CN103040837A - Ophthalmologic intraocular pressure reduction drug for external use - Google Patents
Ophthalmologic intraocular pressure reduction drug for external use Download PDFInfo
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- CN103040837A CN103040837A CN201310011580XA CN201310011580A CN103040837A CN 103040837 A CN103040837 A CN 103040837A CN 201310011580X A CN201310011580X A CN 201310011580XA CN 201310011580 A CN201310011580 A CN 201310011580A CN 103040837 A CN103040837 A CN 103040837A
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- timolol maleate
- potassium sorbate
- tanshinone iia
- timolol
- drug
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Abstract
The invention discloses an ophthalmologic intraocular pressure reduction drug for external use. The drug takes timolol maleate as an active pharmaceutical ingredient; and the drug further comprises potassium sorbate, and the potassium sorbate is added according to the ratio that timolol maleate:potassium sorbate equals to 1:(0.1-5.0). The drug also takes tanshinone IIA as the active pharmaceutical ingredient, and the tanshinone IIA is added according to the ratio that timolol maleate:tanshinone IIA equals to 1:(0.1-5.0). The potassium sorbate-containing timolol maleate eye drops have a lasting medicinal effect, and the frequency for dropping the eye drops can be reduced.
Description
Technical field
The present invention relates to medicinal preparation, relate in particular to the eye local topical preparation that reduces intraocular pressure.
Background technology
The timolol preparation is known intraocular pressure lowering medicine, and its maleate commonly used is rapid-action with reducing iop behind its eye drip, behind the eye drip about 20 minutes intraocular pressure namely begin decline, drop to amplitude peak after 1～2 hour.The timolol ophthalmic preparation of seeing in the market is Timolol maleate eye drops and the timolol maleate gel for eye of 2 administrations on the one.But this timolol ophthalmic preparation intraocular penetration is relatively poor, and the drug level in ocular tissue is relatively low, so its curative effect is limited.Moreover duration of efficacy is short after the existing timolol ophthalmic preparation administration, causes the intraocular pressure fluctuation large, easily causes various eye untoward reaction.If increase every day administration number of times increased medicine itself and antiseptic to the toxicity of ocular tissue.
Summary of the invention
It is good to the object of the invention is to create a kind of ophthalmic permeability, lasting medicine, the ophthalmology external intraocular pressure lowering medicine that side effect is little.
The technical scheme that realizes the object of the invention is that it also comprises potassium sorbate simultaneously take timolol maleate as pharmacodynamic raw materials, the preparation Timolol maleate eye drops.The consumption of potassium sorbate is expressed as by the weight ratio of itself and timolol maleate: timolol maleate: potassium sorbate=1: 0.1～5.0.
Potassium sorbate is colourless to white flake-like crystal or crystalline powder, and soluble in water and ethanol is mainly made at present antiseptic and used, and very strong inhibition putrefaction bacteria and mycete effect are arranged, and the report that is applied to prepare ophthalmic preparation had not been arranged.
Potassium sorbate plays the slow releasing agent effect in drug component of the present invention.Potassium sorbate promotes medicine to divide a word with a hyphen at the end of a line to ophthalmic, and the Timolol maleate eye drops cornea permeability that experiment confirm contains potassium sorbate improves, thereby improves drug bioavailability.The holdup time of potassium sorbate prolong drug in ocular tissue, thereby can reduce the eye drip number of times.
That the inventor carried out once was controlled, the clinical trial of double blinding, parallel control, divide two groups in work with the patient of 332 intraocular pressure 〉=22mmHg, one group is used 0.5% Timolol maleate eye drops (TLA) that contains potassium sorbate by the inventive method preparation, and use once every day (morning); One group is used existing 0.5% Timolol maleate eye drops (THH), sooner or later twice use every day.In two groups, the intrinsic pressure reference value from 25mmHg of average eye drops at most 18mmHg, the minimum 19mmHg that drops to.Result by analysis two groups of curative effects does not have significant difference, has in other words same curative effect.
As optimization, the Timolol maleate eye drops for preparing by the inventive method also contains tanshinone IIA.The consumption of tanshinone IIA is expressed as by itself and timolol maleate weight ratio: timolol maleate: tanshinone IIA=1: 0.1～5.0.The amount ratio of timolol maleate, potassium sorbate, three kinds of primary raw materials of tanshinone IIA is: timolol maleate: potassium sorbate: tanshinone IIA=1: 0.1～5.0: 0.1～5.0.
Tanshinone IIA can reduce lipid peroxide contents, the stabilate film, and can improve superoxide dismutase (SOD) activity, have anti-radical action.Tanshinone IIA also has the effect of blood circulation promoting and blood stasis dispelling simultaneously.Pharmacological research finds that tanshinone IIA can suppress connective tissue proliferation, and expansion limbus of corneae blood vessel increases the corneal nutrition supply, promotes the cornea reparation.Add tanshinone IIA in this ophthalmic preparation, can strengthen the curative effect of timolol maleate intraocular pressure lowering.
Use the adjuvant that above pharmacodynamic raw materials prepares timolol maleate eye drop of the present invention and also comprise osmotic pressure regulator, pH adjusting agent, antibacterial, thickening agent.Their kind is selected and consumption is described below respectively.
1. described antibacterial is the combination in any of any in thimerosal, quaternary ammonium salt, hibitane, chlorobutanol, the parabens or described kind.The consumption of antibacterial is expressed as with the weight ratio with timolol, timolol maleate: antibacterial=1.0:0.002～0.5.
2. described thickening agent is the combination in any of any or described kind in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, polycarbophil, carboxymethyl cellulose, carbomer, the chondroitin sulfate; The consumption of thickening agent is expressed as with the weight ratio with timolol, timolol maleate: thickening agent=1.0:0.1～1.0.Can adopt different polymerization degree, finally make eye drop reach suitable viscosity.
3. the pH value that uses pH adjusting agent to regulate the finished product medicament is 6.0～8.0.Described pH adjusting agent is the combination in any of any or described kind in sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid, the Borax.
5. the osmotic pressure molar density that uses osmotic pressure regulator to regulate eye drop is 250～350mOsmol/kg.Described osmotic pressure regulator is the combination in any of a kind of of sodium chloride, mannitol or two kinds.
The present invention contains the Timolol maleate eye drops lasting medicine of potassium sorbate, and curative effect is reliable, can reduce to drip the medicine number of times, brings convenience to the patient.
The specific embodiment
The invention will be further described by the following examples.
Embodiment 1-3 prepares Timolol maleate eye drops by the inventive method
Raw materials used component and consumption be as shown in the following chart:
Preparation method is, with an amount of water for injection dissolving timolol maleate full dose, add the potassium sorbate stirring and dissolving, with water for injection its dispersion is let cool thickening agent, dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection in addition, stir evenly filtration, merge two liquid, add again and dissolved good timolol maleate, add to the full amount of water for injection, filter, packing, and get final product.The pH value that uses pH adjusting agent to regulate the finished product eye drop is 6.0～8.0.
Embodiment 4-6 preparation contains the Timolol maleate eye drops of tanshinone IIA
Raw materials used component and consumption be as shown in the following chart:
Preparation method is with an amount of water for injection dissolving timolol maleate full dose, to add the potassium sorbate stirring and dissolving, add again the tanshinone IIA stirring and dissolving, with water for injection its dispersion is let cool thickening agent, dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection in addition, stir evenly filtration, merge two liquid, add again and dissolved good timolol maleate, add to the full amount of water for injection, filter, packing, and get final product.The pH value that uses pH adjusting agent to regulate the finished product eye drop is 6.0～8.0.
Embodiment 7-9 preparation contains the Timolol maleate eye drops of tanshinone IIA
Raw materials used component and consumption be as shown in the following chart:
Preparation method is with an amount of water for injection dissolving timolol maleate full dose, to add the potassium sorbate stirring and dissolving, add again the tanshinone IIA stirring and dissolving, with water for injection its dispersion is let cool thickening agent, dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection in addition, stir evenly filtration, merge two liquid, add again and dissolved good timolol maleate, add to the full amount of water for injection, filter, packing, and get final product.The pH value that uses pH adjusting agent to regulate the finished product eye drop is 6.0～8.0.
Experimental example medicine of the present invention and existing Timolol maleate eye drops be the laboratory observation of penetrance within the eye
Experiment purpose: relatively contain the medicine of the present invention and the existing commercially available Timolol maleate eye drops single-dose aqueous humor drug level that does not contain potassium sorbate of potassium sorbate, observation contains/does not contain Timolol maleate eye drops in the penetrance of lagophthalmos.
Experimental technique: adopt new zealand white rabbit, 15 every group.Experimental group uses 0.5% Timolol maleate eye drops (TLA) that contains potassium sorbate by the preparation of the embodiment of the invention 1 method; Matched group uses existing 0.5% Timolol maleate eye drops (THH does not contain potassium sorbate).In 1 day, the eyes single of every rabbit drips eye drop 50 μ l.Animal drip with rear 15,30,60,120 and 180min after put to death 3 new zealand rabbits of every kind of each time point of medicine.Aqueous humor in every rabbit eyes all is removed, and adopts the concentration of timolol in the high effective liquid chromatography for measuring aqueous humor.
The result: 15min behind the experimental group use medicine eye drop of the present invention, the concentration of timolol reaches peak value 3.705 ± 0.3012 μ g/mL, drops to 2.310 ± 1.0658 μ g/mL during 30min, drops to 0.539 ± 0.1431 μ g/mL during to 180min.And matched group drips 15min behind the Timolol maleate eye drops that does not contain potassium sorbate, and peak value 2.239 ± 0.1430 μ g/mL of timolol concentrations are about as much as 60% of medicine peak value of the present invention; Drop to 1.896 ± 0.1303 μ g/mL during matched group 30min, drop to 0.148 ± 0.0282 μ g/mL during 180min, only be 27% of medicine of the present invention.
Drip with behind the medicine of the present invention, the concentration of timolol is all apparently higher than matched group in each time point new zealand rabbit aqueous humor.Dripping with the area under curve (AUC) in the 180min behind the medicine eye drop of the present invention is the twice of matched group.See Table 1.
Table 1 single drips with timolol pharmacokinetic parameter in the medicine aqueous humor of the present invention and the contrast of using existing Timolol maleate eye drops
Conclusion: medicine of the present invention contains the Timolol maleate eye drops of potassium sorbate, shows than the existing Timolol maleate eye drops that does not contain potassium sorbate to absorb faster and keep long retention time.Timolol concentrations proves that all apparently higher than the existing Timolol maleate eye drops that does not contain potassium sorbate potassium sorbate can increase timolol permeability within the eye in the aqueous humor of each time point of whole experimentation medicine of the present invention.
Claims (2)
1. ophthalmology external intraocular pressure lowering medicine, it is characterized in that, it also comprises potassium sorbate simultaneously take timolol maleate as pharmacodynamic raw materials, and the consumption of potassium sorbate is expressed as by the weight ratio of itself and timolol maleate: timolol maleate: potassium sorbate=1: 0.1～5.0.
2. medicine according to claim 1 is characterized in that, used pharmacodynamic raw materials also comprises tanshinone IIA, and the consumption of tanshinone IIA is expressed as by itself and timolol maleate weight ratio: timolol maleate: tanshinone IIA=1: 0.1～5.0; The amount ratio of timolol maleate, potassium sorbate, three kinds of primary raw materials of tanshinone IIA is: timolol maleate: potassium sorbate: tanshinone IIA=1: 0.1～5.0: 0.1～5.0.
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| CN201310011580XA CN103040837A (en) | 2013-01-13 | 2013-01-13 | Ophthalmologic intraocular pressure reduction drug for external use |
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| CN201310011580XA CN103040837A (en) | 2013-01-13 | 2013-01-13 | Ophthalmologic intraocular pressure reduction drug for external use |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176758A (en) * | 2016-06-17 | 2016-12-07 | 北京梅尔森医药技术开发有限公司 | A kind of externally-applied medicinal composition |
Citations (2)
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| CN101394860A (en) * | 2006-01-13 | 2009-03-25 | 范斯坦医药研究院 | Inhibition of inflammatory cytokine production with tanshinones |
| CN102743335A (en) * | 2012-07-30 | 2012-10-24 | 安徽环球药业股份有限公司 | Timolol hydrogenmaleate eye drops and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101394860A (en) * | 2006-01-13 | 2009-03-25 | 范斯坦医药研究院 | Inhibition of inflammatory cytokine production with tanshinones |
| CN102743335A (en) * | 2012-07-30 | 2012-10-24 | 安徽环球药业股份有限公司 | Timolol hydrogenmaleate eye drops and preparation method thereof |
Non-Patent Citations (6)
| Title |
|---|
| 《CLINICAL THERAPEUTICS(R)》 20040210 Private Practice等 A 12-Month, Multicenter, Randomized, Double-Masked, Parallel-Group Comparison of Timolol-LA Once Daily and Timolol Maleate Ophthalmic Solution Twice Daily in the Treatment of Adults with Glaucoma or Ocular Hypertension 第541-551页 权利要求1 第26卷, 第4期 * |
| 《JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS》 20081231 George A. Baklayan et al. Evaluation of Aqueous Humor Concentrations of Istalol(R) and Betimol(R) Following a Single Ocular of Istalol(R) and Betimol(R) Following a Single Ocular 第507-512页 权利要求1 第24卷, 第5期 * |
| GEORGE A. BAKLAYAN ET AL.: "Evaluation of Aqueous Humor Concentrations of Istalol® and Betimol® Following a Single Ocular of Istalol® and Betimol® Following a Single Ocular", 《JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS》 * |
| GEORGE A. BAKLAYAN ET AL.: "Evaluation of Aqueous Humor Concentrations of Istalol® and Betimol® Following a Single Ocular of Istalol® and Betimol® Following a Single Ocular", 《JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS》, vol. 24, no. 5, 31 December 2008 (2008-12-31), pages 507 - 512 * |
| PRIVATE PRACTICE等: "A 12-Month, Multicenter, Randomized, Double-Masked, Parallel-Group Comparison of Timolol-LA Once Daily and Timolol Maleate Ophthalmic Solution Twice Daily in the Treatment of Adults with Glaucoma or Ocular Hypertension", 《CLINICAL THERAPEUTICS®》 * |
| PRIVATE PRACTICE等: "A 12-Month, Multicenter, Randomized, Double-Masked, Parallel-Group Comparison of Timolol-LA Once Daily and Timolol Maleate Ophthalmic Solution Twice Daily in the Treatment of Adults with Glaucoma or Ocular Hypertension", 《CLINICAL THERAPEUTICS®》, vol. 26, no. 4, 10 February 2004 (2004-02-10), pages 541 - 551 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176758A (en) * | 2016-06-17 | 2016-12-07 | 北京梅尔森医药技术开发有限公司 | A kind of externally-applied medicinal composition |
| CN106176758B (en) * | 2016-06-17 | 2019-07-23 | 北京梅尔森医药技术开发有限公司 | A kind of externally-applied medicinal composition |
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Application publication date: 20130417 |