CN112516080B - 一种眼用药物组合物及其制备方法和应用 - Google Patents
一种眼用药物组合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN112516080B CN112516080B CN202011477050.0A CN202011477050A CN112516080B CN 112516080 B CN112516080 B CN 112516080B CN 202011477050 A CN202011477050 A CN 202011477050A CN 112516080 B CN112516080 B CN 112516080B
- Authority
- CN
- China
- Prior art keywords
- preparation
- pharmaceutical composition
- prescription
- sodium
- concentration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 13
- 239000000644 isotonic solution Substances 0.000 claims abstract description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 13
- 230000028327 secretion Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 210000003560 epithelium corneal Anatomy 0.000 claims description 2
- 230000004888 barrier function Effects 0.000 claims 1
- 230000007794 irritation Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 26
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 24
- 206010013774 Dry eye Diseases 0.000 description 24
- 241000699670 Mus sp. Species 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- 239000008215 water for injection Substances 0.000 description 16
- 229920002385 Sodium hyaluronate Polymers 0.000 description 15
- 229940010747 sodium hyaluronate Drugs 0.000 description 15
- 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 15
- 238000004090 dissolution Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- -1 Hydroxy-phenyl ethyl Chemical group 0.000 description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000001954 sterilising effect Effects 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 210000002175 goblet cell Anatomy 0.000 description 8
- 238000004806 packaging method and process Methods 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 208000005494 xerophthalmia Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 239000007951 isotonicity adjuster Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 238000004659 sterilization and disinfection Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 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 description 5
- 239000000022 bacteriostatic agent Substances 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 5
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000001103 potassium chloride Substances 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 5
- 229920000742 Cotton Polymers 0.000 description 4
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960002233 benzalkonium bromide Drugs 0.000 description 4
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 4
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 4
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012982 microporous membrane Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 235000010338 boric acid Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000004890 epithelial barrier function Effects 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940023490 ophthalmic product Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229960004499 scopolamine hydrobromide Drugs 0.000 description 2
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 206010055665 Corneal neovascularisation Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- 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 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010052143 Ocular discomfort Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 125000001980 alanyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 201000000159 corneal neovascularization Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- 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
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61P27/04—Artificial tears; Irrigation solutions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及一种眼用药物组合物及其制备方法和应用,其中,所述药物组合物包含混悬或溶解在眼可接受的等渗溶液中的丙谷二肽,该眼用药物组合物刺激性小、稳定性好且具有特别高的安全性。
Description
本申请是申请日为2018年1月23日、申请号为201810063904.7、发明名称为“一种眼用药物组合物及其制备方法和应用”的中国发明专利申请的分案申请。
技术领域
本发明涉及药物制剂技术领域,具体涉及一种眼用药物组合物及其制备方法,以及其在制备用于缓解和/或改善干眼病症和/或治疗干眼症的眼用制剂中的应用。
背景技术
干眼症是指由于泪液或眼表异常引起的泪膜不稳定和眼部不适以及视觉障碍,并对眼表有潜在损害的一类疾病,其通常表现为干涩感、异物感、疼痛感、烧灼感、眼痒、视物模糊、眼红、畏光、流泪等,长期的眼部不适严重影响患者的生活质量,严重的干眼还可引起角膜炎、角膜新生血管、角膜溃疡甚至危害视力而致盲。目前在世界范围内,干眼症已成为最常见的眼表疾病。近年来,随着空气污染的加重和视频终端使用的增多,干眼症的发病呈快速增加的趋势并向低龄化发展。干眼症患者在阅读、使用计算机、看电视、驾驶等日常活动及工作都会受影响。因此,干眼症已严重地影响着人们的工作效率和生活质量。
干眼症的发生发展影响因素众多。诱发干眼症的因素包括眼表炎症、药物滥用、长期佩戴角膜接触镜、更年期、长期使用电脑以及其他免疫因素等。研究表明,干眼症的主要病理表现为:泪膜稳定性下降后,眼表上皮在干燥环境应激下发生的一系列损害,包括角膜上皮屏障功能损害、结膜杯状细胞密度下降、眼表上皮鳞状化生与眼表炎症。目前,干眼症的主要治疗方法包括人工泪液,皮质类固醇激素以及环孢霉素A(Cyclosporine A,CsA)等免疫抑制剂。但是,人工泪液仅是一种泪液替代品,其本身无治疗作用;皮质类固醇激素及CsA等药物长期使用对眼表均有一定的毒副作用,迄今为止,临床实践中尚无治疗干眼症的特效药物。因此,当下亟需研发一种疗效好、可以长期使用且无明显局部及全身毒副作用的药物用于干眼症的治疗。
发明内容
本发明提供一种眼用药物组合物及其制备方法,以及其在制备用于缓解和/或改善干眼病症和/或治疗干眼症的眼用制剂中的应用。本发明的眼用药物组合物刺激性小、稳定性好且安全性高。
本发明是通过如下技术方案实现的:
一方面,本发明提供了一种眼用药物组合物,其包含混悬或溶解在眼可接受的等渗溶液中的丙谷二肽。
优选地,所述丙谷二肽的浓度为0.1-10%(w/v),优选为1-10%(w/v),更优选为1-5%(w/v),最优选为1%(w/v)。
优选地,所述等渗溶液由等渗剂配制而得;
优选地,所述等渗剂选自氯化钠、氯化钾、硼酸、硼砂、硫酸钠、硫酸钾、硝酸钠、硝酸钾、醋酸钠、甘露醇、甘油、丙二醇、2-(4-正辛基苯乙基)-2-氨基丙二醇盐酸盐和葡萄糖中的一种或多种;
优选地,所述等渗剂为氯化钠和/或氯化钾;
优选地,所述等渗剂的浓度为0.01-3%(w/v),优选为0.1-1%(w/v),更优选为0.4-0.8%(w/v),最优选为0.5%(w/v)。
优选地,所述药物组合物可选地包含抑菌剂;
优选地,所述抑菌剂选自苯扎氯铵、苯扎溴铵、醋酸氯己定、葡萄糖氯己定、三氯叔丁醇、苯氧乙醇、羟苯甲酯、羟苯乙酯和羟苯丙酯中的一种或多种;
优选地,所述抑菌剂选自苯扎氯铵、苯扎溴铵和羟苯乙酯中的一种或多种;
优选地,所述抑菌剂为羟苯乙酯;
优选地,所述抑菌剂的浓度为0.003-0.5%(w/v),优选为0.01-0.05%(w/v),更优选为0.02-0.035%(w/v),最优选为0.03%(w/v)。
优选地,所述药物组合物可选地包括增粘剂;
优选地,所述增粘剂选自玻璃酸钠、羧甲基纤维素钠、甲基纤维素、聚乙二醇、聚乙烯醇和聚维酮中的一种或多种;
优选地,所述增粘剂为玻璃酸钠和/或羧甲基纤维素钠;
优选地,所述增粘剂的浓度为0.01-0.5%(w/v),优选为0.05-0.2%(w/v),更优选为0.1-0.15%(w/v),最优选为0.1%(w/v)。
优选地,所述药物组合物还包括选自磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、硼酸、硼砂、醋酸、醋酸钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、盐酸和磷酸中的一种或多种pH调节剂,所述pH调节剂调节pH值至5.0-9.0,优选至6.0-8.0,更优选至6.5-7.5,最优选至7.0;
优选地,所述pH调节剂选自碳酸钠、碳酸氢钠、氢氧化钠中的一种或多种。
优选地,所述pH调节剂为氢氧化钠;
优选地,所述氢氧化钠的浓度为0.25mol/L。
另一方面,本发明还提供了一种制备上述药物组合物的方法,所述方法包括将丙谷二肽混悬或溶解在等渗溶液中,调节pH值至5.0-9.0,优选至6.0-8.0,更优选至6.5-7.5,最优选至7.0,所得溶液经微孔滤膜过滤、除菌;
优选地,所述方法包括将等渗剂加注射用水搅拌溶解,优选在80-90℃,最优选在85℃下搅拌,然后加入丙谷二肽,搅拌溶解,加入注射用水,加入pH调节剂调节pH值至5.0-9.0,优选至6.0-8.0,更优选至6.5-7.5,最优选至7.0,100℃煮沸消毒后经微孔滤膜过滤、除菌,无菌环境下分装至灭菌眼药瓶中;
优选地,所述方法包括依次将等渗剂、抑菌剂加注射用水搅拌溶解,优选在80-90℃,最优选在85℃下搅拌,溶解后,可选地在搅拌下加入增粘剂并继续搅拌至溶解,然后加入丙谷二肽,搅拌溶解,加入注射用水,加入pH调节剂调节最终pH值至5.0-9.0,优选至6.0-8.0,更优选至6.5-7.5,最优选至7.0,100℃煮沸消毒后经微孔滤膜过滤、除菌,无菌环境下分装至灭菌眼药瓶中。
又一方面,本发明还提供了上述药物组合物在制备用于缓解和/或改善干眼病症和/或治疗干眼症的眼用制剂中的应用。
附图说明
图1示出了小鼠泪液分泌量统计情况,其中:NS表示正常组,DS5表示干眼症组,DS5+Vehicle表示溶剂对照组,DS5+AG表示治疗组;其中,*P<0.05;**P<0.01;***P<0.001;
图2示出了小鼠结膜杯状细胞数量的统计情况,其中:NS表示正常组,DS5表示干眼症组,DS5+Vehicle表示溶剂对照组,DS5+AG表示治疗组;其中,*P<0.05;**P<0.01;***P<0.001;
图3示出了小鼠角膜上皮缺损情况,其中,图3A为小鼠角膜OGD染色典型图片,图3B为小鼠角膜OGD染色荧光强度统计,NS表示正常组,DS5表示干眼症组,DS5+Vehicle表示溶剂对照组,DS5+AG表示治疗组;其中,*P<0.05;**P<0.01;***P<0.001。
具体实施方式
下面将以实施例的方式具体说明本发明的技术方案,但以下实施例或制备例并不限制本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的药材原料、试剂材料等,如无特殊说明,均为市售购买产品。
制备例1
1、处方
玻璃酸钠 | 1.0g |
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法:
称取氯化钠和羟苯乙酯加注射用水800mL(85℃)搅拌溶解,溶解后,在搅拌下,加入玻璃酸钠,并不断搅拌至溶解,然后加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
制备例2
1、处方
玻璃酸钠 | 1.2g |
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 0.2g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法同制备例1
制备例3
1、处方
玻璃酸钠 | 1.5g |
羟苯乙酯 | 0.35g |
氯化钠 | 6.0g |
丙谷二肽 | 50.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.5 |
2、制法同制备例1
制备例4
1、处方
玻璃酸钠 | 1.0g |
羟苯乙酯 | 0.2g |
氯化钠 | 2.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至6.5 |
2、制法同制备例1
制备例5
1、处方
2、制法同制备例1
制备例6
1、处方
玻璃酸钠 | 0.5g |
羟苯乙酯 | 0.1g |
氯化钠 | 1.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至6.0 |
2、制法同制备例1
制备例7
1、处方
玻璃酸钠 | 5.0g |
羟苯乙酯 | 5.0g |
氯化钠 | 30.0g |
丙谷二肽 | 100.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至9.0 |
2、制法同制备例1
制备例8
1、处方
玻璃酸钠 | 0.1g |
羟苯乙酯 | 0.03g |
氯化钠 | 0.1g |
丙谷二肽 | 1.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至5.0 |
2、制法同制备例1
制备例9
1、处方
玻璃酸钠 | 1.0g |
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 1.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法同制备例1
制备例10
1、处方
玻璃酸钠 | 1.0g |
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 50.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法同制备例1
制备例11
1、处方
玻璃酸钠 | 1.0g |
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 100.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法同制备例1
制备例12
1、处方
2、制法
称取氯化钾和苯扎氯铵加注射用水800mL(85℃)搅拌溶解,溶解后,在搅拌下,加入羧甲基纤维素钠,并不断搅拌至溶解,然后加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
制备例13
1、处方
羧甲基纤维素钠 | 1.0g |
苯扎溴铵 | 0.3g |
氯化钾 | 5.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法
称取氯化钾和苯扎溴铵加注射用水800mL(85℃)搅拌溶解,溶解后,在搅拌下,加入羧甲基纤维素钠,并不断搅拌至溶解,然后加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
制备例14
1、处方
羟苯乙酯 | 0.3g |
氯化钠 | 5.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法
称取氯化钠和羟苯乙酯加注射用水800mL(85℃)搅拌溶解,溶解后,加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
制备例15
1、处方
玻璃酸钠 | 1.0g |
氯化钠 | 5.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法
称取氯化钠加注射用水800mL(85℃)搅拌溶解,溶解后,在搅拌下,加入玻璃酸钠,并继续搅拌至溶解,然后加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
制备例16
1、处方
氯化钠 | 5.0g |
丙谷二肽 | 10.0g |
注射用水加至 | 1000mL |
NaOH | 0.25mol/L,调节pH值至7.0 |
2、制法
称取氯化钠加注射用水800mL(85℃)搅拌溶解,溶解后,加入丙谷二肽,搅拌溶解,加入注射用水至1000mL,加入氢氧化钠调节pH值至7.0,100℃煮沸消毒30min,0.22μm微孔滤膜过滤,在无菌下分装至灭菌眼药瓶中,5ml/支。
实验例
动物实验方法:
(1)小鼠干眼症模型的建立及其分组处理
选用健康雌性10-12周龄的C57/BL小鼠,并将其随机平分为4组:正常组(NS)、干眼症组(DS5)、溶剂对照组(DS5+Vehicle)和治疗组(DS5+AG)
干眼症小鼠模型的建立方法:小鼠饲养于干燥环境(相对湿度:<40%,温度:21-23℃)中并联合皮下注射东莨菪碱氢溴酸盐(0.5mg/0.2ml,每次200ul,每天4次,连续5天),诱导出具有干眼表现的小鼠,建模成功。
正常组小鼠处理方法:正常组为正常小鼠,正常小鼠不进行滴眼处理,饲养于温度(21-23)℃,相对湿度50-60%的标准环境中。
干眼症组小鼠处理方法:该组干眼小鼠不经滴眼处理,饲养于温度(21-23)℃,相对湿度<40%的环境中并联合皮下注射东莨菪碱氢溴酸盐(0.5mg/0.2ml,每次200ul,每天4次,连续5天)。
溶剂对照组小鼠处理方法:给干眼小鼠眼部滴加不含丙谷二肽的本发明制剂的溶剂(每次1滴,每天四次,每次间隔4小时,持续处理5天),处理后的小鼠仍处于干燥环境(相对湿度:<40%,温度:21-23℃)中。
治疗组小鼠处理方法:给干眼小鼠眼部滴加制备例1-16制备得到的眼用制剂(每次1滴,每天四次,每次间隔4小时,持续处理5天),处理后的小鼠仍处于干燥环境(相对湿度:<40%,温度:21-23℃)中。
实验过程中对动物的处置符合科学技术部发布的《关于善待实验动物的指导性意见》。
(2)相关指标测定
各组小鼠处理完毕后,对小鼠进行检查,每次检查均由相同的处理人完成,每次检查的时间、地点、光照、温度相同。
对上述各组小鼠进行泪液分泌量测定、角膜OGD染色和结膜杯状细胞数量检测。
①酚红棉线试验检测泪液分泌量:
检查应用酚红棉(Zone-Quick;Lacrimedics,Eastsound,WA)检测小鼠泪液分泌量。裂隙灯下,用眼科镊将酚红棉线置于小鼠眼外眦部下结膜穹窿处,15秒后利用毫米尺测量酚红棉线染色的长度并记录。结果如表1所示。
表1泪液分泌量(mm)
②OGD染色检测角膜上皮屏障功能:
用毛细吸管将0.5μl Oregongreen-dextran(OGD,50mg/ml,70,000molecularweight;Invitrogen)滴入小鼠下结膜囊内,处死小鼠,并用1mL生理盐水进行冲洗,然后活体荧光显微镜(AZ100,Nikon)下观察并拍摄角膜上皮荧光染色情况。应用NIS-element软件测量染色荧光强度并进行记录。结果如表2所示。
表2染色荧光强度(a.u.)
③杯状细胞数量测量:
眼组织标本用10%的福尔马林固定,并石蜡包埋。过碘酸-希夫(PAS)试剂染色,Nikon Eclipse 50i拍照并进行结膜杯状细胞计数。结果如表3所示。
表3结膜杯状细胞数量
实验结果分析:
此外,针对上述实验,本发明还对制备例1、10-12的数据进行分析,分别如图1-3所示,其中:
图1结果显示造模后干眼症组小鼠(DS5)的泪液分泌量明显下降,三组治疗组的泪液分泌量均显著高于溶剂组,且以1%丙谷二肽浓度治疗组(DS5+1%AG)的效果最为显著,***P<0.001。
图2结果显示造模后干眼症组小鼠(DS5)的结膜杯状细胞数量明显下降,三组治疗组的杯状细胞数量均显著高于溶剂组,且以1%浓度组的效果最为显著,*P<0.05。
图3结果显示造模后干眼症组小鼠角膜出现明显的OGD染色,三组治疗组的OGD染色较溶剂组明显减轻,且以1%浓度组的效果最为显著,***P<0.001。
应当理解的是,本文所述发明不限于特定的方法学、实验方案或试剂,因为这些是可以变化的。本文所提供的论述和实例仅是为了描述特定的实施方案呈现而非意在限制本发明的范围,本发明的范围仅受到权利要求的限定。
Claims (8)
1.包含丙谷二肽的眼用药物组合物用于制备增加泪液分泌的药物的用途,其中所述药物组合物包含混悬或溶解在眼可接受的等渗溶液中的丙谷二肽;所述丙谷二肽的浓度为0.1-10%w/v。
2.根据权利要求1所述的用途,其特征在于,所述丙谷二肽的浓度为1-10%w/v。
3.根据权利要求1所述的用途,其特征在于,所述丙谷二肽的浓度为0.1-5%w/v。
4.根据权利要求1所述的用途,其特征在于,所述丙谷二肽的浓度为0.1-1%w/v。
5.包含丙谷二肽的眼用药物组合物用于制备改善角膜上皮屏障功能的药物的用途,其中所述药物组合物包含混悬或溶解在眼可接受的等渗溶液中的丙谷二肽;所述丙谷二肽的浓度为0.1-10%w/v。
6.根据权利要求5所述的用途,其特征在于,所述丙谷二肽的浓度为1-10%w/v。
7.根据权利要求5所述的用途,其特征在于,所述丙谷二肽的浓度0.1-5%w/v。
8.根据权利要求5所述的用途,其特征在于,所述丙谷二肽的浓度为0.1-1%w/v。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011477050.0A CN112516080B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810063904.7A CN108785251B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
CN202011477050.0A CN112516080B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810063904.7A Division CN108785251B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112516080A CN112516080A (zh) | 2021-03-19 |
CN112516080B true CN112516080B (zh) | 2023-09-19 |
Family
ID=64094622
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011477050.0A Active CN112516080B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
CN201810063904.7A Active CN108785251B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810063904.7A Active CN108785251B (zh) | 2018-01-23 | 2018-01-23 | 一种眼用药物组合物及其制备方法和应用 |
Country Status (21)
Country | Link |
---|---|
US (2) | US20210030833A1 (zh) |
EP (2) | EP3744316B1 (zh) |
JP (2) | JP7418351B2 (zh) |
KR (2) | KR102696573B1 (zh) |
CN (2) | CN112516080B (zh) |
AU (2) | AU2019212565B2 (zh) |
BR (1) | BR112020014950A2 (zh) |
CA (1) | CA3089344A1 (zh) |
DK (1) | DK3744316T3 (zh) |
ES (1) | ES2960069T3 (zh) |
FI (1) | FI3744316T3 (zh) |
HR (1) | HRP20231069T1 (zh) |
HU (1) | HUE063566T2 (zh) |
IL (1) | IL276244B1 (zh) |
LT (1) | LT3744316T (zh) |
PL (1) | PL3744316T3 (zh) |
PT (1) | PT3744316T (zh) |
RS (1) | RS64732B1 (zh) |
SG (1) | SG11202007077YA (zh) |
SI (1) | SI3744316T1 (zh) |
WO (1) | WO2019144863A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112516080B (zh) * | 2018-01-23 | 2023-09-19 | 盛元医药广州有限公司 | 一种眼用药物组合物及其制备方法和应用 |
CN109771370B (zh) * | 2019-02-28 | 2021-03-30 | 厦门大学 | 一种眼内手术用前房灌注液及其用途 |
CN113171340B (zh) * | 2021-05-07 | 2022-12-06 | 四川科伦药业股份有限公司 | 一种丙氨酰谷氨酰胺注射液及其生产工艺 |
WO2023098537A1 (zh) * | 2021-12-01 | 2023-06-08 | 盛元医药广州有限公司 | 丙谷二肽的新用途和包含丙谷二肽的眼用组合物 |
CN114869873A (zh) * | 2022-05-05 | 2022-08-09 | 陈小鸟 | 谷氨酰胺在制备治疗干眼症的药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002090380A1 (en) * | 2001-04-17 | 2002-11-14 | Sankt-Peterburgskaya Obschestvennaya Organizatsiya 'institut Bioregulyatsii I Gerontologii Czo Ramn' | Tetrapeptide stimulating the retinal function and the method of its application |
WO2010107069A1 (ja) * | 2009-03-17 | 2010-09-23 | 千寿製薬株式会社 | アミノ酸含有眼科用組成物 |
EP2478010A1 (en) * | 2009-09-16 | 2012-07-25 | Senju Pharmaceutical Co., Ltd. | Partial peptide of lacritin |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3206784C2 (de) * | 1982-02-25 | 1985-05-09 | Pfrimmer & Co Pharmazeutische Werke Erlangen Gmbh, 8520 Erlangen | Glutaminhaltige Zubereitungen für orale oder intravenöse Applikation |
DE59103389D1 (de) * | 1990-05-04 | 1994-12-08 | Ciba Geigy Ag | Substituierte Indole. |
EP0539329A1 (de) * | 1991-10-25 | 1993-04-28 | Ciba-Geigy Ag | Acetylen-Verbindungen, verwendbar als Leukotrien-Antagonisten |
GB9419011D0 (en) * | 1994-09-21 | 1994-11-09 | Peptech Uk Ltd | Use of muramyl peptide compounds |
EP1551399A4 (en) * | 2002-09-30 | 2011-01-05 | Mark A Babizhayev | METHOD FOR THE TOPICAL TREATMENT OF EYE DISEASES AND COMPOSITION AND DEVICE FOR THIS TREATMENT |
WO2005030242A1 (en) * | 2003-09-26 | 2005-04-07 | University Of Florida Research Foundation, Inc | Arginyl-glutamine dipeptide for treatment of pathological vascular proliferation |
PT2114421T (pt) * | 2007-03-05 | 2018-04-17 | Om Pharma | Extrato bacteriano para distúrbios respiratórios e processo para a sua preparação |
US8629099B2 (en) * | 2008-03-25 | 2014-01-14 | Bausch & Lomb Incorporated | Ophthalmic compositions comprising a dipeptide |
JP5911503B2 (ja) * | 2010-11-15 | 2016-04-27 | ラモット・アット・テル・アビブ・ユニバーシテイ・リミテッドRamot At Tel Aviv University Ltd. | アミロイド線維形成関連状態を処置するためのジペプチドアナログ |
US20130225684A1 (en) * | 2012-02-28 | 2013-08-29 | Kyowa Hakko Bio Co., Ltd. | Methods and compositions for enhancement of vision performance |
RU2498570C1 (ru) * | 2012-05-03 | 2013-11-20 | Государственное бюджетное учреждение "Уфимский научно-исследовательский институт глазных болезней Академии наук Республики Башкортостан" | Раствор для хранения роговицы |
AU2015384099B2 (en) * | 2015-02-25 | 2018-04-05 | Mackay Memorial Hospital | Use of short synthetic peptide for the treatment and/or prophylaxis of dry eye disease |
CN107049938B (zh) * | 2017-05-11 | 2021-01-05 | 艾迈德(厦门)生物科技有限公司 | 一种用于治疗干眼的滴眼液 |
CN112516080B (zh) * | 2018-01-23 | 2023-09-19 | 盛元医药广州有限公司 | 一种眼用药物组合物及其制备方法和应用 |
-
2018
- 2018-01-23 CN CN202011477050.0A patent/CN112516080B/zh active Active
- 2018-01-23 CN CN201810063904.7A patent/CN108785251B/zh active Active
-
2019
- 2019-01-22 AU AU2019212565A patent/AU2019212565B2/en active Active
- 2019-01-22 RS RS20230803A patent/RS64732B1/sr unknown
- 2019-01-22 ES ES19743390T patent/ES2960069T3/es active Active
- 2019-01-22 KR KR1020207024348A patent/KR102696573B1/ko active IP Right Grant
- 2019-01-22 US US16/964,108 patent/US20210030833A1/en not_active Abandoned
- 2019-01-22 CA CA3089344A patent/CA3089344A1/en active Pending
- 2019-01-22 KR KR1020247027207A patent/KR20240126076A/ko active Application Filing
- 2019-01-22 DK DK19743390.7T patent/DK3744316T3/da active
- 2019-01-22 PT PT197433907T patent/PT3744316T/pt unknown
- 2019-01-22 WO PCT/CN2019/072664 patent/WO2019144863A1/zh active Application Filing
- 2019-01-22 HU HUE19743390A patent/HUE063566T2/hu unknown
- 2019-01-22 SG SG11202007077YA patent/SG11202007077YA/en unknown
- 2019-01-22 FI FIEP19743390.7T patent/FI3744316T3/fi active
- 2019-01-22 EP EP19743390.7A patent/EP3744316B1/en active Active
- 2019-01-22 PL PL19743390.7T patent/PL3744316T3/pl unknown
- 2019-01-22 SI SI201930640T patent/SI3744316T1/sl unknown
- 2019-01-22 HR HRP20231069TT patent/HRP20231069T1/hr unknown
- 2019-01-22 LT LTEPPCT/CN2019/072664T patent/LT3744316T/lt unknown
- 2019-01-22 IL IL276244A patent/IL276244B1/en unknown
- 2019-01-22 JP JP2020562816A patent/JP7418351B2/ja active Active
- 2019-01-22 EP EP23193774.9A patent/EP4279063A3/en active Pending
- 2019-01-22 BR BR112020014950-0A patent/BR112020014950A2/pt unknown
-
2023
- 2023-11-22 US US18/518,134 patent/US20240148818A1/en active Pending
-
2024
- 2024-01-09 JP JP2024001117A patent/JP2024045187A/ja active Pending
- 2024-08-26 AU AU2024216339A patent/AU2024216339A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002090380A1 (en) * | 2001-04-17 | 2002-11-14 | Sankt-Peterburgskaya Obschestvennaya Organizatsiya 'institut Bioregulyatsii I Gerontologii Czo Ramn' | Tetrapeptide stimulating the retinal function and the method of its application |
WO2010107069A1 (ja) * | 2009-03-17 | 2010-09-23 | 千寿製薬株式会社 | アミノ酸含有眼科用組成物 |
EP2478010A1 (en) * | 2009-09-16 | 2012-07-25 | Senju Pharmaceutical Co., Ltd. | Partial peptide of lacritin |
Non-Patent Citations (4)
Title |
---|
Glutamine-induced Secretion of intestinal Secretory immunoglobulin A:A Mechanistic Perspective;Wenkai Ren等;《Frontiers in Immunology》;20161124;第7卷;第1-9页 * |
张庆宪.丙氨酰谷氨酰胺.《常用新药精汇手册》.河南科学技术出版社,2009, * |
汪多仁等.第五单元 酸与酰胺.《绿色发酵与生物化学品》.科学技术文献出版社,2007,第214-215页. * |
陆彬.药物新剂型与新技术.人民卫生出版社,1998,第419页. * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112516080B (zh) | 一种眼用药物组合物及其制备方法和应用 | |
ES2899597T3 (es) | Colirio para tratar el ojo seco | |
JP6994061B2 (ja) | 4-(7-ヒドロキシ-2-イソプロピル-4-オキソ-4h-キナゾリン-3-イル)-ベンゾニトリルの製剤 | |
Yang et al. | Lacrimal punctal occlusion for the treatment of superior limbic keratoconjunctivitis | |
WO2020175525A1 (ja) | ジクアホソルまたはその塩、ビニル系高分子およびセルロース系高分子を含有する眼科用組成物 | |
WO2024078515A1 (zh) | 一种包含左旋咪唑的眼用药物组合物及其制备方法和应用 | |
US20180221407A1 (en) | Ophthalmic compositions for therapeutic and prophylactic uses | |
RU2581495C1 (ru) | Способ лечения синдрома сухого глаза | |
KR20230007963A (ko) | 이나보글리플로진을 포함하는 안질환의 예방 또는 치료용 약학적 조성물 | |
RU2679319C1 (ru) | Гелеобразная искусственная слеза с антисептическим и репаративным действием | |
RU2812316C2 (ru) | Офтальмологическая фармацевтическая композиция и способы ее получения и применения | |
CN107854470B (zh) | 阿卡他定组合物、其制备方法和用途 | |
CN113262235B (zh) | 新琼寡糖在治疗眼科疾病方面的新用途 | |
Pavičić-Astaloš et al. | Eye drops preservative as the cause of corneal band keratopathy in long-term pilocarpine hydrochloride treatment | |
Chi et al. | Efficacy of combined administration of 0.2% brimonidine and 0.5% betaxolol in treatment of primary open angle glaucoma and ocular hypertension | |
CN117615756A (zh) | 洛索洛芬钠在制备治疗干眼的药物中的应用 | |
CN116270442A (zh) | 一种用于矫正近距离视力的眼用制剂 | |
JP2024515714A (ja) | 散瞳、緑内障、及び他の眼の病態を治療するための方法及び組成物 | |
CN112220749A (zh) | 咪唑立宾以及包含咪唑立宾的组合物的用途 | |
CN111358771A (zh) | 一种硫酸阿托品眼用膜剂及其制备方法 | |
US20140213605A1 (en) | Methods for treating eye disorders using opioid receptor antagonists |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40040114 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |