CN101332173A - Betaxolol hydrochloride in-situ-forming eye gel - Google Patents
Betaxolol hydrochloride in-situ-forming eye gel Download PDFInfo
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- CN101332173A CN101332173A CNA2007101231569A CN200710123156A CN101332173A CN 101332173 A CN101332173 A CN 101332173A CN A2007101231569 A CNA2007101231569 A CN A2007101231569A CN 200710123156 A CN200710123156 A CN 200710123156A CN 101332173 A CN101332173 A CN 101332173A
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- betaxolol hydrochloride
- acid
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- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 229960004347 betaxolol hydrochloride Drugs 0.000 title claims abstract description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 73
- 239000008215 water for injection Substances 0.000 claims abstract description 39
- 239000000872 buffer Substances 0.000 claims abstract description 25
- 230000003204 osmotic effect Effects 0.000 claims abstract description 8
- 239000000499 gel Substances 0.000 claims description 93
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 65
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 64
- 229920000609 methyl cellulose Polymers 0.000 claims description 53
- 239000001923 methylcellulose Substances 0.000 claims description 53
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- 239000011780 sodium chloride Substances 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 26
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 26
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000001509 sodium citrate Substances 0.000 claims description 19
- 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 claims description 19
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 14
- 239000004327 boric acid Substances 0.000 claims description 14
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 10
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 claims description 10
- 239000008118 PEG 6000 Substances 0.000 claims description 9
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 claims description 9
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 9
- VUYXVWGKCKTUMF-UHFFFAOYSA-N tetratriacontaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO VUYXVWGKCKTUMF-UHFFFAOYSA-N 0.000 claims description 9
- 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 claims description 8
- 229920002538 Polyethylene Glycol 20000 Polymers 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 8
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 8
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 8
- 239000004299 sodium benzoate Substances 0.000 claims description 8
- 235000010234 sodium benzoate Nutrition 0.000 claims description 8
- 239000001117 sulphuric acid Substances 0.000 claims description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 6
- 230000002421 anti-septic effect Effects 0.000 claims description 6
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 5
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 238000011065 in-situ storage Methods 0.000 abstract description 7
- 229960004324 betaxolol Drugs 0.000 abstract description 6
- 230000000638 stimulation Effects 0.000 abstract description 3
- 230000006872 improvement Effects 0.000 abstract description 2
- 238000005457 optimization Methods 0.000 abstract description 2
- 239000003755 preservative agent Substances 0.000 abstract description 2
- 230000002335 preservative effect Effects 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 94
- 238000003756 stirring Methods 0.000 description 92
- 238000002347 injection Methods 0.000 description 40
- 239000007924 injection Substances 0.000 description 40
- 210000001508 eye Anatomy 0.000 description 33
- 238000000034 method Methods 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 25
- 239000012528 membrane Substances 0.000 description 25
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 18
- 239000003643 water by type Substances 0.000 description 15
- 239000007853 buffer solution Substances 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000007704 transition Effects 0.000 description 8
- 230000004410 intraocular pressure Effects 0.000 description 7
- 239000004033 plastic Substances 0.000 description 7
- 229920003023 plastic Polymers 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 235000019445 benzyl alcohol Nutrition 0.000 description 6
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical class [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- 210000004087 cornea Anatomy 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229940044476 poloxamer 407 Drugs 0.000 description 2
- 201000004616 primary angle-closure glaucoma Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 1
- 208000009786 Anophthalmos Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 210000005224 forefinger Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940100655 ophthalmic gel Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical class [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 230000009978 visual deterioration Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention discloses a betaxolol in situ forming eye gel and a preparation method thereof. 1000ml of the betaxolol in situ forming eye gel of the present invention contains 0.5 to 5g of betaxolol hydrochloride, 0.05 to 1g of preservative, 1.0 to 7.5g of osmotic pressure regulator and 30 to 150g of gel substrate, and the rest is acid-base buffer and water for injection. The betaxolol in situ forming eye gel adopts the optimization of accessories and the technical improvement to enrich the medicine preparation form of the betaxolol, prolong the resorting time of medicine in eye and improve the curative effect, and the betaxolol in situ forming eye gel does not cause any bad stimulation effect.
Description
[technical field]
The invention belongs to medical technical field, be specifically related to a kind of betaxolol hydrochloride in-situ-forming eye gel.
[background technology]
Instant gel for eye is also named eye with gel on the throne or ocular in-situ gel, its preparation is liquid when room temperature is placed, after splashing into ophthalmic, because the variation of temperature, pH value and ionic strength is converted into gel, can be trapped in ophthalmic in a long time, thereby reach the extended treatment time, strengthen the effect that therapeutic effect reduces drug loss.
Instant gel for eye also is not a kind of very sophisticated pharmaceutical preparation at present, temperature dependent, the instant gel for eye of principle such as pH value and ionic strength immaturity still also in commercialization, this is except the meticulous technology of needs because of this dosage form, suitable adjuvant, the appropriate coupling that also needs instant gel for eye Chinese medicine and technology and adjuvant, otherwise just can not reach room temperature and be placed as liquid state, be converted into gel after splashing into ophthalmic, this field work still needs a large amount of basic research, have only U.S. food Drug Administration to ratify a kind of Timoptic-XE (Timolol Malaeate Ophthalmic Gel forming Solution) listing at present, belong to ionic strength responsive type instant gel for eye, and other ophthalmic remedies still in the anophthalmia gel on the throne emerge.
Patent documentation CN1377706A discloses a kind of ocular in-situ gel preparation with suitable phase transition temperature, it merges the combination that utilizes the different model poloxamer, prepared the ocular in-situ gel preparation that contains medicine and water soluble polymer adjuvant, contain poloxamer 407 and poloxamer 188 in the preparation, also can add concentration less than 3% water soluble polymer adjuvant, this situ-gel has suitable phase transition temperature, can form gel with the liquid condition administration and on the live cornea surface at ambient temperature.It is very expensive pharmaceutic adjuvants that but this patent is used poloxamer 407 and 188, and this working of an invention process is more complicated also, thereby also needs the process of the new instant gel for eye of further research and development.
Betaxolol is a beta-blocker.Mechanism of action is to reduce aqueous humor to generate, and does not influence pupil size and regulative mechanism, and long action time, hypotensive effect can be kept 12 hours.This product is a calcium antagonism, and the blood vessel that can directly expand improves the blood supply of eye, thereby optic nerve is shielded.
The betaxolol hydrochloride eye drop is a white suspension, is applicable to chronic open angle glaucoma, ocular hypertension, and the effect of this product intraocular pressure lowering started from after the medication in 30 minutes, can reach the maximum reducing effect in 2 hours.Behind each some medicine antihypertensive effect was continued 12 hours.
The betaxolol hydrochloride eye drop is a kind of ophthalmic preparation commonly used, but exists the collyrium loss splash into ophthalmic big clinically, and the holdup time is short, and these problems have all limited the curative effect of betaxolol hydrochloride eye drop and more widely-used.
[summary of the invention]
The object of the present invention is to provide a kind of betaxolol hydrochloride in-situ-forming eye gel.
Another object of the present invention is to provide the preparation method of betaxolol hydrochloride in-situ-forming eye gel.
Specifically, 1000 milliliters of betaxolol hydrochloride in-situ-forming eye gels of the present invention contain: betaxolol hydrochloride 0.5-5 gram, and antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-7.5 gram, gel-type vehicle 30-150 gram, surplus is acid-base buffer agent and water for injection.
Contain in above-mentioned 1000 milliliters of gels: betaxolol hydrochloride 2.5 grams, antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-5.5 gram, gel-type vehicle 30-100 gram, surplus is acid-base buffer agent and water for injection.
Above-mentioned acid-base buffer agent is controlled at the pH value of described betaxolol hydrochloride in-situ-forming eye gel between the 4.21-8.67.
Foregoing preservatives is selected from one or more in phenethanol, benzyl alcohol, sodium benzoate, methyl hydroxybenzoate and the ethyl hydroxybenzoate; Described osmotic pressure regulator is a sodium chloride; Described acid-base buffer agent is selected from hydrochloric acid, sulphuric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium citrate, citric acid, triethanolamine, diethanolamine, the ethanolamine 2 kinds or multiple; Described gel-type vehicle is selected from one or more in Polyethylene Glycol, methylcellulose, ethyl cellulose, polyacrylic acid and the sodium polyacrylate.
Above-mentioned acid-base buffer agent is selected from hydrochloric acid and triethanolamine, and the mol ratio of the two is 1: 0.5-2.
Above-mentioned acid-base buffer agent is selected from hydrochloric acid and sodium citrate, and the mol ratio of the two is 1: 0.2-2.
Above-mentioned gel-type vehicle is selected from Polyethylene Glycol and methylcellulose, and the weight ratio of the two is 1: 50-5000.
Above-mentioned Polyethylene Glycol is selected from one or more among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000, PEG-6000, PEG-10000 and the PEG-20000.
Above-mentioned Polyethylene Glycol is selected from one or more among PEG-1500, PEG-4000 and the PEG-6000.
The preparation method of betaxolol hydrochloride in-situ-forming eye gel of the present invention is: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, antiseptic is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and stir behind the adding acid-base buffer agent, crossing microporous filter membrane filters, filtrate reheat to 40 ℃, add osmotic pressure regulator and gel-type vehicle while hot, be stirred to room temperature, add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Instant gel for eye is divided into three kinds: responsive to temperature type, pH value responsive type and ionic strength responsive type, wherein the responsive to temperature type instant gel for eye is easy to industrialization relatively, the present invention also coagulates-the glue realization by the responsive to temperature type eyes, but grope to find the stability of responsive to temperature type gel and can under the local temperature of people's eyeball, be converted into the pH value of gel and instant gel at once whether stable relation is close through inventor's experiment.The inventor adopts the acid-base buffer agent of larger capacity to guarantee pH value stable of instant gel for eye, thereby has guaranteed that gel has responsive and suitable phase transition temperature.
The present invention has enriched the pharmaceutical dosage form of betaxolol hydrochloride classics side by the optimization of adjuvant and the improvement of technology, has prolonged medicine greatly in the eye holdup time, has improved curative effect, and does not have the pessimal stimulation reaction.
[specific embodiment]
Following embodiment and experimental example further describe the present invention, but described embodiment and experimental example only are used to illustrate the present invention rather than restriction the present invention.In the invention in the methylcellulose methoxyl content be 27-32%.
Embodiment 1
Prescription: betaxolol hydrochloride 0.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Sodium citrate 7.6 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 2
Prescription: betaxolol hydrochloride 1 gram sulphuric acid (0.15mol/L) 200 milliliters
Sodium citrate 10.5 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 3
Prescription: betaxolol hydrochloride 2.5 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram sodium benzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 25.0 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, and adding sodium citrate, sodium hydroxide and sodium benzoate, stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 4
Prescription: betaxolol hydrochloride 0.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 5
Prescription: betaxolol hydrochloride 2.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 14.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 6
Prescription: betaxolol hydrochloride 5 gram hydrochloric acid (0.15mol/L) 250 milliliters
Triethanolamine 30 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 7
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Diethanolamine 8 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 8
Prescription: betaxolol hydrochloride 1 gram hydrochloric acid (0.15mol/L) 400 milliliters
Ethanolamine 16 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 9
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Sodium citrate 7.6 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 10
Prescription: betaxolol hydrochloride 0.5 gram sulphuric acid (0.15mol/L) 200 milliliters
Sodium citrate 9.6 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 11
Prescription: betaxolol hydrochloride 1 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram sodium benzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 25.0 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, be cooled to 60 ℃ while stirring, in addition Borneolum Syntheticum is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and add sodium citrate, sodium hydroxide and sodium benzoate stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 12
Prescription: betaxolol hydrochloride 2.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 13
Prescription: betaxolol hydrochloride 2.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 10.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 14
Prescription: betaxolol hydrochloride 5 grams 0.8 gram hydrochloric acid (0.05mol/L) 250 milliliters
Triethanolamine 10 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 15
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Diethanolamine 18 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 16
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Ethanolamine 21 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 17
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 400 milliliters
Sodium citrate 8.6 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose, PEG-1000 and PEG-400 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply heavy-amount to 1000 milliliters, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 18
Prescription: betaxolol hydrochloride 2.5 gram sulphuric acid (0.15mol/L) 200 milliliters
Sodium citrate 17.6 gram methylcellulose 5.0 gram benzyl alcohol 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-1000,70 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, benzyl alcohol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding sodium citrate, stir more than 30 minutes, stir after adding sulphuric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add sodium chloride, methylcellulose and PEG-1000 while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 19
Prescription: betaxolol hydrochloride 2.5 gram sodium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram sodium benzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-4000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, and adding sodium citrate, sodium hydroxide and sodium benzoate, stir more than 30 minutes, stir after adding boric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-4000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 20
Prescription: betaxolol hydrochloride 2.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Boric acid 5.6 gram methylcellulose 5.0 gram methyl hydroxybenzoate 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,100 grams
Water for injection is an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, methyl hydroxybenzoate is dissolved in the ethanol, is added dropwise to while stirring in the above solution, and adds boric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 21
Prescription: betaxolol hydrochloride 2.5 gram potassium hydroxide (0.1mol/L) 200 milliliters
Citric acid 11.0 gram methylcellulose 5.0 gram ethyl hydroxybenzoates 0.5 gram
5 milliliters of sodium chloride of ethanol, 5.0 gram PEG-6000,50 grams
PEG-20000 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, ethyl hydroxybenzoate is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding citric acid and potassium hydroxide, stir more than 30 minutes, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃ adds PEG-20000, PEG-6000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stir and make it form even gel, promptly aseptic subpackaged.
Embodiment 22
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.15mol/L) 250 milliliters
Triethanolamine 30 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1500,35 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding triethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 23
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.05mol/L) 400 milliliters
Diethanolamine 18 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-1000,20 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding diethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-1500 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
Embodiment 24
Prescription: betaxolol hydrochloride 2.5 gram hydrochloric acid (0.05mol/L) 400 milliliters
Ethanolamine 12 gram methylcellulose 5.0 gram phenethanol 0.5 gram
5 milliliters of sodium chloride of ethanol, 2.5 gram PEG-10000,10 grams
PEG-400 5 gram waters for injection are an amount of
Method for making: with the water for injection heated and boiled, be cooled to 80 ℃, add betaxolol hydrochloride, phenethanol is dissolved in the ethanol, be added dropwise to while stirring in the above solution, and adding ethanolamine, stir more than 30 minutes, stir after adding hydrochloric acid again, cross microporous filter membrane (0.22 μ m) and filter, filtrate reheat to 40 ℃, add PEG-400, PEG-10000 and methylcellulose while hot, be stirred to room temperature (18-25 ℃), add the injection water again and supply weight to 1000 milliliter, stirring makes it form even gel, and is promptly aseptic subpackaged.
The pH value of experimental example 1-gel of the present invention is measured
1 method summary
This method is made indicating electrode with glass electrode, makes reference electrode with saturated calomel electrode, with pH4,7 or 9 standard buffer solutions location, measures the pH value of gel.
2 instruments
2.1 acidometer: measuring range 0～14pH; Accuracy of reading≤0.02pH.
2.2 the pH glass electrode, isopotential point is about pH7.
2.3 saturated calomel electrode.
2.4 thermometer: 0～100 ℃ of measuring range.
2.5 plastic cup: 50 milliliters.
2.6 the scientific calculator of band wire regression equation.
3 reagent
3.1 pH4 standard buffer solution
Accurately take by weighing 10.21 gram Potassium Hydrogen Phthalates (KHC8H2O4), be dissolved in reagent water and be settled to 1L.Because this solution dilution effect is little, needn't be dry before the weighing.It is mouldy that this solution is placed several Zhou Houhui, adds a little microsolubility phenol or its chemical compound (as thymol) and make antifungus agent and can prevent that here phenomenon takes place.
3.2 pH7 standard buffer solution
Accurately take by weighing 3.5 grams respectively through 120 ± 10 ℃ of dry 2h and be cooled to the pure disodium hydrogen phosphate,anhydrous of top grade (Na2HPO4) of room temperature, and 3.40 gram top grade pure phosphoric acid potassium dihydrogens (KH2PO4), be dissolved in reagent water together and be settled to 1L.The solution for preparing should be avoided being stain by Atmospheric Carbon Dioxide.6 Zhou Houying prepare again.
3.3 pH9 standard buffer solution
Accurately take by weighing the 3.81 gram pure Boraxs of top grade (Na2B4O710H2O), be dissolved in the reagent water of no carbon dioxide and be settled to 1L.The solution for preparing should be avoided contacting with Atmospheric Carbon Dioxide as far as possible.Should prepare again all around.
The pH value of above-mentioned standard buffer solution under condition of different temperatures is as shown in table 1.
The pH value of table 1 standard buffer solution under different temperatures
4 analytical procedures
4.1 the preparation of electrode
4.1.1 new glass electrode or put no glass electrode for a long time should place the pH4 standard buffer solution to soak diel in advance.Finish using, also should be placed in the above-mentioned buffer and soak, be not placed on the medium-term and long-term immersion of reagent water.If find that grunge pollution is arranged, preferably be placed on 0.1mol/L hydrochloric acid in the use, the 0.1mol/L sodium hydroxide, circulation immersion is each 5 minutes in the 0.1mol/L hydrochloric acid.After cleaning with reagent water, in the pH4 buffer, soak again.
4.1.2 preferably be immersed in before saturated potassium chloride electrode uses in the weak solution of 10 times of saturated potassium chloride solution dilutions.During storage the inlet jam-pack of upper end, breakdown then during use.Should often note injecting saturated potassium chloride solution to certain liquid level from inlet.
4.2 instrumental correction
After instrument is opened half an hour, press the regulation of instrument description, return to zero, operating procedures such as temperature-compensating and full scale correction.
4.3 pH location
As the case may be, select following a kind of method location.
4.3.1 single-point location
Select a kind of pH value and the approaching standard buffer solution of tested gel phase for use.Before the location earlier with reagent water flushing electrode and plastic cup more than 2 times.Electrode bottom water droplet is blotted lightly (not going wiping) with clean filter paper then in order to avoid electrode bottom static electrification causes the reading instability with filter paper.To locate buffer and pour in the plastic cup, immerse electrode, shake the plastic cup several seconds slightly.Measure gelling temp (requiring consistent), find the pH value of location buffer under this temperature, instrument is positioned to this pH value with location buffer temperature.Repeat zeroing, proofread and correct and locate 1～2 time, till stable.
4.3.2 twice location
Get the pH7 standard buffer solution earlier according to last method location.Behind the electrode wash clean, another localization criteria buffer (if tested gel is acid, is selected the pH4 buffer; If alkalescence is selected the pH9 buffer) pour in the plastic cup, after electrode bottom water droplet blots gently with filter paper, electrode is immersed in the cup, shake the several seconds slightly, press read switch.Adjust the pH value that the slope knob makes the reading indication or shows the second location buffer under this probe temperature.Repeat 1～2 time two point location be operated to stable till.
4.3.3 3 return the location
Three plastic cups of wash clean are inserted pH4,7,9 standard buffer solutions respectively.Get one of them earlier by behind the 4.3.1 location, measure the pH value of two standard buffer solutions in addition again.The standard value of three standard buffer solutions under probe temperature and corresponding pH value reading value are stored at the enterprising line retrace of computer.If the regressand value of being obtained by three reading values differs with standard value and all is not more than 0.02pH unit, can think that instrument and electrode are normal, can carry out the pH mensuration of gel.
4.4 the mensuration of gel
After plastic cup and electrode cleaned with reagent water, the tested gel flushing of reuse 2 times or more than.Then, immerse electrode and carry out pH value and measure.Take reading.
5. the pH value data of gel of the present invention see Table 1
The pH value of table 1 gel of the present invention
Description of test thus, gel pH value of the present invention is between the 4.21-8.67.
The phase transition temperature of experimental example 2-gel of the present invention is measured
The assay method of phase transition temperature is with reference to the method for testing of patent documentation CN1377706A Instructions Page 3 experiment one, and the gained data are temperature range, see the following form 2
The phase transition temperature of table 2 gel of the present invention
Description of test thus, the phase transition temperature of gel of the present invention be between 28-34 ℃, can satisfy at instant gel room temperature of the present invention to be in liquid state, is converted into the solid, shaped gel after splashing into ophthalmic, reaches the effect of prolong drug delay effect.
Instant gel for eye is divided into three kinds: responsive to temperature type, pH value responsive type and ionic strength responsive type, wherein the responsive to temperature type instant gel for eye is easy to industrialization relatively, the present invention also realizes by the responsive to temperature type instant gel for eye, but grope to find the stability of responsive to temperature type gel and can under the local temperature of people's eyeball, be converted into the pH value of gel and instant gel at once whether stable relation is close through inventor's experiment.The inventor adopts the acid-base buffer agent of larger capacity to guarantee pH value stable of instant gel for eye, thereby has guaranteed that gel has responsive and suitable phase transition temperature.
The test that the eye of experimental example 3-instant gel for eye of the present invention stimulates
40 New Zealand white rabbit are divided into 10 groups, in each group rabbit conjunctival capsule, splash into instant gel for eye of the present invention (embodiment 1,4,7,9,12,16,18,20,22 and 24) respectively, stimulation test is with interior high frequency points left eye, per 45 minutes once, each 1, and be contrast with normal saline point right eye simultaneously, continuous 4 times.Each treated animal conjunctiva of regular check, iris and cornea tissue there is no reactions such as hyperemia, edema, secretions adhesion behind eye dripping.This shows that instant gel for eye of the present invention is safe, and is non-stimulated to ocular tissue.
Experimental example 4-instant gel for eye of the present invention is treated early stage angle closure glaucoma and is observed
1. data and method
1.1 the early stage angle closure glaucoma patient of clinical data is totally 10 examples (16), male 8 examples (13), and women 2 examples (3), the age, intraocular pressure was at (20.1 ± 5.5) millimetres of mercury before the treatment at 52～78 years old.
1.2 Therapeutic Method: clean both hands, head is steeved, left hand thumb and forefinger draw back palpebra inferior respectively, the right hand drip in the general 1-2 of distance eyes centimetre place far away 1 (embodiment 1) each 1 in experimenter's ill eyeball, 1 day 3-4 time, all patient's follow-up observation intraocular pressures, vision, the visual field changed 6 months as a result.
1.3 varieties of intraocular pressure: treat intraocular pressure＜21 millimetress of mercury of 11 of 7 people in back 1 year, the intraocular pressure control rate is 68.7%.
1.4 vision changes: the 1st day vision of postoperative improves and stablizes 8 of 5 people, keeps 7 of original vision person 4 people, 1 of visual deterioration person 1 people.
1.5 the visual field changes: 7 of 5 people broaden one's vision, 9 no changes of 5 people.
2. discuss: primary angle-closure glaucoma is one of serious irreversibility diseases causing blindness.China is the hotspot of angle closure glaucoma, and its prevalence is 14 times of American-European countries.It raises to cut the prevention intraocular pressure iris week in early days.The present invention of preliminary experiment proof has certain treatment curative effect to primary angle-closure glaucoma.
Claims (8)
1. betaxolol hydrochloride in-situ-forming eye gel, it is characterized in that containing in 1000 milliliters of described gels: betaxolol hydrochloride 0.5-5 gram, antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-7.5 gram, gel-type vehicle 30-150 gram, surplus is acid-base buffer agent and water for injection.
2. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 1, it is characterized in that containing in 1000 milliliters of described gels: betaxolol hydrochloride 2.5 grams, antiseptic 0.05-1 gram, osmotic pressure regulator 1.0-5.5 gram, gel-type vehicle 30-100 gram, surplus is acid-base buffer agent and water for injection.
3. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 2, it is characterized in that described acid-base buffer agent is controlled at the pH value of described replacement content instant gel for eye between the 4.21-8.67.
4. according to the arbitrary described betaxolol hydrochloride in-situ-forming eye gel of claim 1-3, it is characterized in that described antiseptic is selected from one or more in phenethanol, benzyl alcohol, sodium benzoate, methyl hydroxybenzoate and the ethyl hydroxybenzoate; Described osmotic pressure regulator is a sodium chloride; Described acid-base buffer agent is selected from hydrochloric acid, sulphuric acid, boric acid, sodium hydroxide, potassium hydroxide, sodium citrate, citric acid, triethanolamine, diethanolamine, the ethanolamine 2 kinds or multiple; Described gel-type vehicle is selected from one or more in Polyethylene Glycol, methylcellulose, ethyl cellulose, polyacrylic acid and the sodium polyacrylate.
5. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 4, it is characterized in that described acid-base buffer agent is selected from hydrochloric acid and triethanolamine, the mol ratio of the two is 1: 0.5-2.
6. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 4, it is characterized in that described acid-base buffer agent is selected from hydrochloric acid and sodium citrate, the mol ratio of the two is 1: 0.2-2.
7. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 4, it is characterized in that described gel-type vehicle is selected from Polyethylene Glycol and methylcellulose, the weight ratio of the two is 1: 50-5000.
8. according to the described betaxolol hydrochloride in-situ-forming eye gel of claim 7, it is characterized in that described Polyethylene Glycol is selected from one or more among PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000, PEG-6000, PEG-10000 and the PEG-20000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101231569A CN101332173A (en) | 2007-06-29 | 2007-06-29 | Betaxolol hydrochloride in-situ-forming eye gel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101231569A CN101332173A (en) | 2007-06-29 | 2007-06-29 | Betaxolol hydrochloride in-situ-forming eye gel |
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| CN101332173A true CN101332173A (en) | 2008-12-31 |
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|---|---|---|---|
| CNA2007101231569A Pending CN101332173A (en) | 2007-06-29 | 2007-06-29 | Betaxolol hydrochloride in-situ-forming eye gel |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727423A (en) * | 2012-06-20 | 2012-10-17 | 贵州大学 | Betaxolol hydrochloride ion-sensitive eye-use in-situ gel and preparation method thereof |
| CN104188937A (en) * | 2014-08-01 | 2014-12-10 | 广东药学院 | Montmorillonite-inlaid solid lipid nanoparticle preparation and preparation method thereof |
| CN105963677A (en) * | 2016-05-03 | 2016-09-28 | 宋钦 | Eye nursing gel and preparation method thereof |
-
2007
- 2007-06-29 CN CNA2007101231569A patent/CN101332173A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727423A (en) * | 2012-06-20 | 2012-10-17 | 贵州大学 | Betaxolol hydrochloride ion-sensitive eye-use in-situ gel and preparation method thereof |
| CN104188937A (en) * | 2014-08-01 | 2014-12-10 | 广东药学院 | Montmorillonite-inlaid solid lipid nanoparticle preparation and preparation method thereof |
| CN104188937B (en) * | 2014-08-01 | 2017-05-31 | 广东药学院 | It is a kind of to inlay solid lipid nano-particle preparation of montmorillonite and preparation method thereof |
| CN105963677A (en) * | 2016-05-03 | 2016-09-28 | 宋钦 | Eye nursing gel and preparation method thereof |
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Open date: 20081231 |