和苯扎溴铵中至少一种;所述尼泊金类化合物具体为羟苯乙酯;
所述抑菌剂在所述滴眼剂中的质量百分含量为0.001-0.1%;具体为0.05%;
所述pH调节剂具体选自磷酸盐、醋酸盐、枸橼酸盐、碳酸盐、盐酸、硼酸和磷酸中至少一种;所述磷酸盐具体选自磷酸氢二钠和磷酸二氢钾中至少一种。
还可包括缓冲液;具体可为PBS缓冲液。
所述眼用制剂为如下组成的眼用制剂a1、a2、a3或眼用制剂b:
所述眼用制剂a1的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂a1总质量的百分含量为0.05%;
所述眼用制剂a2的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂a2总质量的百分含量为0.05%。
所述眼用制剂a3的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂a3总质量的百分含量为0.05%。
所述眼用制剂为如下组成的眼用制剂b:
抑菌剂苯扎氯铵占所述眼用制剂b总质量的百分含量为0.05%。
另外,上述本发明提供的眼用制剂在制备治疗近视的产品中的应用及以所述眼用制剂为有效成分的治疗近视的产品或所述眼用制剂联合所述眼用制剂在制备治疗近视的产品中的应用或以所述滴眼剂联合所述眼用制剂为有效成分的治疗近视的产品,以及所述眼用制剂在制备矫正角膜屈光度的产品中的应用及以所述眼用制剂为有效成分的矫正角膜屈光度的产品或所述眼用制剂联合所述眼用制剂在制备矫正角膜屈光度的产品中的应用及以所述眼用制剂联合所述眼用制剂为有效成分的矫正角膜屈光度的产品也属于本发明的保护范围。
具体的,所述产品的形态为液态或固态;
所述产品具体为滴眼剂或眼用凝胶。
所述眼用制剂的给药方式为:正常室温下药物在限定范围内持续停留眼表25-30min,必要时需要去除角膜上皮组织。
本发明通过程序性改变角膜组织的微观构造,间接形成角膜的生物力学性质的梯度差,继而改变角膜曲率实现降低角膜屈光力的目的。从使用形式看,本发明从既往的手术治疗方式改变为用药治疗方式;从治疗机制看,本发明从既往的减法手术改变为加法治疗;从治疗目标看,本发明和既往的治疗方式均指向同一目标,即改变角膜的屈光力从而矫治近视。因此,在实现近视治疗这一目的上,本发明无论是形式还是内容,均具有突破性。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。下述实施例中所用玻璃酸钠(CAS9067-32-7)购自圣克鲁斯生物技术公司(Santa CruzBiotechnology,Inc),产品编号sc-204004;所用海藻酸钠(CAS9005-38-3)购自圣克鲁斯生物技术公司(Santa Cruz Biotechnology,Inc),产品编号sc-278679。所用转谷氨酰胺酶活性定义如下:采用Fork和Cole(1965)报道的分光Hydroxamale分析法测量。最终反应物包含0.1M Tris-HCl缓冲液,pH 6.0,30mM CBZ-L-glutaminylglycine,0.1M hydroxylamine。于37℃与酶溶液反应10min后,添加氯化铁/三氯醋酸试剂(0.7%,w/v)中止酶反应。离心(8000r/min,15min)去除沉淀后,所形成的红色于525nm测量其吸光度。用L-glutaminicacid/r-monohydroxamic acid作标准曲线。1单位转谷氨酰胺酶活力(U)定义为1min产生1μM hydroxamic acid所需要的酶量)。所用微生物型转谷氨酰胺酶2(mTgase-2)购自ZEDIRA公司(Zedira GmbH,Darmstadt,Germany),产品编号为T001。所用组织型转谷氨酰胺酶2(tTgase-2)购自同一公司,产品编号为T002。所用赖氨酰氧化酶为购自Abcam(Abcam,Cambridge,MA,USA)公司的重组人LOX蛋白,分子量为32kDa,产品编号ab240764(100ug)。LOX各亚型的催化结构域高度保守,因此对于LOX的具体亚型无特别限制。所用II型胶原酶购自Worthington公司(Worthington,USA)。
实施例1
按照本领域已知的制备方法,按照如下组成制备组合滴眼液,滴眼液分A液和B液。依据治疗目标不同,A液分为a1\a2\a3三种不同规格:
所述滴眼剂a1的组成如下:
抑菌剂苯扎氯铵占所述滴眼剂a1总质量的百分含量为0.05%;
pH 7.4
所述滴眼剂a2的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂a2总质量的百分含量为0.05%;
pH 7.4
所述滴眼剂a3的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂a3总质量的百分含量为0.05%;
pH 7.4
所述滴眼剂b的组成如下:
抑菌剂苯扎氯铵占所述眼用制剂b总质量的百分含量为0.05%;
pH 7.4
实施例2:角膜屈光度改变效果观察1
受试样品:实施例1制备的滴眼液a1
对照样品:平衡盐溶液(NaCl 7.2g/L、Na2HPO4 1.48g/L、KH2PO4 0.43g/L、pH7.2-7.4,等渗)
实验动物:新西兰大白兔5只,3月龄
实验方法:对新西兰大白兔的角膜中央范围给药,使用药物是实施例1中的试剂a1,使用附带的给药控制装置控制给药范围为角膜中心直径约4mm,给药时间为30min。后持续观察角膜的毒性反应及屈光度变化。
实验结果:饲养8周后,与对照组进行比较。对照组平均屈光度48.51±1.42D,实验组47.57±1.93D兔角膜平均屈光度降低约0.93±1.13D。
实施例3:角膜屈光度改变效果观察2
受试样品:实施例1制备的滴眼液a2
对照样品:平衡盐溶液(NaCl 7.2g/L、Na2HPO4 1.48g/L、KH2PO4 0.43g/L、pH7.2-7.4,等渗)
实验动物:新西兰大白兔5只,3月龄
实验方法:对新西兰大白兔的角膜中央范围给药,使用药物是实施例1中的试剂a2,使用附带的给药控制装置控制给药范围为角膜中心直径约4mm,给药时间为30min。后持续观察角膜的毒性反应及屈光度变化。
实验结果:饲养8周后,与对照组进行比较。对照组平均屈光度48.73±2.01D,实验组47.95±2.24D兔角膜平均屈光度降低约0.77±1.66D。
实施例4:角膜屈光度改变效果观察3
受试样品:实施例1制备的滴眼液a 3
对照样品:平衡盐溶液(NaCl 7.2g/L、Na2HPO4 1.48g/L、KH2PO4 0.43g/L、pH7.2-7.4,等渗)
实验动物:新西兰大白兔5只,3月龄
实验方法:对新西兰大白兔的角膜中央范围给药,用药为前述配方a3,使用附带的给药控制装置控制给药范围为角膜中心直径约4mm,给药时间为30min。后持续观察角膜的毒性反应及屈光度变化。
实验结果:饲养8周后,与对照组进行比较。对照组平均屈光度48.52±1.71D,实验组47.11±1.47D兔角膜平均屈光度降低约1.40±2.37D。
实施例5:角膜屈光度改变效果观察3
受试样品:实施例1制备的滴眼液a1+b
对照样品:平衡盐溶液(NaCl 7.2g/L、Na2HPO4 1.48g/L、KH2PO4 0.43g/L、pH7.2-7.4,等渗)
实验动物:新西兰大白兔5只,3月龄
实验方法:对新西兰大白兔的角膜中央范围给药,用药为前述配方药剂a1,使用附带的给药控制装置控制给药范围为角膜中心直径约4mm,同时使用前述配方药剂b,使用范围为控制装置外围2mm环形区,给药时间为30min。后持续观察角膜的毒性反应及屈光度变化。
实验结果:饲养8周后,与对照组进行比较。对照组平均屈光度48.3±3.89D,实验组44.03±2.24D兔角膜平均屈光度降低约4.33±4.06D。
Claims (9)
1.一种组合的眼用制剂,其有效成分包括酶、眼表稳定剂和渗透压调节剂;
所述酶选自转谷氨酰胺酶、赖氨酰氧化酶和II型胶原酶中至少一种;
所述渗透压调节剂选自氯化钠、氯化钙和氯化钾中至少一种。
2.根据权利要求1所述的眼用制剂,其特征在于:所述眼表稳定剂选自玻璃酸钠、海藻酸钠、卡波姆和羧甲基纤维素钠中至少一种;
所述转谷氨酰胺酶、赖酰胺氧化酶和眼表稳定剂的用量比为100U:5-10ug:0.1-0.3g;具体为100U:5-10ug:0.2g;
所述氯化钠、氯化钾和氯化钙同时使用时,所述氯化钠、氯化钾和氯化钙的质量比具体为0.8:0.02:0.01;
所述渗透压调节剂与所述转谷氨酰胺酶的用量比为0.8-0.9g:100U;具体为0.82g:100U或0.83g:100U;
所述渗透压调节剂与所述赖氨酰氧化酶的用量比为0.8-0.9g:5-10ug;具体为0.82g:5ug或0.83g:5ug。
3.根据权利要求1或2所述的眼用制剂,其特征在于:所述眼用制剂的pH值为5.5-7.5;具体为7.4;
所述眼用制剂中还包括水、抑菌剂、pH调节剂和渗透压调节剂;
所述酶与所述水的用量比为0.1U-2U:0.01-0.1ug:1mL;
具体的,所述转谷氨酰胺酶、赖氨酰氧化酶与所述水的用量比为0.1U-2U:0.01-0.1ug:1mL;更具体为0.5U:0.01ug:1mL、2U:0.01ug:1mL、1U:0.01ug:1mL或0.25U:0.01ug:1mL;0.5U:0.1ug:1mL、2U:0.1ug:1mL、1U:0.1ug:1mL或0.25U:0.1ug:1mL;
所述抑菌剂具体选自硫柳汞、季铵盐类化合物和尼泊金类化合物中至少一种;所述季铵盐类化合物具体选自苯扎氯铵和苯扎溴铵中至少一种;所述尼泊金类化合物具体为羟苯乙酯;
所述抑菌剂在所述滴眼剂中的质量百分含量为0.001-0.1%;具体为0.05%;
所述pH调节剂具体选自磷酸盐、醋酸盐、枸橼酸盐、碳酸盐、盐酸、硼酸和磷酸中至少一种;所述磷酸盐具体选自磷酸氢二钠和磷酸二氢钾中至少一种。
6.权利要求1-5任一所述眼用制剂在制备治疗近视的产品中的应用;
以权利要求1-5任一所述眼用制剂为有效成分的治疗近视的产品。
权利要求1-5任一所述眼用制剂联合6所述眼用制剂在制备治疗近视的产品中的应用;
以权利要求1-5任一所述滴眼剂联合6所述眼用制剂为有效成分的治疗近视的产品。
7.权利要求1-5任一所述眼用制剂在制备矫正角膜屈光度的产品中的应用;
以权利要求1-5任一所述眼用制剂为有效成分的矫正角膜屈光度的产品。
权利要求1-5任一所述眼用制剂联合6所述眼用制剂在制备矫正角膜屈光度的产品中的应用;
以权利要求1-5任一所述眼用制剂联合6所述眼用制剂为有效成分的矫正角膜屈光度的产品。
8.根据权利要求6或7所述的产品,其特征在于:所述产品的形态为液态或固态;
所述产品具体为滴眼剂或眼用凝胶。
9.根据权利要求6-8任一所述的应用或产品,其特征在于:所述眼用制剂的给药方式为:正常室温下药物在限定范围内持续停留眼表25-30min,必要时需要去除角膜上皮组织。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111461971.2A CN114225016B (zh) | 2021-12-02 | 2021-12-02 | 一种用于抑制近视及圆锥角膜进展的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111461971.2A CN114225016B (zh) | 2021-12-02 | 2021-12-02 | 一种用于抑制近视及圆锥角膜进展的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114225016A true CN114225016A (zh) | 2022-03-25 |
CN114225016B CN114225016B (zh) | 2024-07-09 |
Family
ID=80752846
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111461971.2A Active CN114225016B (zh) | 2021-12-02 | 2021-12-02 | 一种用于抑制近视及圆锥角膜进展的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114225016B (zh) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1299257A (zh) * | 1998-03-09 | 2001-06-13 | 伊斯塔药品公司 | 角膜硬化剂在酶学角膜曲率矫正术中的应用 |
CN1390133A (zh) * | 1999-09-15 | 2003-01-08 | 布鲁斯·H·德伍尔夫森 | 用于在角膜曲率矫形镜片佩戴期间或之后稳定角膜组织的组合物 |
WO2014204357A2 (ru) * | 2013-06-18 | 2014-12-24 | Zakharov Ivan Dmitrievich | Лекарственное средство для лечения кератоконуса и других дегенеративных заболеваний роговицы и фармацевтические препараты на его основе |
CN105031668A (zh) * | 2015-09-09 | 2015-11-11 | 北京大学第一医院 | 一种实现活体兔角膜扩张模型的装置及其构建方法 |
CN105535946A (zh) * | 2015-12-14 | 2016-05-04 | 北京大学第一医院 | 转谷氨酰胺酶在加强角膜力学性质中的应用及生物制剂 |
CN107412748A (zh) * | 2015-09-09 | 2017-12-01 | 北京大学第医院 | 一种基于ii型胶原酶的离体兔角膜扩张模型及构建装置 |
WO2021007578A1 (en) * | 2019-07-11 | 2021-01-14 | University Of Utah Research Foundation | Multi-agent ocular formulations and treatment methods |
CN112426405A (zh) * | 2020-12-04 | 2021-03-02 | 山东中观明视医药科技有限公司 | 预防及控制近视发展的药物组合物、滴眼液及其制备方法与应用 |
CN113633760A (zh) * | 2020-04-27 | 2021-11-12 | 北京大学第一医院 | 转谷氨酰胺酶在抑制或延缓近视药物中的应用 |
-
2021
- 2021-12-02 CN CN202111461971.2A patent/CN114225016B/zh active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1299257A (zh) * | 1998-03-09 | 2001-06-13 | 伊斯塔药品公司 | 角膜硬化剂在酶学角膜曲率矫正术中的应用 |
CN1390133A (zh) * | 1999-09-15 | 2003-01-08 | 布鲁斯·H·德伍尔夫森 | 用于在角膜曲率矫形镜片佩戴期间或之后稳定角膜组织的组合物 |
WO2014204357A2 (ru) * | 2013-06-18 | 2014-12-24 | Zakharov Ivan Dmitrievich | Лекарственное средство для лечения кератоконуса и других дегенеративных заболеваний роговицы и фармацевтические препараты на его основе |
CN105031668A (zh) * | 2015-09-09 | 2015-11-11 | 北京大学第一医院 | 一种实现活体兔角膜扩张模型的装置及其构建方法 |
CN107412748A (zh) * | 2015-09-09 | 2017-12-01 | 北京大学第医院 | 一种基于ii型胶原酶的离体兔角膜扩张模型及构建装置 |
CN105535946A (zh) * | 2015-12-14 | 2016-05-04 | 北京大学第一医院 | 转谷氨酰胺酶在加强角膜力学性质中的应用及生物制剂 |
WO2021007578A1 (en) * | 2019-07-11 | 2021-01-14 | University Of Utah Research Foundation | Multi-agent ocular formulations and treatment methods |
CN113633760A (zh) * | 2020-04-27 | 2021-11-12 | 北京大学第一医院 | 转谷氨酰胺酶在抑制或延缓近视药物中的应用 |
CN112426405A (zh) * | 2020-12-04 | 2021-03-02 | 山东中观明视医药科技有限公司 | 预防及控制近视发展的药物组合物、滴眼液及其制备方法与应用 |
Non-Patent Citations (2)
Title |
---|
李燕;陈建苏;李晓霞;王伟;: "转谷氨酰胺酶交联胶原凝胶构建三维角膜基质", 眼科研究, no. 10, 10 October 2009 (2009-10-10) * |
翟英;张斌;吴玉潭;陈金桂;李先芝;李丽颜;郭秀瑾;: "近视眼屈光度与角膜曲率及角膜厚度的关系分析", 现代中西医结合杂志, no. 13, 1 May 2008 (2008-05-01) * |
Also Published As
Publication number | Publication date |
---|---|
CN114225016B (zh) | 2024-07-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Pallikaris et al. | Corneal ectasia induced by laser in situ keratomileusis | |
CN102811610B (zh) | 无刺激性眼科聚维酮碘组合物 | |
US20230130851A1 (en) | Recombinant modified fibroblast growth factors and therapeutic uses thereof | |
JP6862366B2 (ja) | 眼のウイルス感染症の治療のための医薬品 | |
CN101972470B (zh) | 一种眼用原位凝胶 | |
JP6820658B2 (ja) | ジピリダモールを用いる眼疾患の治療において使用するための組成物 | |
CN101972224B (zh) | 一种眼用原位凝胶 | |
CN114225016A (zh) | 一种用于抑制近视及圆锥角膜进展的方法 | |
CN103977011B (zh) | 含有曲伏前列素和噻吗洛尔的眼用凝胶剂及其制备方法 | |
CN114929245A (zh) | 用于治疗干性年龄相关性黄斑变性(amd)或继发于干性amd的地图样萎缩的抗c5剂 | |
CN102008488B (zh) | 一种曲安奈德眼用制剂及其制备方法 | |
CN103432065B (zh) | 一种治疗青光眼的复合物凝胶及其制备方法 | |
JP6774928B2 (ja) | Casp2に対する二本鎖rna化合物およびその使用 | |
JP6114182B2 (ja) | 角膜創傷治癒のためのケトロラク組成物 | |
TWI585205B (zh) | MicroRNA-328反股組合物與其醫療用途 | |
CN104606666A (zh) | 重组牛碱性成纤维细胞生长因子滴眼液 | |
Tao et al. | Intravitreous delivery of Αb-crystallin ameliorates N-methyl-N-nitrosourea induced photoreceptor degeneration in mice: an in vivo and ex vivo study | |
Radojkovic | Cysteamine eye drops in the treatment of cystinosis–an Australian perspective | |
JP2019510788A (ja) | ヒト嚢胞性線維症肺上皮における気道表面の生理機能の小分子介在性回復 | |
CN112206312A (zh) | 一种包含pedf的用于治疗干眼的药物组合物 | |
CN114246826A (zh) | 一种不含防腐剂低刺激性的单剂量包装地夸磷索钠滴眼液及其制备方法 | |
CN104546692A (zh) | 重组牛碱性成纤维细胞生长因子眼用凝胶 | |
RU2811435C2 (ru) | Рекомбинантные модифицированные факторы роста фибробластов и их терапевтическое применение | |
KR20140046781A (ko) | 보체인자 h를 포함하는 맥락막 신생혈관 생성 예방 또는 치료용 조성물 | |
RU2104679C1 (ru) | Офтальмологическое лекарственное средство |
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 |