CN100413503C - Compound ocular medicinal composition - Google Patents
Compound ocular medicinal composition Download PDFInfo
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- CN100413503C CN100413503C CNB200510000253XA CN200510000253A CN100413503C CN 100413503 C CN100413503 C CN 100413503C CN B200510000253X A CNB200510000253X A CN B200510000253XA CN 200510000253 A CN200510000253 A CN 200510000253A CN 100413503 C CN100413503 C CN 100413503C
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- betaxolol
- brimonidine
- eye
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960004324 betaxolol Drugs 0.000 claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 35
- 229960003679 brimonidine Drugs 0.000 claims abstract description 32
- 239000000839 emulsion Substances 0.000 claims abstract description 12
- 239000000725 suspension Substances 0.000 claims abstract description 11
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims description 65
- 239000000243 solution Substances 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 28
- 238000009472 formulation Methods 0.000 claims description 7
- 239000003186 pharmaceutical solution Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000004410 intraocular pressure Effects 0.000 abstract description 23
- 239000003937 drug carrier Substances 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 2
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 abstract 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- IWEGDQUCWQFKHS-UHFFFAOYSA-N 1-(1,3-dioxolan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(CC2OCCO2)N=C1 IWEGDQUCWQFKHS-UHFFFAOYSA-N 0.000 description 30
- 229960004347 betaxolol hydrochloride Drugs 0.000 description 30
- 229960001724 brimonidine tartrate Drugs 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000004372 Polyvinyl alcohol Substances 0.000 description 19
- 229940003677 alphagan Drugs 0.000 description 19
- 229960000686 benzalkonium chloride Drugs 0.000 description 19
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 19
- 229920002451 polyvinyl alcohol Polymers 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 18
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 17
- 230000003203 everyday effect Effects 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000002002 slurry Substances 0.000 description 14
- 230000001954 sterilising effect Effects 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- 230000000699 topical effect Effects 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 210000001328 optic nerve Anatomy 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 229910052979 sodium sulfide Inorganic materials 0.000 description 10
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003889 eye drop Substances 0.000 description 7
- 229940012356 eye drops Drugs 0.000 description 7
- 229960002668 sodium chloride Drugs 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000001117 sulphuric acid Substances 0.000 description 6
- 235000011149 sulphuric acid Nutrition 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 229940079101 sodium sulfide Drugs 0.000 description 5
- 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 4
- 229930195725 Mannitol Natural products 0.000 description 4
- -1 Polyoxyethylene Polymers 0.000 description 4
- 229910021538 borax Inorganic materials 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 235000010339 sodium tetraborate Nutrition 0.000 description 4
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 210000000554 iris Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- WSWCOQWTEOXDQX-UHFFFAOYSA-N 2,4-Hexadienoic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 108060003345 Adrenergic Receptor Proteins 0.000 description 2
- 102000017910 Adrenergic receptor Human genes 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 210000001742 aqueous humor Anatomy 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 229950007919 egtazic acid Drugs 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000008569 process 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
- 230000001681 protective effect Effects 0.000 description 2
- 230000009467 reduction 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
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- GDWRKZLROIFUML-UHFFFAOYSA-N 4-phenylbutan-2-ol Chemical compound CC(O)CCC1=CC=CC=C1 GDWRKZLROIFUML-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 208000030768 Optic nerve injury Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a compound ophthalmic remedy composition prepared from two kinds of active ingredients, wherein the two kinds of active ingredients are brimonidine and betaxolol, and the weight ratio of the brimonidine to the betaxolol is 0.004 to 40:1. The composition can be mixed with pharmaceutically acceptable carriers to be prepared into clinically acceptable preparations, comprising suspension preparations, emulsion or solution preparations. The composition is clinically used for reducing intra-ocular pressure and for treating glaucoma.
Description
Technical field
The present invention relates to a kind of compound recipe eye medicine combination, particularly relate to the glaucomatous compound recipe eye medicine combination of a kind of treatment.
Background technology
Open angle glaucoma is cause irreversible infringement and the defect of visual field of looking the nipple position owing to intraocular pressure raises, and causes a kind of oculopathy of losing one's sight at last, does not still have the radical cure method at present.Mainly be to reduce intraocular pressure with medicine to develop clinically with disease controlling.Increased intraocular pressure is main indication of this disease.The high intraocular pressure of persistence can cause the damage of optic nerve, and retinal nerve fibre layer is damaged, and serious pathologic such as constriction of visual field changes.Therefore select for use and have the intraocular pressure of reduction the Drug therapy of function of protecting optic nerve is arranged simultaneously is one of optimum selection of ophthalmologist.
Intraocular pressure raises normally because ophthalmic water liquid produces too much or water liquid can't unimpeded discharge or both have concurrently.Need the open angle glaucoma patient of Drug therapy too much to cause intraocular pressure to raise owing to ophthalmic water liquid produces mostly.Alpha's adrenoceptor agonists class and Beta adrenoceptor blocker class ocular hypotensive agents owner reduce intraocular pressure by the generation that suppresses ophthalmic water liquid.Alpha-2 type epinephrine selective agonist brimonidine (Brimonidine) can act on Alpha-2 type adrenoceptor specifically to reach reducing iop.Alphagan (Alphagan is Brimonidine, 0.2% trade name) is the 2-adrenergic agonist components of latest generation in listing in 1996.To the selectivity height of Alpha-2 receptor, there is not similar other drug by acting on of the side effect of Alpha-1 receptor to heart and blood pressure generation.The mechanism of intraocular pressure lowering is to reduce aqueous humor to generate.Brimonidine also has function of protecting optic nerve except reducing iop is arranged.Because normal phase intraocular pressure increases, and can cause optic nerve aixs cylinder demyelination, optic nerve extruding and optic nerve ischemia, thus cause optic nerve injury.Select for use brimonidine promptly can reduce intraocular pressure, simultaneously function of protecting optic nerve is arranged again, so Alphagan has become the glaucomatous line medicine of treatment clinically.
Betaxolol (Betaxolol) belongs to Beta adrenoceptor blocker class, to the selectivity height of Beta-1 receptor, does not have similar other drug by acting on the side effect of Beta-2 receptor to heart and the generation of respiratory system.The mechanism of intraocular pressure lowering is to reduce aqueous humor to generate.Clinically use Bei Teshu (Bei Teshu is Betaxolol, 0.5% trade name) drug effect is remarkable and safety is fine, simultaneously optic nerve is also had protective effect.Because the intraocular pressure lowering pharmacology of these two medicines of brimonidine and betaxolol mechanism is different, it is formed compound preparation is a very ideal intraocular pressure lowering, the prescription of protection optic nerve.
Summary of the invention
The object of the invention is to provide a kind of compound recipe eye medicine combination of being made up of brimonidine and two kinds of active component of betaxolol; The object of the invention also is to provide the compound method of this compound recipe eye medicine combination.
The present invention seeks to be achieved through the following technical solutions.
Compound recipe eye medicine combination of the present invention is made by the active component of following weight portion:
Brimonidine (Brimonidine) 0.004～40.0 weight portion, betaxolol (Betaxolol) 1.0 weight portions;
Above-mentioned two kinds of active component brimonidines and betaxolol optimum ratio are: 0.01～1: 1.0; Above-mentioned two kinds of active component brimonidines and betaxolol optimum ratio also can be: 1～10.0: 1.0; Above-mentioned two kinds of active component brimonidines and betaxolol optimum ratio also can be: 0.004～0.01: 1.0; Above-mentioned two kinds of active component brimonidines and betaxolol optimum ratio also can be: 10.0～40.0: 1.0; The best proportioning of above-mentioned two kinds of active component brimonidines and betaxolol is: 0.4: 1.
Above-mentioned two kinds of active component brimonidines and betaxolol can be that any its chemically can be accepted the salt of form, as: brimonidine tartrate, betaxolol hydrochloride, sulphuric acid betaxolol etc.
The concentration of brimonidine and betaxolol is 0.02%～2% and 0.05%～5% respectively by weight in the present composition; Brimonidine and betaxolol concentration summation are 0.07%～7% by weight;
The optium concentration of brimonidine and betaxolol is 0.2% and 0.5% respectively by weight in the present composition; Brimonidine and betaxolol concentration summation are 0.7% by weight in the compound preparation.
Compound recipe eye medicine combination of the present invention is mixed with pharmaceutically acceptable carrier, can be mixed with clinical acceptable various dosage forms such as solution, suspension or Emulsion etc.The acid-base value scope of compound preparation solution and suspension is between pH5 to pH8.
Pharmaceutically acceptable carrier described in the above-mentioned preparation method can be to be applicable to the desired reagent of ophthalmic preparation, comprises antibiotic antiseptic, cosolvent and viscous agent etc.
Described antibiotic antiseptic can be a benzalkonium chloride, and the west softens this, methaform, methyl butex, propylparaben, phenethyl ethanol, disodium edetate, 2,4-hexadienoic acid, M or other known reagent in the Europe.Employed concentration range is 0.001% to 1.0% by weight.
Described cosolvent can be Polyoxyethylene Sorbitol Fatty Acid Esters 20,60 and 80, the addition polymers F-68 of polypropylene glycol and oxirane, F-84 and P-103, cyclodextrin or other available reagents.Employed concentration range is from 0.01% to 2% by weight.
Described viscous agent can be a polyvinyl alcohol, and polyethylene arsenic is coughed up alkane, methylcellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxy methocel, hydroxypropyl cellulose or other available reagents.Employed concentration range is from 0.01% to 2% by weight.
The present composition and compound preparation of the present invention all can strengthen drug effect by different pharmacology; play the effect of Synergistic; thereby the generation that can suppress water liquid in the eye reduces intraocular pressure significantly, again optic nerve is had protective effect, is used for the glaucoma topical medications.
The dosage summation of Alphagan and two medicines of Bei Teshu is 0.001 milligram to 10 milligrams of every eye.Through experimentation, all dosage ratios of the present composition all have the intraocular pressure of reduction, protect optic nerve and treat glaucomatous effect.
Following experimental example and embodiment are used to further specify but are not limited to the present invention.
Experimental example Alphagan (0.2%), Bei Teshu (0.5%) use separately and Alphagan/Bei Teshu unites use to the clinical observation in month of glaucoma reducing iop relatively
One, patient's data
30 routine patients (totally 60 eyes) all are the outpatient.Wherein male 20 examples, women 10 examples; 60 years old mean age (42-88 year), average course of disease 12 years (2-23).
Two, diagnostic criteria
1, be higher than 22 millimetress of mercury and be lower than 34 millimetress of mercury with every intraocular pressure clinically, two intraocular pressures differ that to be less than 5 millimetress of mercury be that standard is selected patient.
2, get rid of the capable patient who cuts operative treatment iris laser week.
Three, Therapeutic Method
10 patients (20 eyes) use Alphagan, each 1 of every day 2 times; 10 patients (20 eyes) use Bei Teshu, each 1 of every day 2 times; 10 patients (20 eyes) are 1 Alphagan of point earlier, puts 1 Bei Teshu after five minutes again, every day 2 times; Totally 30 routine patients (60 eyes), 28 is 1 course of treatment.Before medication and medication one day after, a week, two weeks, three weeks, all around with in examining, the vision of record patient, conjunctiva, cornea, iris, eyelashes color, pupil, crystal, optical fundus and flatten intraocular pressure.Check the room angular field of view before the medication.
Four, therapeutic outcome
(1) drug effect:
Average intraocular pressure (millimetres of mercury) Alphagan Bei Teshu Alphagan+Bei Teshu
24.07+ before the medication/-4.27 23.92+/-2.57 24.29+/-2.68
One day 20.51+/-3.14 21.34+/-3.56 20.34+/-3.46
One all 19.32+/-3.56 20.76+/-3.34 19.20+/-2.67
Two all 18.64+/-4.67 20.13+/-2.42 18.24+/-3.24
Three all 18.41+/-2.56 19.86+/-2.78 17.73+/-2.98
18.50+/-2.84 19.67+/-2.50 17.50+/-3.25 all around
Average blood pressure lowering
Amplitude (%) Alphagan Bei Teshu Alphagan+Bei Teshu
Before the medication
One day/14.8 10.8 16.3
One week 19.7 13.2 21.0
Two weeks 22.6 15.8 24.9
Three weeks 23.5 17.0 27.0
All around 23.1 17.8 28.0
Annotate: the Chinese translation of Brimonidine is a brimonidine, Brimonidine, and 0.2% commodity are called Alphagan (Alphagan); The Chinese translation of Betaxolol is a betaxolol, Betaxolol, and 0.5% commodity are called Bei Teshu (Betopic).
(2) side effect:
After the medication, only foreign body sensation appears in individual patients, and the eye stimulation does not influence the continuation medication.Examination of eyes, vision, anterior ocular segment, obvious change is not seen on optical fundus, the visual field, iris color does not all occur obviously unusual.Whole body is not also seen apparent side effect.Three groups (Alphagan, Bei Teshu and Alphagan/Bei Teshu) patient does not have obvious difference.
Five, conclusion
Glaucoma patient uses Alphagan intraocular pressure lowering function to be better than Bei Teshu in a short time.Alphagan and Bei Teshu unite use can further reduce intraocular pressure, and obviously is better than Alphagan statistically or Bei Teshu uses separately.
Following embodiment all can reach the effect of above-mentioned experimental example.
Embodiment 1(pharmaceutical solutions)
The brimonidine tartrate, micronization 3.0mg+5% 0.2%+5%
Betaxolol hydrochloride, micronization 5.6mg+5% 0.5%+5%
Benzalkonium chloride 0.001ml
Polyvinyl alcohol 1.0mg
Disodium edetate 0.1mg
Sodium chloride 3.0mg
Sodium sulfide 12.0mg
A. polyvinyl alcohol is put to 0.3 milliliter of pure water and stirred evenly, autoclaving sterilization, the solution of sterilizing is cooled to room temperature;
B. with benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfide, brimonidine tartrate and betaxolol hydrochloride at room temperature are dissolved in 0.7 milliliter of pure water, filter-sterilized;
C. the solution that A and B step are made mixes until even and becomes a phase, adds sulphuric acid or hydrochloric acid or sodium hydroxide regulating acid-base value to 6.8, in the eyedrops bottle of then solution being packed into.
The eye topical, every day twice, each one to two.
3.0mg brimonidine tartrate is equivalent to 2.0mg brimonidine 5.6mg betaxolol hydrochloride and is equivalent to the 5.0mg betaxolol in the above-mentioned preparation.
Embodiment 2(pharmaceutical solutions)
The brimonidine tartrate, micronization 1.5g+5% 0.02%+5%
Betaxolol hydrochloride, micronization 28.0g+5% 0.5%+5%
Benzalkonium chloride 0.005L
Polyvinyl alcohol 5.0g
Disodium edetate 0.5g
Sodium chloride 15g
Sodium sulfide 60g
A. polyvinyl alcohol is put to 1.5 liters of pure water and stirred evenly, autoclaving sterilization, the solution of sterilizing is cooled to room temperature;
B. with benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfide, brimonidine tartrate and betaxolol hydrochloride at room temperature are dissolved in 3.5 liters of pure water, filter-sterilized;
C. the solution that A and B step are made mixes until even and becomes a phase, adds sulphuric acid or hydrochloric acid or sodium hydroxide regulating acid-base value to 6.8, in the eyedrops bottle of then solution being packed into.
The eye topical, every day twice, each one to two.
1.5g brimonidine tartrate is equivalent to the 1.0g brimonidine in the above-mentioned preparation; 28.0g betaxolol hydrochloride is equivalent to the 25.0g betaxolol.
Embodiment 3(suspension formulations)
The brimonidine tartrate, micronization 1.5g+5% 0.2%+5%
Betaxolol hydrochloride, micronization 11.2g+5% 2.0%+5%
Benzalkonium chloride 0.05mL
Polyvinyl alcohol 0.5g
Ka Bomo 974P 2.0g
Mannitol 16.5g
The general 0.125g of its Roseau
Disodium edetate 0.05g
Sodium chloride 0.5g
A. the preparation of powder slurry
In the pure hot water of 20 grams, 50 to 70 degree, it is general to add its Roseau, stirs; Other adds pure hot water to 30 gram of 50 to 70 degree, gets the general solution of its Roseau, filters; After quick cool cycles mesohigh is sterilized, finished circulation, under 50 to 55RPM,, get the powder slurry through ball-type powder process 18 to 19 hours.
B.2% the preparation of Ka Bomo (Carbomer) slurry
In the pure hot water of 400 grams, 50 to 70 degree, add the rich mould 974P of card, stir evenly; Add pure water to 500 gram, stir, filter, De Kabomo 974P slurry 100 grams.
C. the preparation of preparation concentrate
In the pure hot water of 100 grams, 50 to 70 degree, add following ingredients mannitol successively, polyvinyl alcohol, sodium chloride, egtazic acid disodium and benzalkonium chloride filter; Add the rich mould 974P slurry of card (seeing the B step); Add pure water again and restrain the agent concentrate to getting 275.
Brimonidine tartrate and betaxolol hydrochloride are dissolved in 100 gram pure water, make solution.
D. aseptic mixing
After brimonidine tartrate and betaxolol hydrochloride solution (the seeing the C step) aseptic filtration, add preparation concentrate (seeing the C step); With sodium hydroxide or hydrochloric acid acid adjustment basicity to 6.8+/-0.2; Add powder slurry (seeing the A step), shifted all powder slurries as much as possible; Add pure water to 500 and restrain and stir, promptly get suspension formulations.
The eye topical, every day twice, each one to two.
1.5g brimonidine tartrate is equivalent to the 1.0g brimonidine in the above-mentioned preparation; 11.2g betaxolol hydrochloride is equivalent to the 10.0g betaxolol.
Embodiment 4(Emulsion)
The brimonidine tartrate, micronization 6.0g+5% 0.2%+5%
Betaxolol hydrochloride, micronization 28.0g+5% 1.25%+5%
Benzalkonium chloride 0.001L
Polyvinyl alcohol 2.0g
Disodium edetate 10g
Sodium chloride 40g
Sodium borate 1.3g
Boric acid 96g
Prepare aqueous emulsion according to following method:
A. with boric acid, sodium borate, disodium edetate, benzalkonium chloride, brimonidine tartrate, betaxolol hydrochloride and sodium chloride add in the 400 gram pure water successively, dissolve and stir to limpid; Solution filters, aseptic sterilization.
B. 1600 gram pure water are heated to 90 degree, add polyvinyl alcohol, be stirred to evenly; When stirring, be heated to the aseptic sterilization of 121 degree 30 to 45 minutes; Be cooled to 50 to 55 degree, add the solution of A step preparation; Continue to be stirred to room temperature, get aqueous emulsion; With the aqueous emulsion eyedrops bottle of packing into.
The eye topical, every day twice, each one to two.
6.0g brimonidine tartrate is equivalent to the 4.0g brimonidine in the above-mentioned preparation; 28.0g betaxolol hydrochloride is equivalent to the 25.0g betaxolol.
Embodiment 5(suspension formulations)
The brimonidine tartrate, micronization 1.5g+5% 0.03%+5%
Betaxolol hydrochloride, micronization 16.8g+5% 0.50%+5%
Benzalkonium chloride 0.3mL
Polyvinyl alcohol 3.0g
Ka Bomo 974P 12g
Mannitol 99g
The general 0.75g of its Roseau
Disodium edetate 0.3g
Sodium chloride 3g
A. the preparation of powder slurry
To the pure hot water of 200 grams, 50 to 70 degree, it is general to add its Roseau, stirs; Other adds pure hot water to 300 gram of 50 to 70 degree, gets the general solution of its Roseau, filters; After quick cool cycles mesohigh is sterilized, finished circulation, under 50 to 55RPM,, get the powder slurry through ball-type powder process 18 to 19 hours.
B.2% the preparation of Ka Bomo (Carbomer) slurry
In the pure hot water of 4000 grams, 50 to 70 degree, add the rich mould 974P of card, stir evenly; Add pure water to 5000 gram, stir, filter, De Kabomo 974P slurry 1250 grams.
C. the preparation of preparation concentrate
In the pure hot water of 1000 grams, 50 to 70 degree, add following ingredients mannitol successively, polyvinyl alcohol, sodium chloride, egtazic acid disodium and benzalkonium chloride filter; Add the rich mould 974P slurry of card (seeing the B step); Add pure water again and restrain the agent concentrate to getting 1750.
Brimonidine tartrate and betaxolol hydrochloride are dissolved in 1000 gram pure water, make solution.
D. aseptic mixing
After brimonidine tartrate and betaxolol hydrochloride solution (the seeing the C step) aseptic filtration, add preparation concentrate (seeing the C step); With sodium hydroxide or hydrochloric acid acid adjustment basicity to 6.8+/-0.2; Add powder slurry (seeing the A step), shifted all powder slurries as much as possible; Add pure water to 3000 and restrain and stir, promptly get suspension formulations.
The eye topical, every day twice, each one to two.
1.5g brimonidine tartrate is equivalent to the 1.0g brimonidine in this preparation; 16.8g betaxolol hydrochloride is equivalent to the 15.0g betaxolol.
Embodiment 6(pharmaceutical solutions)
The brimonidine tartrate, micronization 15g+5%
*0.2%+5%
Betaxolol hydrochloride, micronization 11.2g+5%
*0.2%+5%
Benzalkonium chloride 0.005L
Polyvinyl alcohol 5.0g
Disodium edetate 0.5g
Sodium chloride 15g
Sodium sulfide 60g
A. polyvinyl alcohol is put to 1.5 liters of pure water and stirred evenly, autoclaving sterilization, the solution of sterilizing is cooled to room temperature;
B. with benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfide, brimonidine tartrate and betaxolol hydrochloride at room temperature are dissolved in 3.5 liters of pure water, filter-sterilized;
C. the solution that A and B step are made mixes until even and becomes a phase, adds sulphuric acid or hydrochloric acid or sodium hydroxide regulating acid-base value to 6.8, in the eyedrops bottle of then solution being packed into.
The eye topical, every day twice, each one to two.
15g brimonidine tartrate is equivalent to the 10g brimonidine in the above-mentioned preparation; 11.2g betaxolol hydrochloride is equivalent to the 10g betaxolol.
Embodiment 7(pharmaceutical solutions)
Brimonidine tartrate micronization 30g+5% 1.0%+5%
Betaxolol hydrochloride micronization 11.2g+5% 0.5%+5%
Benzalkonium chloride 0.002L
Polyvinyl alcohol 2.0g
Disodium edetate 0.2g
Sodium chloride 6g
Sodium sulfide 24g
A. polyvinyl alcohol is put to 0.6 liter of pure water and stirred evenly, autoclaving sterilization, the solution of sterilizing is cooled to room temperature;
B. with benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfide, brimonidine tartrate and betaxolol hydrochloride at room temperature are dissolved in 1.4 liters of pure water, filter-sterilized;
C. the solution that A and B step are made mixes until even and becomes a phase, adds sulphuric acid or hydrochloric acid or sodium hydroxide regulating acid-base value to 6.8, in the eyedrops bottle of then solution being packed into.
The eye topical, every day twice, each one to two.
30g brimonidine tartrate is equivalent to the 20g brimonidine in the above-mentioned preparation; 11.2g betaxolol hydrochloride is equivalent to the 10g betaxolol.
Embodiment 8(pharmaceutical solutions)
Brimonidine tartrate micronization 75.6g+5% 2.0%+5%
Betaxolol hydrochloride micronization 11.2g+5% 0.4%+5%
Benzalkonium chloride 0.0025L
Polyvinyl alcohol 2.5g
Disodium edetate 0.25g
Sodium chloride 7.5g
Sodium sulfide 30g
A. polyvinyl alcohol is put to 0.75 liter of pure water and stirred evenly, autoclaving sterilization, the solution of sterilizing is cooled to room temperature;
B. with benzalkonium chloride, disodium edetate, sodium chloride, sodium sulfide, brimonidine tartrate and betaxolol hydrochloride at room temperature are dissolved in 1.75 liters of pure water, filter-sterilized;
C. the solution that A and B step are made mixes until even and becomes a phase, adds sulphuric acid or hydrochloric acid or sodium hydroxide regulating acid-base value to 6.8, in the eyedrops bottle of then solution being packed into.
The eye topical, every day twice, each one to two.
75.6g brimonidine tartrate is equivalent to the 50g brimonidine in the above-mentioned preparation; 11.2g betaxolol hydrochloride is equivalent to the 10g betaxolol.
Embodiment 9(Emulsion)
Brimonidine tartrate micronization 12.0g+5% 4.0%+5%
Betaxolol hydrochloride micronization 1.12g+5% 0.5%+5%
Benzalkonium chloride 0.01mL
Polyvinyl alcohol 0.2g
Disodium edetate 0.1g
Sodium chloride 0.4g
Sodium borate 0.013g
Boric acid 0.96g
A. with boric acid, sodium borate, disodium edetate, benzalkonium chloride, brimonidine tartrate, betaxolol hydrochloride and sodium chloride add in the 40 gram pure water successively, dissolve and stir to limpid; Solution filters, aseptic sterilization.
B. 160 gram pure water are heated to 90 degree, add polyvinyl alcohol, be stirred to evenly; When stirring, be heated to the aseptic sterilization of 121 degree 30 to 45 minutes; Be cooled to 50 to 55 degree, add the solution of A step preparation; Continue to be stirred to room temperature, get aqueous emulsion; With the aqueous emulsion eyedrops bottle of packing into.
The eye topical, every day twice, each one to two.
12g brimonidine tartrate is equivalent to the 8.0g brimonidine in the above-mentioned preparation; 1.12g betaxolol hydrochloride is equivalent to the 1.0g betaxolol.
Embodiment 10(pharmaceutical solutions)
Brimonidine 7 grams, betaxolol 1000 grams are pressed the conventional compound method of pharmaceutics, add to be applicable to the desired reagent of ophthalmic preparation, are mixed with solution.
The eye topical, every day twice, each one to two.
Embodiment 11(suspension formulations)
Brimonidine 20 grams, betaxolol 1 gram is pressed the conventional compound method of pharmaceutics, adds to be applicable to the desired reagent of ophthalmic preparation, is mixed with suspension.
The eye topical, every day twice, each one to two.
Embodiment 12(Emulsion)
Brimonidine 30 grams, betaxolol 1 gram is pressed the conventional compound method of pharmaceutics, adds to be applicable to the desired reagent of ophthalmic preparation, is mixed with Emulsion.
The eye topical, every day twice, each one to two.
Claims (6)
1. a compound recipe eye medicine combination is characterized in that said composition is to be made by the active component of following weight proportion: brimonidine 0.4 weight portion, betaxolol 1 weight portion.
2. compound recipe eye medicine combination as claimed in claim 1 is characterized in that brimonidine and betaxolol are any salt of chemically accepting form.
3. compound recipe eye medicine combination as claimed in claim 1 or 2 is characterized in that said composition mixes with the carrier of pharmaceutically accepting, and is mixed with suspension formulations, Emulsion or pharmaceutical solutions.
4. compound recipe eye medicine combination as claimed in claim 3, the acid-base value scope that it is characterized in that described solution dosage or suspension formulations is between pH5 to pH8.
5. as claim 1, the application of 2 or 4 described compound recipe eye medicine combinations in preparation treatment glaucoma medicine.
6. the application of compound recipe eye medicine combination as claimed in claim 3 in preparation treatment glaucoma medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200510000253XA CN100413503C (en) | 2005-01-07 | 2005-01-07 | Compound ocular medicinal composition |
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|---|---|---|---|
| CNB200510000253XA CN100413503C (en) | 2005-01-07 | 2005-01-07 | Compound ocular medicinal composition |
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| CN100413503C true CN100413503C (en) | 2008-08-27 |
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| CN102349910B (en) * | 2011-08-31 | 2014-03-19 | 北京秦武田制药有限公司 | Compound medicinal composition for ophthalmology and preparation method thereof |
| CN103006662A (en) * | 2011-09-20 | 2013-04-03 | 北京秦武田制药有限公司 | Brimonidine and betaxolol composition for local ophthalmology application |
| WO2020065085A1 (en) * | 2018-09-28 | 2020-04-02 | Galderma Research & Development | Pharmaceutical composition comprising brimonidine, and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278162A (en) * | 1997-11-05 | 2000-12-27 | 千寿制药株式会社 | Sustained-release eye drops |
| CN1402634A (en) * | 1999-11-30 | 2003-03-12 | 爱尔康公司 | Use of beta-adrenoceptor antagonists for manufacture of medicament for treatment of disorders of outer retina |
| CN1516588A (en) * | 2002-04-19 | 2004-07-28 | �ո��� | Combination of brimonidine and timolol for topical ophthalmic application |
-
2005
- 2005-01-07 CN CNB200510000253XA patent/CN100413503C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278162A (en) * | 1997-11-05 | 2000-12-27 | 千寿制药株式会社 | Sustained-release eye drops |
| CN1402634A (en) * | 1999-11-30 | 2003-03-12 | 爱尔康公司 | Use of beta-adrenoceptor antagonists for manufacture of medicament for treatment of disorders of outer retina |
| CN1516588A (en) * | 2002-04-19 | 2004-07-28 | �ո��� | Combination of brimonidine and timolol for topical ophthalmic application |
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