CN102085175B - Ophthalmic gel and preparation method thereof - Google Patents
Ophthalmic gel and preparation method thereof Download PDFInfo
- Publication number
- CN102085175B CN102085175B CN2009102497802A CN200910249780A CN102085175B CN 102085175 B CN102085175 B CN 102085175B CN 2009102497802 A CN2009102497802 A CN 2009102497802A CN 200910249780 A CN200910249780 A CN 200910249780A CN 102085175 B CN102085175 B CN 102085175B
- Authority
- CN
- China
- Prior art keywords
- gel
- eye
- water
- latanoprost
- timolol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to an ophthalmic gel and a preparation method thereof, in particular to the ophthalmic gel. The ophthalmic gel comprises effective quantity of latanoprost and timolol or salts thereof for treatment and/or prevention, a gel matrix, a surfactant and water. The invention also comprises the ophthalmic gel, an ophthalmic preparation of a medicinal excipient mixed with the ophthalmic gel before being used, and the preparation method of the ophthalmic gel. The ophthalmic gel has the favorable effects of treating eye diseases, and has less adverse effects on a cardiovascular system and a respiratory system of the whole body.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to and can be used for treating glaucomatous gel for eye, be specifically related to contain the gel for eye of active component latanoprost and timolol or its salt.
Background technology
Glaucoma is generally defined as one group and threatens and infringement optic nerve visual performance, mainly clinical levy Hou Qun or the oculopathy relevant with the rising of pathologic intraocular pressure.The rising of intraocular pressure is a key factor in the Deterioration of Optic Nerve in Glaucoma progress.If intraocular pressure has surpassed eyeball inner tissue, especially the limit that can bear of retina optic nerve, will be to each tissue (comprising cornea, iris and crystalline lens) in the eyeball, especially the optic nerve visual function brings infringement, and the most typical and the most outstanding performance is the pitting atrophy of papilla of optic nerve and damaged the dwindling of characteristic in the visual field.Take effective treatment as untimely, the visual field may total loss, eventually to blind.The pathophysiological process that intraocular pressure raises in the glaucoma mainly contains three aspects: the speed that ciliary processes generates aqueous humor increases, the resistance increment that aqueous humor flows out by trabecular reticulum approach or tunica uvea sclera approach, and the venous pressure of episclera increases.Overwhelming majority part glaucomas are because of due to the ah outflow resistance increment.For glaucomatous possibility Etiologic Mechanism, present effective measures clinically adopt the whole bag of tricks exactly, and the aqueous humor circulation of multilated is restored balance again; control pathologic intraocular pressure; reach the safe target intraocular pressure level of each individuality, stop and prevent the infringement of optic nerve, the protection visual function.Reduce intraocular pressure and be the at present effective Therapeutic Method of attested glaucoma.The intraocular pressure of using at present reduces medicine and comprises plan choline drugs with function, beta-2 adrenoceptor agonist, beta-2 adrenoceptor blocker, carbonic anhydrase inhibitors, alpha adrenergic receptor agonist and prostaglandins medicine.Wherein the beta-2 adrenoceptor blocker is positioned at β on the ciliary body non-pigmented epithelium cells by blocking-up
2Adrenoceptor reduces aqueous humor and generates, and is most widely used intraocular pressure lowering medicine; The prostaglandins medicine increases tunica uvea sclera approach aqueous humor drainage by the collagenic connective tissue in degraded ciliary body muscle gap, is the present local intraocular pressure lowering medicine of the most effective eye.
Because the generation of defect of visual field has invisible and gradual due to chronic intraocular hypertension and durative intraocular hypertension later stage, especially at primary open angle glaucoma, not obvious or do not have specificity to be difficult for realizing because of early clinical manifestation, when medical in case find visual deterioration, be late cases often, defect of visual field is serious.For this type of patient, be necessary to formulate the therapeutic scheme of a basic reduction intraocular pressure, but reducing medicine, conventional intraocular pressure usually is not enough to obtain suitable result, need to select the different intraocular pressure lowering medicine use in conjunction of physiological action this moment.Timolol is intraocular pressure lowering medicine the most frequently used in the beta-2 adrenoceptor blocker, and latanoprost is prostaglandin F
2 αThe medicine that side effect is light in the derivant, the intraocular pressure lowering effect is stronger, its compound preparation draws smooth thiophene eye drop
In calendar year 2001, go on the market at a plurality of state approvals such as Sweden, Britain respectively, and went on the market in China's approval in 2008.Yet the sickness rate of glaucoma in the old people is higher, and timolol has the cardiovascular system untoward reaction of respiratory system of unifying, thereby draws the clinical practice of smooth thiophene eye drop to have potential safety hazard, has limited its application.
Therefore, still need clinically a kind of Novel medicine feeding technology for latanoprost and timolol or its salt administration, reducing by two kinds of active component when eye share, the systemic adverse reactions due to the timolol improves its service efficiency.
Summary of the invention
The object of the present invention is to provide that a kind of new treatment is effective, untoward reaction is little and be expected to improve being used for the treatment of and/or preventing the particularly glaucomatous gel for eye that comprises latanoprost and timolol or its salt of oculopathy of drug bioavailability.
The inventor is surprised to find that, latanoprost and timolol or its salt are made the gel that comprises gel-type vehicle and surfactant, not only have the effect of good treatment ocular disease, and systemic adverse reactions is very little.The present invention is based on above-mentioned discovery and be accomplished.
For this reason, first aspect present invention provides a kind of gel for eye, it comprises the latanoprost that treats and/or prevents effective dose and timolol or its salt (its officinal salt for example, particularly for example timolol or its salt), gel-type vehicle agent, surfactant, He Shui.
According to each gel for eye of first aspect present invention, wherein said gel-type vehicle agent is to be selected from following one or more: cellulose derivative, crosslinked acrylate copolymer, poloxamer, alginic acid, hyaluronic acid sodium, gellan gum (Gellan Gum), polyvinylpyrrolidone, crospolyvinylpyrrolidone, polyvinyl alcohol, Polyethylene Glycol.In one embodiment, described cellulose derivative includes but not limited to hydroxypropyl emthylcellulose, methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and salt thereof for example sodium carboxymethyl cellulose, hydroxyethyl-cellulose, preferred hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, more preferably hydroxypropyl methylcellulose 2910.In one embodiment, described crosslinked acrylate copolymer includes but not limited to carbomer, Polycarbophil.In one embodiment, in one embodiment described, described carbomer is selected from Carbopol, Carbomer971, Carbopol 941, carbomer 973, Acritamer 940, carbomer 934, preferred Carbopol.
According to each gel for eye of first aspect present invention, wherein said gel-type vehicle agent is to be selected from following one or more: carbomer, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol.
According to each gel for eye of first aspect present invention, wherein said gel-type vehicle agent is the combination of carbomer and polyvinyl alcohol.In one embodiment, the combination of described carbomer and polyvinyl alcohol be carbomer and polyvinyl alcohol with 1: 0.5 to 1: 10 combination of weight ratio, be preferably with 1: 1 to 1: 5 combination of weight ratio.
According to each gel for eye of first aspect present invention, wherein said surfactant is selected from polyoxyethylene hydrogenated Oleum Ricini, Polysorbate.
According to each gel for eye of first aspect present invention, wherein said surfactant is selected from polyoxyl 40 hydrogenated castor oil, Cremophor RH60, polyoxy 35 Oleum Ricini, polyoxyethylene sorbitan monoleate.
According to each gel for eye of first aspect present invention, the w/w percent by this gel wherein comprises:
Latanoprost 0.001-0.02%,
Timolol or its salt 0.05-2%,
Gel-type vehicle agent 0.05-10%,
Surfactant 0.02-2%,
Water is an amount of, adds to 100%.
According to each gel for eye of first aspect present invention, the w/w percent by this gel wherein comprises:
Latanoprost 0.001-0.01%,
Timolol or its salt 0.05-1%,
Gel-type vehicle agent 0.1-6%,
Surfactant 0.05-1%,
Water is an amount of, adds to 100%.
According to each gel for eye of first aspect present invention, the w/w percent by this gel wherein comprises:
Latanoprost 0.001-0.005%,
Timolol or its salt 0.05-0.5%,
Gel-type vehicle agent 0.5-6%,
Surfactant 0.05-0.5%,
Water is an amount of, adds to 100%.
According to each gel for eye of first aspect present invention, wherein also contain the pH value regulator.In an embodiment of first aspect present invention gel for eye, described pH value regulator be selected from boric acid, Borax, sodium hydroxide, hydrochloric acid, phosphate buffered solution, the acetate buffer solution etc. any or multiple.According to the present invention, the use amount of described pH value regulator in preparation can change because of many factors, described factor is pH value regulator type and intensity thereof for example, prescription forms, the physics and chemistry stability of medicine and preparation etc., those skilled in the art understand, the target pH value that the amount of this pH value regulator in gel of the present invention can easily be regulated according to hope is determined, for example the target pH value in hope is in the situation of 6.5-7.5, after having mixed all prescription compositions that most material particularly dewaters to locate, at preparation standardize solution (to final weight and/or volume) before, pH value regulator with Sq carries out the pH value adjusting to preparation, can easily determine the concrete consumption of pH value regulator in preparation thus.In an embodiment of first aspect present invention gel for eye, the pH value of described gel for eye is 4.5-8.5, and preferred pH value is 5.5-7.5, and preferred pH value is 6.0-7.0.
According to each gel for eye of first aspect present invention, wherein can also contain osmotic pressure regulator, the example that can be used for osmotic pressure regulator of the present invention include but not limited in propylene glycol, glycerol, glucose, sodium chloride, mannitol, the sorbitol etc. any or multiple.According to the present invention, the use amount of described osmotic pressure regulator in preparation can change because of many factors, described factor is osmotic pressure regulator type and intensity thereof for example, prescription forms, the physics and chemistry stability of medicine and preparation etc., those skilled in the art understand, the target osmotic pressure that the amount of this osmotic pressure regulator in gel of the present invention can easily be regulated according to hope is determined, for example the target osmotic pressure of hope for body fluid substantially first-class ooze or slightly high situation of oozing under, after having mixed all prescription compositions that most material particularly dewaters to locate, at preparation standardize solution (to final weight and/or volume) before, osmotic pressure regulator with Sq carries out the osmotic pressure adjusting to preparation, can easily determine the concrete consumption of osmotic pressure regulator in preparation thus.In one embodiment, gel for eye of the present invention contains 0-15.0% (w/w), preferred 0.01-10% (w/w), more preferably 0.01-5% (w/w), the more preferably osmotic pressure regulator of 0.05-2% (w/w) more substantially.In addition, also can tentatively determine the consumption of osmotic pressure regulator in preparation by Theoretical Calculation according to existing physical chemistry knowledge.
According to each gel for eye of first aspect present invention, wherein also contain one or more and be selected from following antibacterial: phenethanol, phenoxyethanol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzalkonium chloride, chlorobutanol, benzalkonium bromide, cetrimonium bromide.In further embodiment, described antibacterial is to be selected from ethylparaben, benzalkonium chloride, the cetrimonium bromide one or more.In embodiment further, described antibacterial benzalkonium chloride accounts for the 0.001-0.05% (w/w) of this eye drop total amount.Preferably, described antibacterial accounts for the 0.005-0.02% (w/w) of this eye drop total amount.Preferably, described antibacterial accounts for the 0.008-0.01% (w/w) of this eye drop total amount.
According to each gel for eye of first aspect present invention, wherein also contain cyclodextrin, for example α, β, γ cyclodextrin, particularly beta cyclodextrin, more particularly hydroxypropyl beta cyclodextrin.
According to each gel for eye of first aspect present invention, wherein also contain chelating agent, be selected from ethylenediaminetetraacetic acid, disodiumedetate, preferred disodiumedetate.
According to each gel for eye of first aspect present invention, it is characterized in that it has the prescription shown in the embodiment of the invention and forms.
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.05 weight portion approximately,
Timolol maleate is 3.4 weight portions approximately,
Polyoxyl 40 hydrogenated castor oil is 1.0 weight portions approximately,
Benzalkonium chloride is 0.08 weight portion approximately,
One hypophosphite monohydrate sodium dihydrogen is 4.0 weight portions approximately,
Sodium hydrogen phosphate is 5.3 weight portions approximately,
Hydroxypropyl emthylcellulose (60SH-50) is 50 weight portions approximately,
Sodium chloride is 4.8 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions.
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.05 weight portion approximately,
Timolol maleate is 3.4 weight portions approximately,
Polyoxyl 40 hydrogenated castor oil is 1.0 weight portions approximately,
Benzalkonium chloride is 0.08 weight portion approximately,
One hypophosphite monohydrate sodium dihydrogen is 4.0 weight portions approximately,
Sodium hydrogen phosphate is 5.3 weight portions approximately,
Sodium carboxymethyl cellulose is 50 weight portions approximately,
Sodium chloride is 4.8 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions.
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.05 weight portion approximately,
Timolol maleate is 3.4 weight portions approximately,
Polyoxyl 40 hydrogenated castor oil is 1.0 weight portions approximately,
Benzalkonium chloride is 0.08 weight portion approximately,
Polyvinyl alcohol is 5 weight portions approximately,
Carbopol P is 40 weight portions approximately,
Glycerol is 20 weight portions approximately,
Sodium hydroxide is 1.75 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions,
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.2 weight portion approximately,
Timolol maleate is 27.4 weight portions approximately,
Polyoxyl 40 hydrogenated castor oil is 20 weight portions approximately,
Benzalkonium chloride is 0.1 weight portion approximately,
Hydroxypropyl emthylcellulose (60SH-50) is 50 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions.
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.1 weight portion approximately,
Timolol maleate is 13.7 weight portions approximately,
Polyoxyethylene sorbitan monoleate is 10 weight portions approximately,
Benzalkonium chloride is 0.1 weight portion approximately,
Sodium carboxymethyl cellulose is 40 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions.
According to each gel for eye of first aspect present invention, it comprises following proportioning and forms:
Latanoprost is 0.01 weight portion approximately,
Timolol maleate is 0.68 weight portion approximately,
Polyoxyethylene sorbitan monoleate is 0.1 weight portion approximately,
Benzalkonium chloride is 0.1 weight portion approximately,
Carbomer is 2 weight portions approximately,
Water for injection is an amount of, adds to 1000 weight portions.
As used herein, words " approximately " has the implication of well known to a person skilled in the art, refer to especially the general standard deviation that those skilled in the art understand, the standard deviation that for example represents mentioned numerical value and this numerical value 10% with interior (for example 8% with interior, 5% with interior, in 2%) numerical range, for example mention " approximately 2 weight portions ", expression comprises the scope (being that standard deviation is 10%) of " 1.8-2.2 weight portion ".
Second aspect present invention provides the preparation method of each described gel for eye of first aspect present invention, it comprises gel-type vehicle agent component is water-solublely swollenly formed gel-type vehicle after fully with an amount of, other components are added in the gel-type vehicle after with water dissolution, and stirring, and the step of fill.
Second aspect present invention provides the preparation method of each described gel for eye of first aspect present invention, and it may further comprise the steps:
I) make gel-type vehicle agent component suitable quantity of water swelling, dissolving, sterilization, for subsequent use;
Ii) the active medicine latanoprost is mixed with surfactant, add suitable quantity of water and make medicine dissolution;
Iii) add active medicine timolol or its salt, and optional antibacterial, pH adjusting agent, osmotic pressure regulator etc., stir;
Iv) make above i) and the iii) mixing of materials of gained, mend and add water to the prescription full dose, stir, fill, and get final product.
In an embodiment of second aspect present invention preparation method, can prepare as follows gel for eye of the present invention:
(i) measure the matrix powder end by prescription, be dispersed in a small amount of water, stir, placed 24 hours, make the abundant swelling of gel-type vehicle agent component, 121 ℃ of 30min sterilizations, for subsequent use;
(ii) with the surfactant of active medicine latanoprost adding recipe quantity, the water that adds an amount of 80-90 ℃ makes medicine dissolution;
(iii) add active medicine timolol or its salt, and optional antibacterial, pH adjusting agent, osmotic pressure regulator etc., stir and make dissolving;
(iv) medicine in (iii) and the substrate (ii) are mixed, stirred packing 30-60 minute.
The gel for eye that contains the gel for eye that comprises latanoprost and timolol or its salt that can make according to the inventive method, its outward appearance is clear and bright, aseptic, toxicity is low, zest is low particularly without sand type, can provide a kind of safe and effective, ophthalmic preparation that untoward reaction is little for clinical.
The below to various aspects of the present invention and their benefit be further described.
As used herein, phrase " by the w/w percent of this gel " refers in this gel 100g, the weight grams of the component that wherein comprises is this w/w percent, i.e. common represented g/100g, or be expressed as % (w/w).In the present invention, as not indicating in addition, % is w/w percent.
In this article, for the metering of timolol or its salt, if do not specialize in base or in salt shape, be timolol in its base all then.
As used herein, term " gel-type vehicle agent " is the general designation to the adjuvant that can form gel substrate, and the adjuvant that can be used in this article forming gel-type vehicle includes but not limited to cellulose derivative, crosslinked acrylate copolymer, poloxamer, alginic acid, hyaluronic acid sodium, gellan gum, polyvinylpyrrolidone, crospolyvinylpyrrolidone, polyvinyl alcohol, Polyethylene Glycol etc.
Gel for eye of the present invention is a kind of waterborne compositions, wherein makes water as medium or solvent or excipient or the carrier of said composition.Although ophthalmic preparation of the present invention does not specifically note that used water accounts for the percent of ophthalmic preparation gross weight, perhaps do not specifically note the amount of institute's water during ophthalmic preparation of the present invention in preparation, but, those skilled in the art know that, as the medium or solvent or excipient or the carrier that drip with preparation, the amount of this water adds to the gel for eye full dose with water and calculates, and this is in the liquid preparation general metering method that adopts in the process for preparation of eye drop, injection or gel for eye of the present invention for example.
In gel for eye of the present invention, described antibacterial can be one or more combination in any.In one embodiment, described antibacterial is benzalkonium chloride, and its amount accounts for the 0.001-0.02% (w/w) of ophthalmic preparation of the present invention, preferred 0.005-0.01% (w/w), more preferably 0.008% (w/w).
Preparation of the present invention can be placed in any needed doser that is suitable for ophthalmic preparation.This device can be that eye use drug-supplying system, such as sterilization with aluminum pipe or multiple tube, plastic bottle etc.
The object of the present invention is to provide a kind of gel for eye use that contains active component latanoprost and timolol or its salt, reduce preparation to the zest of eye, simultaneously expectation reduces the caused systemic adverse reactions of timolol.The inventor finds, after in preparation of the present invention, using gel-type vehicle agent (high molecular polymer), can very effectively stick to ocular surface, thereby prolong drug is in the retention time of ocular surface, reduce medicine from the loss of nasolacrimal duct, and then reduce the systemic adverse reactions of medicine.
The specific embodiment:
Further specify the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the usefulness that specifically describes more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Although for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify, material therefor of the present invention and operational approach are well known in the art.
Embodiment 1
Prepare gel for eye use by following prescription proportioning.
Latanoprost 0.05g
Timolol maleate 3.42g
Polyoxyl 40 hydrogenated castor oil 1.0g
Benzalkonium chloride 0.08g
One hypophosphite monohydrate sodium dihydrogen 4.05g
Sodium hydrogen phosphate 5.30g
Hydroxypropyl emthylcellulose (60SH-50) 50g
Sodium chloride 4.8g
Water for injection adds to 1000g
Preparation method: get the hydroxypropyl emthylcellulose of recipe quantity with an amount of water for injection swelling, spend the night, 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; Get the recipe quantity latanoprost, add the recipe quantity polyoxyl 40 hydrogenated castor oil, mix homogeneously adds 80-90 ℃ the about 500g of water for injection, stirring makes dissolving, add successively benzalkonium chloride, timolol maleate, a hypophosphite monohydrate sodium dihydrogen, sodium hydrogen phosphate, sodium chloride and stir and make dissolving, 0.22 μ m filters, and adds in the hydroxypropyl methylcellulose matrix, moisturizing is to 1000g, stir, packing, and get final product.
Embodiment 2
With embodiment 1 operation, substitute hydroxypropyl emthylcellulose with sodium carboxymethyl cellulose, make gel for eye use.
Embodiment 3
Prepare gel for eye use by following prescription proportioning.
Latanoprost 0.05g
Timolol maleate 3.42g
Polyoxyl 40 hydrogenated castor oil 1.0g
Benzalkonium chloride 0.08g
Polyvinyl alcohol 5g
Carbopol P 40g
Glycerol 20g
Sodium hydroxide 1.75g
Water for injection adds to 1000g
Preparation method: get the Carbopol P of recipe quantity with an amount of water for injection swelling, spend the night, 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; The polyvinyl alcohol of getting recipe quantity ℃ makes dissolving with an amount of water for injection heating in water bath to 90, and 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; Get the recipe quantity latanoprost, add the recipe quantity polyoxyl 40 hydrogenated castor oil, mix homogeneously, the about 500g of water for injection that adds 80-90 ℃ stirs and makes dissolving, adds successively recipe quantity benzalkonium chloride, timolol maleate, glycerol, sodium hydroxide and stirs and make dissolving, 0.22 μ m filters, add in the Carbopol P substrate, stir, add again poly-vinyl alcohol solution, moisturizing is to 1000g, stir, packing, and get final product.
Embodiment 4
Prepare gel for eye use by following prescription proportioning.
Latanoprost 0.2g
Timolol maleate 27.36g
Polyoxyl 40 hydrogenated castor oil 20g
Benzalkonium chloride 0.1g
Hydroxypropyl emthylcellulose (60SH-50) 50g
Sodium hydroxide is an amount of
Water for injection adds to 1000g
Preparation method: get the hydroxypropyl emthylcellulose of recipe quantity with an amount of water for injection swelling, spend the night, 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; Get the recipe quantity latanoprost, add the recipe quantity polyoxyl 40 hydrogenated castor oil, mix homogeneously, the about 500g of water for injection that adds 80-90 ℃, stirring makes dissolving, adds successively benzalkonium chloride, timolol maleate, sodium chloride and stirs and make dissolving, and 0.22 μ m filters, add in hydroxypropyl emthylcellulose and the carbomer substrate, moisturizing is to 1000g, and sodium hydroxide is regulated pH value to 6.5～7.0, stirs, packing, and get final product.
Embodiment 5
Prepare gel for eye use by following prescription proportioning.
Latanoprost 0.1g
Timolol maleate 13.68g
Polyoxyethylene sorbitan monoleate 10g
Benzalkonium chloride 0.1g
Sodium carboxymethyl cellulose 40g
Sodium hydroxide is an amount of
Water for injection adds to 1000g
Preparation method: get the sodium carboxymethyl cellulose of recipe quantity with an amount of water for injection swelling, spend the night, 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; Get the recipe quantity latanoprost, add the recipe quantity polyoxyethylene sorbitan monoleate, mix homogeneously, the about 500g of water for injection that adds 80-90 ℃, stirring makes dissolving, adds successively benzalkonium chloride, timolol maleate and stirs and make dissolving, and 0.22 μ m filters, add in the sodium carboxymethyl cellulose substrate, moisturizing is to 1000g, and sodium hydroxide is regulated pH value to 6.5～7.0, stirs, packing, and get final product.
Embodiment 6
Prepare gel for eye use by following prescription proportioning.
Latanoprost 0.01g
Timolol maleate 0.684g
Polyoxyethylene sorbitan monoleate 0.1g
Benzalkonium chloride 0.1g
Carbomer 2g
Sodium hydroxide is an amount of
Water for injection adds to 1000g
Preparation method: get the carbomer of recipe quantity with an amount of water for injection swelling, spend the night, 121 ℃ of pressure sterilizings 30 minutes are crossed 400 mesh sieves, and are for subsequent use; Get the recipe quantity latanoprost, add the recipe quantity polyoxyethylene sorbitan monoleate, mix homogeneously, the about 500g of water for injection that adds 80-90 ℃, stirring makes dissolving, adds successively benzalkonium chloride, timolol maleate and stirs and make dissolving, and 0.22 μ m filters, add in the carbomer substrate, sodium hydroxide is regulated pH value to 6.5～7.0, and moisturizing stirs to 1000g, packing, and get final product.
Embodiment 1-1
Prepare ophthalmic preparation by following prescription proportioning.
Latanoprost 0.05g
Timolol maleate 3.42g
Benzalkonium chloride 0.2g
One hypophosphite monohydrate sodium dihydrogen 4.05g
Sodium hydrogen phosphate 5.30g
Sodium chloride 4.8g
Water for injection adds to 1000ml
Preparation method: the approximately 950ml that fetches water, adding timolol maleate, a hypophosphite monohydrate sodium dihydrogen, sodium hydrogen phosphate, sodium chloride stir and make dissolving; Get the recipe quantity benzalkonium chloride and add water and make 50% solution, join in the latanoprost, stir more than 60 minutes; Two kinds of solution are mixed, in 101 ℃～103 ℃ heating 10～11 minutes.Solution is cooled to approximately 25 ℃, supplies the water yield, stir, fill, and get final product.
Illustrate: the side's of Clicking here method for making preparation and eye drop, easily from the loss of nasolacrimal duct, and be absorbed into whole body through nasolacrimal duct, and cause the unify systemic adverse reactions of respiratory system of cardiovascular system.And the prescription gained preparation of embodiment 1-6 is there are no defects.
Embodiment 3-1
Prepare ophthalmic preparation by following prescription proportioning.
Latanoprost 0.05g
Timolol maleate 3.42g
Benzalkonium chloride 0.2g
Glycerol 20g
Sodium hydroxide is an amount of
Water for injection adds to 1000ml
Preparation method: get benzalkonium chloride and add water and make 50% solution, add latanoprost, stir more than 60 minutes; Add approximately 950ml of water, made the latanoprost dissolving in 10～11 minutes in 101 ℃～103 ℃ heating.Solution is cooled to approximately 25 ℃, and adding timolol maleate, glycerol stir and make dissolving, and sodium hydroxide is regulated pH value to 6.5～7.0, and moisturizing stirs to 1000ml, fill, and get final product.
Illustrate: the side's of Clicking here method for making preparation and eye drop, in storage process, latanoprost is easily degraded; And eye drop is easily from the loss of nasolacrimal duct, and is absorbed into whole body through nasolacrimal duct, and causes the unify systemic adverse reactions of respiratory system of cardiovascular system.
Experimental example 1: the eye irritation test of gel for eye use of the present invention
Rabbit single and repeatedly give gel for eye use of the present invention, all not finding has the obvious stimulation effect to tested rabbit eyes.
Test objective:
Observe the animal via eye and give the irritant reaction that produces behind the gel for eye use of the present invention situation.
Experimental animal:
New zealand rabbit, body weight 2.0-2.5kg, the male and female dual-purpose is provided by Shenyang Pharmaceutical University experimental animal center, and animal subject is without any inflammatory reaction and ocular injury.
Tested medicine:
Gel for eye use of the present invention (embodiment 4).
Test method:
Adopt consubstantiality left and right sides self-contrast method, select 4 of rabbit, test that the eyes to every animal check in front 24 hours, have the animal of eye irritation symptom, cornea defective and conjunctival damage can not be used for test.
(1) single-dose eye irritant test:
1 of gel for eye use of the present invention (approximately 0.03g) is splashed in the rabbit conjunctiva of right eye capsule, and the excipient that left eye splashes into equivalent in contrast.Then passive closed 10 seconds of administration relief lagophthalmos splashes into 2% fluorescein sodium, 1,2,4,24,48,72 hour to 7 days local excitation response situation after usefulness slit lamp (YZ5E1 type, Suzhou Medical Equipment General Factory) the observation administration.
(2) multiple dosing eye irritant test:
1 of gel for eye use of the present invention (approximately 0.03g) is splashed in the rabbit conjunctiva of right eye capsule, left eye splashes into commensurability excipient in contrast, and then passive closed 10 seconds of administration relief lagophthalmos splashes into 2% fluorescein sodium, observe with slit lamp (YZ5E1 type, Suzhou Medical Equipment General Factory).Administration every day 1 time, successive administration 14 days.1,2,4,24,48,72 hour to 7 days observation Ocular irritation response situation after the front and last administration of administration every day.
Criterion:
According to table 1, the irritant reaction score value addition of cornea, iris and conjunctiva of each animal gets total mark observing time with each, and one group integration summation divided by number of animals, is namely got last score value.Press table 2 and judge its stimulation degree.
Table 1 an irritant reaction score value standard
Table 2 eye irritation evaluation criterion
Result of the test:
Each time point of each animal of administration group does not find that all tested medicine has the obvious stimulation effect to the animal subject eye behind single and the multiple dosing, it stimulates comprehensive mean scores to be 0, and each time point of each animal of matched group is not found to give behind the excipient animal subject eye is had the obvious stimulation effect yet.Eye irritation is evaluated as nonirritant.Each is organized each animals administer and viewing duration and is showed no agitation, the Deviant Behavior activity such as drowsiness.
Conclusion (of pressure testing):
Gel for eye use single of the present invention and multiple dosing do not find that tested rabbit eyes is had the obvious stimulation effect.
Through above identical test, the result shows that embodiment 1,2,3,5,6 sample also have the eye irritation result of the test similar to above embodiment 4 gained.In addition, the sample of embodiment 1-1 and 3-1 is tested as stated above, be found that the zest of these two samples is obviously larger, and demonstrate larger systemic side effects.
Claims (9)
1. gel for eye, it comprises latanoprost and timolol or its salt, gel-type vehicle agent, surfactant and the water that treats and/or prevents effective dose, wherein, described gel-type vehicle agent is crosslinked acrylate copolymer and polyvinyl alcohol, and described crosslinked acrylate copolymer is carbomer; Described surfactant is polyoxyethylene hydrogenated Oleum Ricini; And the w/w percent by this gel wherein comprises:
Latanoprost 0.0005-0.02%,
Timolol or its salt 0.01-2%,
Gel-type vehicle agent 0.05-10%,
Surfactant 0.02-2%,
Water is an amount of, adds to 100%.
2. according to claim 1 gel for eye, the w/w percent by this gel wherein comprises:
Latanoprost 0.001-0.01%,
Timolol or its salt 0.01-1%,
Gel-type vehicle agent 0.1-6%,
Surfactant 0.05-1%,
Water is an amount of, adds to 100%.
3. according to claim 1 gel for eye, the w/w percent by this gel wherein comprises:
Latanoprost 0.001-0.005%,
Timolol or its salt 0.01-0.5%,
Gel-type vehicle agent 0.5-6%,
Surfactant 0.05-0.5%,
Water is an amount of, adds to 100%.
4. according to claim 1 to 3 each gel for eye, wherein also contain pH value regulator, osmotic pressure regulator, antibacterial, cyclodextrin and/or chelating agent.
5. according to claim 4 gel for eye, wherein
Described pH value regulator be selected from boric acid, Borax, sodium hydroxide, hydrochloric acid, phosphate buffered solution and the acetate buffer solution any or multiple;
Described osmotic pressure regulator be selected from propylene glycol, glycerol, glucose, sodium chloride, mannitol and the sorbitol any or multiple;
Described antibacterial be selected from phenethanol, phenoxyethanol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzalkonium chloride, chlorobutanol, benzalkonium bromide and the cetrimonium bromide any or multiple;
Described cyclodextrin is selected from α cyclodextrin, beta cyclodextrin, γ cyclodextrin and hydroxypropyl beta cyclodextrin;
Described chelating agent is selected from ethylenediaminetetraacetic acid and disodiumedetate.
6. according to claim 5 gel for eye, wherein, described cyclodextrin is beta cyclodextrin.
7. according to claim 5 gel for eye, wherein, described cyclodextrin is hydroxypropyl beta cyclodextrin.
8. each gel for eye in 7 according to claim 5, wherein, described chelating agent is disodiumedetate.
9. each the preparation method of gel for eye of claim 1 to 8, it may further comprise the steps:
I) make gel-type vehicle agent component suitable quantity of water swelling, dissolving, sterilization, for subsequent use;
Ii) the active medicine latanoprost is mixed with surfactant, add suitable quantity of water and make medicine dissolution;
Iii) add active medicine timolol or its salt, and optional antibacterial, pH adjusting agent, osmotic pressure regulator, stir;
Iv) make above i) and the iii) mixing of materials of gained, mend and add water to the prescription full dose, stir, fill, and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102497802A CN102085175B (en) | 2009-12-02 | 2009-12-02 | Ophthalmic gel and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102497802A CN102085175B (en) | 2009-12-02 | 2009-12-02 | Ophthalmic gel and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102085175A CN102085175A (en) | 2011-06-08 |
| CN102085175B true CN102085175B (en) | 2013-01-30 |
Family
ID=44097339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102497802A Active CN102085175B (en) | 2009-12-02 | 2009-12-02 | Ophthalmic gel and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102085175B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103977011B (en) * | 2013-02-07 | 2017-04-19 | 沈阳兴齐眼药股份有限公司 | Travoprost and timolol-containing ophthalmic gel and preparation method thereof |
| CN103977008B (en) * | 2013-02-07 | 2017-03-08 | 沈阳兴齐眼药股份有限公司 | Gel for eye containing Dorzolamide and timolol and preparation method thereof |
| CN106214624A (en) * | 2016-08-22 | 2016-12-14 | 北京中燕瑞康医药科技开发有限公司 | For treating timolol maleate preparation and the application thereof of baby's Superficial hemangioma |
| CN113750042B (en) * | 2020-06-05 | 2023-05-05 | 武汉武药科技有限公司 | Pharmaceutical composition and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473046A (en) * | 2000-11-13 | 2004-02-04 | �ź㴫 | Improved treatment |
| CN1634071A (en) * | 2004-11-05 | 2005-07-06 | 武汉大学 | Gel agent for treating glaucoma and its preparing process |
| CN101342178A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of latanoprost for eyes |
| CN101342176A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of timolol maleate for eyes |
-
2009
- 2009-12-02 CN CN2009102497802A patent/CN102085175B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1473046A (en) * | 2000-11-13 | 2004-02-04 | �ź㴫 | Improved treatment |
| CN1634071A (en) * | 2004-11-05 | 2005-07-06 | 武汉大学 | Gel agent for treating glaucoma and its preparing process |
| CN101342178A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of latanoprost for eyes |
| CN101342176A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of timolol maleate for eyes |
Non-Patent Citations (1)
| Title |
|---|
| 蒋幼芹.青光眼的药物治疗.《中华眼科杂志》.2006,第42卷(第2期),190-192页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102085175A (en) | 2011-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220040152A1 (en) | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism | |
| CN102046149B (en) | Stable ophthalmic formulations | |
| CN102159186A (en) | A ophthalmic flurbiprofen ester nano-emulsion in-situ gel formulation and the preparation method thereof | |
| CN104490861A (en) | Sustained-release nepafenac eye-drops preparation | |
| CN102085175B (en) | Ophthalmic gel and preparation method thereof | |
| KR20080081175A (en) | Topical mecamylamine formulations for ocular administration and uses thereof | |
| JP4158203B2 (en) | Non-steroidal anti-inflammatory ophthalmic suspension | |
| CN102085203B (en) | Ophthalmic preparation of levofloxacin and prednisolone acetate and preparation method thereof | |
| WO2005067891A1 (en) | Compositions comprosing memantine and polyanionic polymers for administration to the eye | |
| CN107412211A (en) | Aminoadamantan amine single nitric acid ester type compound ophthalmic composition and its preparation and application | |
| CN103977011B (en) | Travoprost and timolol-containing ophthalmic gel and preparation method thereof | |
| CN101396361B (en) | Medicine composition containing L-carnosine for suspending the development of the cataract | |
| CN102018656A (en) | Eye gel containing latanoprost used as effective component and preparation method thereof | |
| CN115645420A (en) | Application of mannose and medicinal derivatives thereof in preparation of medicines for preventing and/or treating age-related macular degeneration | |
| WO2023147318A2 (en) | Aqueous cevimeline compositions and methods of use | |
| CN116898800A (en) | Preservative-free ophthalmic pharmaceutical emulsion and use thereof | |
| CN109106684A (en) | A kind of non-steroidal anti-inflammatory gel for eye use and preparation method thereof | |
| CN112220749A (en) | Mizoribine and application of composition containing mizoribine | |
| CN116473918A (en) | Brimonidine tartrate eye drops and preparation method thereof | |
| NZ623037B2 (en) | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 110027 No. 12, 4, three street, Shenyang economic and Technological Development Zone, Liaoning, China Applicant after: SHENYANG XINGQI PHARMACEUTICAL Co.,Ltd. Address before: 110027 No. 12, 4, three street, Shenyang economic and Technological Development Zone, Liaoning, China Applicant before: SHENYANG SINQI PHARMACEUTICAL Co.,Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: SHENYANG XINGQI MEDICINE CO., LTD. TO: SHENYANG SINQI EYE PHARMACEUTICAL CO., LTD. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder |
Address after: No. 25 Xinyunhe Road, Shenyang Area, China (Liaoning) Pilot Free Trade Zone, Shenyang City, Liaoning Province, 110167 Patentee after: SHENYANG XINGQI PHARMACEUTICAL Co.,Ltd. Address before: 110027 No. 12, 4, three street, Shenyang economic and Technological Development Zone, Liaoning, China Patentee before: SHENYANG XINGQI PHARMACEUTICAL Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder |