CN102716074B - Bimatoprost eye drops and preparation method thereof - Google Patents
Bimatoprost eye drops and preparation method thereof Download PDFInfo
- Publication number
- CN102716074B CN102716074B CN 201210215456 CN201210215456A CN102716074B CN 102716074 B CN102716074 B CN 102716074B CN 201210215456 CN201210215456 CN 201210215456 CN 201210215456 A CN201210215456 A CN 201210215456A CN 102716074 B CN102716074 B CN 102716074B
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- China
- Prior art keywords
- bimatoprost
- preparation
- injection
- water
- eye drop
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- 229960002470 bimatoprost Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 239000003889 eye drop Substances 0.000 title claims description 41
- 229940012356 eye drops Drugs 0.000 title claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 239000008215 water for injection Substances 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 15
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims description 12
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- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000009602 toxicology test Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a bimatoprost composition. The composition comprises an effective treatment dose of bimatoprost, non-ionic surfactant and a pharmaceutically acceptable carrier; the invention also provides a preparation method for the bimatoprost composition; and by the bimatoprost composition, the problem of low dissolubility of bimatoprost in the preparation process can be solved, the stability of bimatoprost at high temperature is improved, and the forming of relative substances is reduced.
Description
Technical field
The invention belongs to medical technical field, relate to new prostaglandins anti-glaucoma medicine preparation, specifically a kind of eye drop that contains Bimatoprost and preparation method thereof.
Background technology
Glaucoma is the too high oculopathy that causes optic nerve lesion of a class intraocular pressure (IOP), is the blind topmost reason of world's second largest diseases causing blindness, irreversibility.
At present glaucoma treatment is intended to reduce IOP, and appearance efficient, the newtype drug derivatives of prostaglandins that has no side effect, for glaucoma patient has brought Gospel.The prostaglandins medicine more and more is subject to patient's welcome with the safety of good intraocular pressure lowering effect and brilliance, the domestic prostaglandins medicine that has gone on the market comprises at present: latanoprost, travoprost and Bimatoprost.
Bimatoprost (Bimatoprost) is a kind of synthetic prostaglandin analog, has the activity that reduces the intraocular pressure activity.Its chemical name is:
(Z)-and 7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2[(1E, 3S)-3-hydroxyl-5-phenyl-1-pentenyl] cyclopenta]-5-N-ethyl heptene amide.
Bimatoprost is second filial generation prostatitis element class anti-glaucoma medicine, has become abroad a line anti-glaucoma agents.Different from latanoprost and travoprost, it is a kind of synthetic prostatitis amide, optionally simulate the effect of naturally occurring prostatitis amide, had dual Hypotensive Mechanism, can reduce intraocular pressure through trabecular reticulum and two outflow approach of Fructus Vitis viniferae sclera by increasing aqueous humor.External clinical studies show is dripped once (evening) Bimatoprost every day, can reduce intraocular pressure 7～8mmHg.Drip first with approximately after 4 hours intraocular pressure begin to reduce, effect reaches maximum within 8～12 hours.The average intraocular pressure lowering effect of external existing bibliographical information Bimatoprost can reach more than 30%, compares with timolol, and reducing iop has significant difference.No matter compare with latanoprost, be glaucoma, normal-pressure glaucoma or ocular hypertension, and Bimatoprost intraocular pressure lowering amplitude is larger; Up-to-date foreign study shows: for the glaucomatous in the daytime intraocular pressure control of exfoliative, Bimatoprost also has better effect than latanoprost.Compare with travoprost, Bimatoprost also provides better intraocular pressure lowering effect, more patient is arranged by using Bimatoprost can reach lower target intraocular pressure.
The route of administration of Bimatoprost is the eye drip administration, the Bimatoprost eye drop went on the market in the U.S. in 2006, commodity are called the Lumigan eye drop, its disclosed prescription is Bimatoprost 0.03%, benzalkonium chloride (antiseptic) 0.005%, adjuvant are sodium chloride, sodium hydrogen phosphate, citric acid.As described in its subsidiary description, the PH of this commercially available eye drop is 6.8-7.8, and osmotic pressure is 290mOsmol/kg.
As everyone knows, the process for preparation of eye drop is generally dosing-filtration-fill, and wherein filtering is 0.22 micron aseptic filtration, and is must step.Bimatoprost is insoluble drug, benzalkonium chloride in original prescription is except as the antiseptic, owing to itself also being a kind of surfactant, so can play the effect of part solubilising, but this solubilization is far from being enough to Bimatoprost, because Bimatoprost is almost insoluble in water.Therefore very easy of membrane retention or absorption in the preparation process of this commercially available Bimatoprost eye drop, content decrease after causing filtering.The prior art that addresses the above problem is for increasing initial inventory according to the content after filtering, and feeds intake such as 130%, obtains the medicinal liquid of 100% content after the filtration.
But the problem that thereupon occurs is to waste raw material.The Bimatoprost raw material is because synthetic being difficult for is very expensive, and units up to ten thousand one gram increases inventory and can greatly increase production cost.The aqueous solution of Bimatoprost is also unstable simultaneously, and is particularly more unstable under the environment to illumination and heat.The passing in time of the aqueous solution of Bimatoprost can produce certain degradation impurity, and the existence of degradation impurity can affect the toxicology characteristic of said preparation.
Therefore, be badly in need of a kind of stability-enhanced Bimatoprost eye drop in this area, and the method for the Bimatoprost eye drop that can reduce production costs.
Summary of the invention
The purpose of this invention is to provide a kind of stable eye drop of Bimatoprost and preparation method thereof that contains, to reach safety, effectively to treat glaucomatous purpose.
In order to achieve the above object, the present inventor finds through large quantity research, adds non-ionic surface active agent and can greatly improve its dissolubility in the Bimatoprost ophthalmic preparation, can solve the problem of preparation process Raw waste.Simultaneously, we also find, compare with disclosed prescription, add non-ionic surface active agent, have improved the stability of Bimatoprost ophthalmic preparation.
The adding non-ionic surface active agent improves its deliquescent beneficial effect and sees embodiment 6.
Add non-ionic surface active agent raising stable beneficial effect see embodiment 7.
One aspect of the present invention provides a kind of preparation composition for eyes that contains Bimatoprost, and described compositions comprises Bimatoprost, non-ionic surface active agent and the pharmaceutically acceptable carrier for the treatment of effective dose.
The consumption of Bimatoprost of the present invention is 0.001-0.5% (w/v), is preferably 0.03% (w/v).
Ionic surfactant pack of the present invention is drawn together Determination of Polyoxyethylene Non-ionic Surfactants and polyol-based non-ionic surfactant, preferably HCO60, polyoxyethylene hydrogenated Oleum Ricini 40, polyoxyethylene castor oil 35, polyoxyethylene sorbitan monoleate, Polyethylene Glycol-stearate and combination thereof.
In a preferred embodiment of the present invention, the consumption of described non-ionic surface active agent is 0.001-10% (w/v), preferably 0.01-6% (w/v).
In the present invention, described pharmaceutically acceptable carrier is conventional in the art, and described pharmaceutically acceptable carrier includes but not limited to the component of one or more isoosmotic adjusting agent, PH regulator, antibacterial and solvent.
Dosage form at ophthalmic preparation of the present invention is gel for eye use or eye drop, and preferably, the dosage form of described ophthalmic preparation is eye drop.
In the present invention, described isoosmotic adjusting agent is the usual component in the preparation of this area, can be selected from the mixture of any one or multiple arbitrary proportion in sodium chloride, glucose, mannitol, glycerol, propylene glycol, borate buffer or phosphate buffer and mixing thereof, Borax or the Chile saltpeter.Preferred osmotic pressure regulator is sodium chloride, glucose or the two mixture, or the combination of borate buffer or phosphate buffer.More preferably osmotic pressure regulator is the combination of sodium chloride and borate buffer or phosphate buffer
In preferred embodiment of the present invention, described isoosmotic adjusting agent is sodium chloride, and content is the combination of 0.3-0.6% (w/v) and buffer 0.5-1.5% (w/v); Most preferably, described isoosmotic adjusting agent be 0.5% (w/v) sodium chloride and 0.8% (w/v) phosphate buffer or with the combination of 1.2% (w/v) borate buffer.The borate buffer of the preferred 1.0-1.5% of described buffer (w/v) (take boric acid and Borax weight and account for composition total weight percent) or content are the phosphate buffer of 0.8-1.2% (w/v) (in the weight of sodium hydrogen phosphate and citric acid and account for composition total weight percent).Preferably, buffer is boronic acid containing 1.15%, the borate buffer of Borax 0.05% (w/v); Or phosphoric acid disodium hydrogen 0.75%, the phosphate buffer of citric acid 0.05% (w/v) is with the weighing scale of described compositions.
Described antibacterial is the usual component in the preparation of this area, can be selected from the mixture of any one or multiple arbitrary proportion in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzyl alcohol, phenethanol, sorbic acid, salicylic acid, chlorobutanol, benzalkonium chloride, benzalkonium bromide, thimerosal or the phenoxyethanol.Preferably antibacterial is ethylparaben and propyl p-hydroxybenzoate mixture, content is 0.01-0.04% (w/v), benzalkonium chloride, and content is that 0.005-0.01% (w/v) or benzalkonium bromide content are 0.015-0.05% (w/v).More preferably, described antibacterial is selected from 0.03% (w/v) ethylparaben and propyl p-hydroxybenzoate mixture, 0.005% (w/v) benzalkonium chloride, or 0.01% (w/v) benzalkonium bromide.
The pH value of described eye drop aqueous solution is 5.0～9.0.Preferred pH value is 6.0～8.0.Described PH regulator is selected from the usual component in the preparation of this area, and the routine that it is selected and content all can be followed is in the industry considered.Described PH regulator can be selected sodium hydroxide and/or hydrochloric acid, citric acid, sulphuric acid, sodium citrate, triethanolamine and composition thereof.Preferably, described PH regulator is selected from hydrochloric acid or sodium hydroxide.
As known in the art, need often to use buffer that pH value is adjusted to a required scope that is suitable for a usefulness.Known many buffer that comprises inorganic acid salt are such as hac buffer, borate buffer, Palitzschs buffer solution, phosphate buffered solution, Sha Shi phosphate buffered solution, lucky Fei Shi buffer or citrate buffer.
Described solvent is selected from the usual component in the preparation of this area, and the routine that it is selected and content all can be followed is in the industry considered.Preferably, described solvent is selected from normal saline and/or water for injection.
In addition, preparation of the present invention can also comprise other usual component in the ophthalmic preparation, such as thickening agent or viscosity intensifier, extender, antioxidant, metal chelating agent etc.
A kind of excipient commonly used in ophthalmic composition is viscosity intensifier or thickening agent.Use the thickening agent can be for various reasons, comprise from the improved formulations form contacting to improve bioavailability to make things convenient for administration with eyeball to increase.Viscosity intensifier can comprise the polymer that contains hydrophilic group, hydrophilic group such as monosaccharide, polysaccharide, ethylene oxide group, oh group, carboxylic acid or other charged functional groups.Be not in order to limit the scope of the invention, the example of the viscosity intensifier that some are useful is methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, polyvidone, polyvinyl alcohol and Polyethylene Glycol.
Extender can be selected from the mixture of any one or multiple arbitrary proportion in mannitol, sorbitol or the xylitol.
Antioxidant can be selected from the mixture of any one or multiple arbitrary proportion in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, citric acid, tartaric acid, phosphoric acid, vitamin C, vitamin E, lecithin or the aminoacid.
Metal chelating agent can be selected from the mixture of any one or multiple arbitrary proportion in disodiumedetate, calcium disodium chelate, tartaric acid, phosphoric acid or the two mercapto ethyl glycines.The preferable alloy chelating agent is disodiumedetate, calcium disodium chelate, calcium disodium chelate and calcium disodium chelate mixture.
Bimatoprost preparation composition for eyes of the present invention also can be prepared into various pharmaceutically acceptable dosage forms.Preferably, the dosage form of described compositions is gel for eye use or eye drop.More preferably, the dosage form of described compositions is eye drop.
Preparation method of the present invention is that non-ionic surface active agent is dissolved in the water for injection, adds Bimatoprost, and stirring, heating make dissolving; Other get osmotic pressure regulator, antibacterial, buffer and or other pharmaceutically acceptable carriers such as viscosifier be dissolved in the water for injection that boils, stir and make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
The packing of product of the present invention can be taked multiple-unit container, props up such as 2.5ml/, also can take unit dose package, props up such as 0.4ml/, and every disposable, and wherein unit dose package can add or not add antiseptic as required.
According to a kind of Bimatoprost eye drop that preparation method of the present invention prepares, preparation technology is reasonable, and easy operating can make the impurity of its generation obviously reduce simultaneously, and stability increases, and not only is of value to and improves the quality of products, and can also improve curative effect.
The specific embodiment
Further specify by the following specific embodiment, how these examples just for making and use thing of the present invention that direction and guidance are provided, and be not intended to by any way and limit the scope of the invention.
Embodiment 1
Prescription:
Preparation technology: HCO60 is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, Benzalkonii Chloridum, EDTA-2Na, boric acid, Borax and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
Embodiment 2
Prescription:
Preparation technology: polyoxyethylene hydrogenated Oleum Ricini 40 is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, benzalkonium bromide, EDTA-2Na, methylcellulose, boric acid, Borax and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
Embodiment 3
Prescription:
Preparation technology: polyoxyethylene hydrogenated Oleum Ricini 35 is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, Benzalkonii Chloridum, sodium pyrosulfite, sodium hydrogen phosphate, citric acid and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
Embodiment 4
Prescription:
Preparation technology: polyoxyethylene sorbitan monoleate is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, ethylparaben, propyl p-hydroxybenzoate, sodium hydrogen phosphate, citric acid and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
Embodiment 5
Prescription:
Preparation technology: polyoxyethylene sorbitan monoleate is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, benzalkonium chloride, sodium carboxymethyl cellulose, sodium pyrosulfite, EDTA-2Na, sodium hydrogen phosphate, citric acid and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
Embodiment 6 Bimatoprost eye drops prescription is to the comparison of Bimatoprost dissolubility
To carrying out the comparison of Bimatoprost dissolubility by the prescription B that has added non-ionic surfactant polyoxyethylene castor oil hydrogenated 60 in the open prescription A that has gone on the market and the prescription, compare two prescriptions changes in solubility in preparation technology.
Prescription A
Preparation technology: take by weighing the Bimatoprost of recipe quantity in water for injection, stirring, heating make dissolving; Other gets sodium chloride, Benzalkonii Chloridum, sodium hydrogen phosphate, citric acid in water for injection, stirs to make dissolving; After being cooled to room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling namely gets sample A in the plastics eyedrops bottle.
Prescription B
Preparation technology: HCO60 is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, Benzalkonii Chloridum, EDTA-2Na, boric acid, Borax and is dissolved in the water for injection that boils, and stirs to make dissolving; After being cooled to room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling namely gets sample B in the plastics eyedrops bottle.
Test sample A, the forward and backward content of sample B filtering with microporous membrane sees Table 1
Conclusion: the prescription filtering with microporous membrane front and back content that adds non-ionic surface active agent does not have to change substantially, and the front content of filtering with microporous membrane is lower among the sample A, and content decrease after filtering may be that principal agent does not dissolve fully, and tunicle has been held back.
Detection method of content: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica, take the mixed solution of water-acetonitrile of containing 0.03% trifluoroacetic acid-methanol (72: 18: 10) as mobile phase, flow velocity is 1ml/min, the detection wavelength is 210nm, and number of theoretical plate calculates by the Bimatoprost peak should be not less than 6000.
Algoscopy: precision takes by weighing approximately 60mg of Bimatoprost reference substance, dissolve and be diluted to the solution that concentration is 0.06mg/ml with retarder thinner [mixed solution of water-acetonitrile-methanol (78: 22: 10)], solution in contrast: precision measures this product 5ml, put in the 25ml measuring bottle, add retarder thinner to scale, shake up, as need testing solution; Precision measures reference substance solution and each 100ul of need testing solution, the injection liquid chromatography, and the record chromatogram is pressed external standard method with calculated by peak area, and be get final product.
Embodiment 7 stability experiments
Adopt the formula preparation Bimatoprost eye drop among the embodiment 4, press commercially available back, place simultaneously listing sample " Lu Meigen " (not containing surfactant), carry out influence factor's experiment and stability experiment.Result such as table 2:
By the study on the stability experiment, this eye drop visible foreign matters, pH value, character, content, related substance etc. are all up to specification, and compare with commercially available sample, and the stability of embodiment 1,4 prescription preparations is higher than commercially available sample.
Embodiment 8 Bimatoprost eye drops and commercially available Lu Meigen eye drop toxicology test are relatively
One, test specimen
The embodiment of the invention 1 Bimatoprost eye drop specification: 2.5ml trial-production
The embodiment of the invention 4 Bimatoprost eye drop specification: 2.5ml trial-production
Commercially available Lu Meigen eye drop specification: 2.5ml lot number: 71412 manufacturing enterprises: U.S. Ai Ligen drugmaker
(test specimen of embodiment of the invention prescription preparation is according to " requiring to carry out drug content, its related substances, pH value, visible foreign matters, visual examination under 2005 editions two appendix eye drop items of Chinese pharmacopoeia.Be the test specimen after up-to-standard.)
Two, test objective
Take listing Lu Meigen eye drop as contrast, observe behind the animal eyes contact test sample irritant reaction situation to conjunctiva, cornea and iris.
Three, test method and process
(1) single-dose test: get 8 of healthy white rabbit, be divided into 2 groups, left eye all adopts the listing product in contrast with the prescription of the embodiment of the invention 1, example 4, right eye.Respectively at 2h, 6h, 24h, 48h, 72h and used fluorescent staining in 7 days before the eye drip and behind the eye drip, slit lamp observation is to the irritative response of conjunctiva, cornea and iris.
(2) multiple dosing test: get 8 of healthy white rabbit, be divided into 2 groups, left eye all adopts the listing product in contrast with the prescription of the embodiment of the invention 1, example 4, right eye.Every day, eye drip was 5 times, and continuous 14 days, respectively at using fluorescent staining in 2,4,6,8,10,12,14 days before the eye drip and behind the eye drip, slit lamp observation was to the irritative response of conjunctiva, cornea and iris.Testing standard:
The score value result:
1. single-dose result of the test
2. multiple dosing result of the test
Four, conclusion
To testing result with the score value statistical calculations, the embodiment of the invention 1,4 and commercially available eye drop behind single-dose, all non-stimulated, illustrate that this prescription does not increase zest.
Behind multiple dosing, find that the zests of the embodiment of the invention 1,4 prescriptions with commercially available eye drop, do not increase zest, and can be observed the present embodiment in the experimentation and write out a prescription that the holdup time obviously is longer than commercially available eye drop within the eye.
Claims (1)
1. Bimatoprost eye drop, it is active component that this eye drop contains Bimatoprost, adopts following method to be prepared from:
Prescription:
Bimatoprost 0.75g
Benzalkonium chloride 0.125g
HCO60 12.5g
Sodium chloride 12.5g
EDTA-2Na 1.25g
Boric acid 28.75g
Borax 1.25g
Water for injection adds to 2500ml
Make 1000
Preparation technology: HCO60 is dissolved in the water for injection, adds Bimatoprost, stirring, heating make dissolving; Other gets sodium chloride, Benzalkonii Chloridum, EDTA-2Na, boric acid, Borax and is dissolved in the water for injection that boils, and stirs to make dissolving; Be cooled to after the room temperature two liquid are merged, filter, be diluted to the preparation full dose with water for injection, regulate pH value to 6.5～8.0, by 0.22 μ m filtering with microporous membrane, sterile filling and get final product in the plastics eyedrops bottle.
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| EP4051234A1 (en) * | 2019-10-31 | 2022-09-07 | Rafarm S.A. | Bimatoprost 0.01% solution compositions for the treatment of ocular hypertension |
| CN111632025A (en) * | 2020-03-04 | 2020-09-08 | 吉林大学第一医院 | A kind of bimeprost ophthalmic temperature-sensitive in situ gel and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688317A (en) * | 2002-09-09 | 2005-10-26 | 参天制药株式会社 | Clear eye drops containing the active ingredient latanoprost |
| CN102083413A (en) * | 2008-05-30 | 2011-06-01 | 参天制药株式会社 | Method and composition for treating ocular hypertension and glaucoma |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688317A (en) * | 2002-09-09 | 2005-10-26 | 参天制药株式会社 | Clear eye drops containing the active ingredient latanoprost |
| CN102083413A (en) * | 2008-05-30 | 2011-06-01 | 参天制药株式会社 | Method and composition for treating ocular hypertension and glaucoma |
Non-Patent Citations (4)
| Title |
|---|
| 新型抗青光眼药物——卢美根;法玛林珂上海医药咨询服务有限公司;《眼科》;20071231;第16卷(第1期);2-3 * |
| 法玛林珂上海医药咨询服务有限公司.新型抗青光眼药物——卢美根.《眼科》.2007,第16卷(第1期),2-3. |
| 白洁等.贝美前列素滴眼液疗效及经济学评价研究综述.《中国执业药师》.2009,第16卷(第11期),28-31. |
| 贝美前列素滴眼液疗效及经济学评价研究综述;白洁等;《中国执业药师》;20091130;第16卷(第11期);28-31 * |
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