CN102743760B - Bacteriostatic agent GellanGum-containing externally-used composite for eyes - Google Patents
Bacteriostatic agent GellanGum-containing externally-used composite for eyes Download PDFInfo
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Abstract
The invention relates to a bacteriostatic agent GellanGum-containing externally-used composite for eyes, which is composed of the externally-used composite for eyes and one or more medicinal auxiliary materials which are applicable to eyes, and the composite is characterized by comprising the bacteriostatic agent and GellanGum with amount of less than 0.1%.
Description
Technical field:
The present invention relates to a kind of eye topical composition, a kind of eye topical composition of bacteriostatic agent gellan gum.
Background technology
Eyes are important sensory organ of human body, and its structure is meticulous, even if slight damage also can affect greatly people's life, study, ability to work; Therefore eye external preparation is as the sterile preparation that is directly used in eye performance therapeutical effect, and its safety is paid close attention to by people always.
Eye external preparation refers to not oral administration, drug administration by injection, be directly used in eye mucosa or pass through the pharmaceutical preparation of eye mucosal treatment intraccular part tissue treatment ocular disease, comprise the preparations such as eye drop, collyrium, Eye ointments, eye ointment, gel for eye, eye mask agent, eye pill, 2010 editions appendix IG of Chinese Pharmacopoeia are shown in the definition of above-mentioned preparation type.
In recent years countries in the world to the prescription of eye external preparation gradually to the prescription future development of injection.At present, the eye external preparation great majority that domestic market is used are multiple-unit container, once behind preparation Kaifeng, easily use and preservation process in by tear and airborne microbial contamination, thereby produce safety hidden danger.In order to prevent in use microbial contamination of eye external preparation, in most of eye external preparation (comprising antibiotics), all added antibacterial.Antibacterial claims again antiseptic, refers to the chemical drugs that can prevent or suppress pathogenic microorganism growth and reproduction, by disturbing growth, breeding and the metabolism of microbial organisms to bring into play bacteriostasis.But the antibacterial using in eye external preparation at present all has zest or side effect in various degree to eye.The kind of antiseptic is a lot, and conventional antiseptic comprises: 1. most popular in the domestic eye drop of parabens is ethyl hydroxybenzoate, and ethylparaben, also has methyl hydroxybenzoate, propylparaben in addition; 2. alcohols is conventional benzyl alcohol, ethanol, phenethanol, chlorobutanol etc.; 3. organic acid is conventional comprises benzoic acid, sorbic acid, dehydroacetic acid etc.; 4. phenols is conventional phenol, Moschus phenol, chlorocresol etc.; 5. ammonium class is conventional benzalkonium bromide (benzalkonium bromide), benzalkonium chloride (benzalkonium chloride) etc.; 6. other are conventional hibitane, thimerosal etc.People's report (lagophthalmos irritant experiments of several conventional antibacterial in eye drop such as Liang Guangjiang, China Dispensary the 21st the 21st phase of volume in 2010,1964) " to the zest of eyes, ascending arrangement is followed successively by thimerosal, benzalkonium chloride, benzalkonium bromide, chlorhexidine, chlorobutanol, ethyl hydroxybenzoate, boric acid to conventional several antibacterial.After multiple dosing, because medication increased frequency, so eye irritant reaction mean scores is apparently higher than single-dose group." " Becquet F etc. has studied the pathology effects of multiple conventional antibacterial normal concentration to conjunctival tissue such as chlorination hexadecane trimethylammonium, Benasept, thimerosal, methyl hydroxybenzoate to the people such as Liu Aiming report (ocular surface injury of antibacterial in ophthalmic preparation; Journal of Chinese Hospital Pharmacy .99. .. rolled up for the 1st phase; 371), after one month with monoclonal antibody row histology and immunologic test, find epithelial cell keratinization, the cornea and conjunctiva infringements such as conjunctiva essential layer, epithelial layer, limbus of corneae position inflammatory infiltration, no significant difference between various antibacterial; ... the infringement based on antibacterial to eye table, has the therapeutical effect of the counteracting medicine that negative effect that scholar thinks that antibacterial causes may be to a certain degree, especially the ocular surface injury of the antibacterial in artificial tears to xerophthalmia patient." people such as State Food and Drug Administration's drug evaluation center Ning Lili report (multiple dose ophthalmic preparation not being added to the thinking of antibacterial; Chinese Journal of New Drugs the 18th the 7th phase of volume in 2009; 589) " all added antibacterial, be used for preventing the secondary pollution of microorganism in use procedure in most of ophthalmic preparation (comprising antibiotics).But there is the superficial cell toxicity to eye in antibacterial, the problem being caused by antibacterial abuse in recent years more and more receives publicity, ... the basic research results such as clinical research, zoopery and cell in vitro cultivation show: the antibacterial using in ophthalmic preparation at present all has zest in various degree to eye, as use excessive Hai Huidui ocular tissue to produce infringement.Have ophthalmic preparation that scholar investigated bacteriostatic agent to the histological impact of animal eye, result is observed the abnormal conditions such as microspike disappearance that damage, corneal epithelial cell appear in tear lipid layer.”
Carried out the research of a large amount of multiple dose eye external preparation that does not contain antibacterial both at home and abroad, people's reports such as State Food and Drug Administration's drug evaluation center Ning Lili (do not add the thinking of antibacterial to multiple dose ophthalmic preparation, Chinese Journal of New Drugs the 18th the 7th phase of volume in 2009,589) the multiple dose eye external preparation going on the market both at home and abroad through retrieval is antibiotics, but not antibiotic multiple dose eye external preparation also not listing at present, this is mainly because broad-spectrum antibiotic drug can play antibacterial action, can add antibacterial.And non-antibiotic medicament itself does not possess antibacterial or antibacterial action, when being used, do not add multiple dose antibacterial, in use can pollute, thereby it is healthy to affect eye; And interpolation antibacterial, antibacterial has again certain toxicity, when there is wound face in eye, to the absorption of antibacterial, can increase, and main be that antibacterial has zest to wound surface, thereby affect wound healing, can cause again the damage to eye surface mucosa, this just becomes an awkward problem.
Therefore in multiple dose eye external preparation, the reasonable use of antibacterial and quality control are one of key issues guaranteeing ophthalmic preparation safety, effectiveness; In preparation prescription screening and quality research process, how under the condition of using antibacterial, to effectively reduce the untoward reaction of antibacterial, just become a practical problem.
Gellan gum (GellanGum) is a kind of microorganism edible glue of the U.S. Kelco company exploitation eighties in 20th century.It is to belong to (Pseudomonaseloden) under neutrallty condition by vacation list brain bacillus waterweed, take glucose as carbon source, ammonium nitrate is in the culture medium that is made into of nitrogenous source and some inorganic salts, the extracellular polysaccharide colloid producing through aerobic fermentation, it is a kind of ion-sensitive type macromolecular material, when cation exists, can form gel, good stability, toxicity are little, biodegradable, the adjuvant of Chang Zuowei gel in eye external preparation.As Chinese patent application CN200810105214.x discloses a kind of instant gel for eye, in gel-type vehicle, contain the gellan gum that accounts for composition total weight 0.4%-0.7%.
Summary of the invention:
The ocular tissue damage of using antibacterial to cause in order to solve multiple dose eye topical composition, our surprised discovery in experiment, by adding micro-gellan gum just can reduce the infringement of antibacterial to ocular tissue.
Above-mentioned eye externally-applied medicinal composition is multiple dose eye externally-applied medicinal composition.Multiple dose eye externally-applied medicinal composition refers to common external medicament for the eyes, and surpass 24 hours service time from unpacking, and mostly generally is 7 days.
The invention provides a kind of eye externally-applied medicinal composition, the pharmaceutically useful adjuvant that is applicable to eye by eye external used medicine and one or more eye compositions forms, and it is characterized in that containing the gellan gum below antibacterial and 0.1%.
The present invention also provides the application of gellan gum in the eye externally-applied medicinal composition of preparation reduction antibacterial toxicity.
Described eye externally-applied medicinal composition, described antibacterial is parabens, alcohols, organic acid, phenols, ammonium class, hibitane, one or more in thimerosal.Be preferably ethyl hydroxybenzoate, methyl hydroxybenzoate, propylparaben, benzyl alcohol, ethanol, phenethanol, chlorobutanol etc., benzoic acid, sorbic acid, dehydroacetic acid, phenol, Moschus phenol, chlorocresol, benzalkonium bromide, benzalkonium chloride, hibitane, one or more in thimerosal.
Described eye externally-applied medicinal composition, described antibacterial is preferably cationic antibacterial, more preferably benzalkonium chloride, benzalkonium bromide or polyquaternary ammonium salt (polyquaternium), antibacterial is benzalkonium chloride, benzalkonium bromide more preferably.
Described eye externally-applied medicinal composition, described eye external used medicine is preferably glucocorticoid.The preferred cortisone of described glucocorticoid, fluorometholone, dexamethasone, prednisolone, prednisone, hydrocortisone, Rimexolone (Rimexolone), loteprednol (Loteprednol), budesonide, ciclesonide, alclometasone, algestone, beclometasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, chlorine ripple Buddhist nun alcohol, deflazacort, desonide, desoximetasone, diflorasone, diflucortolone, difluprednate, flucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocortolone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, halcinonide, Halobetasol Propionate, halometasone, halopredone acetate, hydrocortamate, medrysone, meprednisone, first Bo Nisonglong, mometasone, paramethasone, prednicarbate, ripple prednylidene 21-diethylaminoacetatte, triamcinolone, triamcinolone acetonide, amcinonide, fluticasone, mazipredone, tixocortol, a kind of compound in triamcinolone or its ester or its salt, be preferably a kind of in cortisone, fluorometholone, dexamethasone, prednisolone, prednisone, hydrocortisone, Rimexolone (Rimexolone), loteprednol, fluticasone, mometasone, betamethasone, methylprednisolone and pharmaceutically useful salt or carboxylate, more preferably cortisone acetate, dexamethasone sodium phosphate, fluorometholone, prednisolone acetate, prednisolone acetate, hydrocortisone acetate, Rimexolone, Loteprednol etabonate (Loteprednol etabonate).
Described eye externally-applied medicinal composition can be liquid eye drop, liquid suspendible eye drop.
Described eye externally-applied medicinal composition can be a gel, Eye ointments.
The acid-base value of described eye externally-applied medicinal composition is generally between the receivable pH4-9 of ophthalmology, and osmotic pressure is generally receivable at eye, does not cause in malaise symptoms ground scope.
Described eye externally-applied medicinal composition, described in be applicable to eye pharmaceutically useful adjuvant include but are not limited to carrier, pH adjusting agent, cosolvent, osmotic pressure regulator, viscosity modifier, antioxidant, antibacterial, buffer agent, suspending agent, local anesthetic, surfactant, solubilizing agent, wetting agent, emulsifying agent, stabilizing agent, filler, protective agent, solvent.
Described eye externally-applied medicinal composition, active component wherein can be aptly mixes with nontoxic medicine organic carrier or nontoxic medicine inorganic carrier.Typical pharmaceutically acceptable carrier is for example: mixture, vegetable oil, poly alkylene glycol, petroleum base gel, ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate, Eye ointments substrate, gel for eye substrate and other normally used acceptable carriers of water, the mixable solvent of Shui Heshui (for example low-level chain triacontanol or aromatics alkanol).
Described eye externally-applied medicinal composition, preferably make eye drop, described eye drop pharmaceutic adjuvant comprises one or more in carrier, buffer agent, isotonic agent, antibacterial, stabilizing agent, antioxidant, surfactant, acidity-basicity regulator, chelating agent, absorption enhancer, thickening agent, wetting agent; The pharmaceutic adjuvant of Eye ointments comprises one or more in substrate, stabilizing agent, antibacterial, and the substrate of Eye ointments is that matter is one or more in hydro carbons, lipoid and animal and plant oils and fats, and the substrate of gel for eye is macromolecular material; One or more in substrate carbomer, hydroxyethyl-cellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, carboxy methyl cellulose, CVP Carbopol ETD2050, polyvidone, polyvinyl alcohol, Hyaluronic Acid, gellan gum and the salt thereof of gel for eye.
Described eye externally-applied medicinal composition can be mixed with liquid preparation, semi-solid preparation, aerosol, and above-mentioned preparation type can be understood according to the related definition in pharmaceutics (the 5th edition, People's Health Publisher, Cui Fude chief editor, 2003).
Described eye externally-applied medicinal composition, the pharmaceutically useful adjuvant that is applicable to eye that can also add includes but are not limited to the antibacterial such as benzalkonium chloride, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate (methyl hydroxybenzoate), ethylparaben (ethyl hydroxybenzoate), propyl p-hydroxybenzoate (propylparaben), chlorobutanol; Glycerol, propylene glycol, sodium chloride, potassium chloride, Sorbitol, mannitol isosmoticity regulator; The viscosity modifiers such as sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, polyvinyl pyrrolidone; The pH adjusting agents such as phosphoric acid and salt thereof, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethane.Surfactant can be used nonionic, cation, anion and amphoteric surfactant etc.As Tweens, spans, Myrij class, tyloxapol etc., tween 80 for example, HCO60, Polyethylene Glycol-stearate, Macrogol 4000, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, the surfactants such as polyoxyethylene one polyoxypropylene diols and analog thereof; Antioxidant is as vitamin E, sodium thiosulfate, sodium sulfite etc.
Described eye externally-applied medicinal composition, when making Eye ointments, described adjuvant can also include but are not limited to that antibacterial, stabilizing agent etc. are all can be for the adjuvant of Eye ointments.
Concrete grammar can be according to the formulation method preparation of eye preparation or according to relevant books, for example method preparation of the related preparations in pharmaceutics (the 5th edition, People's Health Publisher, Cui Fude chief editor, 2003).
Described eye externally-applied medicinal composition compositions, described in add gellan gum, gellan gum to account for below 0.1% of pharmaceutical composition when being applicable to there is antibacterial in the pharmaceutically useful adjuvant of eye.Gellan gum can not be as the coagulant of gel in this case.
As everyone knows, in eye gel, also can use gellan gum as gel, but use amount all will be more than 0.1%, (technical scheme as disclosed in Chinese patent application CN200810105214.x, gellan gum consumption is 0.4-0.7%) otherwise cannot produce gelatification, so the effect that above-mentioned gellan gum and antibacterial are used is to reduce the toxic action of antibacterial, and cannot open gelatification simultaneously.By cell toxicity test, show, added each experimental group of 0.1% following gellan gum, all can significantly alleviate antibacterial and bring cytotoxicity.
The specific embodiment:
In following examples, the buffer of sodium hydrogen phosphate, sodium dihydrogen phosphate can be according to the related data preparation in Chinese Pharmacopoeia 2005 editions.
Particle diameter in following examples refers to corresponding particle diameter when cumulative particle sizes percentile reaches 90%, all according to the light scattering determining in 2010 editions appendix 73 of Chinese Pharmacopoeia.
Embodiment 1
Get the ethyl hydroxybenzoate of recipe quantity, propylparaben is dissolved in the water for injection of recipe quantity 50%, be heated to 80～90 ℃, the tween 80 that adds recipe quantity, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium chloride makes to dissolve, with No. 3 sintered filter funnels, filter, stand-by as <1> liquid, sodium carboxymethyl cellulose is dissolved in the water for injection of recipe quantity 30%, with the buchner funnel that is lined with 200 order nylon cloths, filter, be heated to 80～90 ℃, the gellan gum that adds recipe quantity, hydrocortisone acetate stirs evenly, insulation 30min, be chilled to 40～50 ℃ as <2> liquid, <1> liquid and <2> liquid are merged, the water for injection that adds surplus.The eye drop pH modulating is 6.7
Embodiment 2
Get the ethyl hydroxybenzoate of recipe quantity, propylparaben is dissolved in the water for injection of recipe quantity 50%, be heated to 80～90 ℃, the tween 80 that adds recipe quantity, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium chloride makes to dissolve, with No. 3 sintered filter funnels, filter, stand-by as <1> liquid, sodium carboxymethyl cellulose is dissolved in the water for injection of recipe quantity 30%, with the buchner funnel that is lined with 200 order nylon cloths, filter, be heated to 80～90 ℃, the gellan gum that adds recipe quantity, fluorometholone stirs evenly, insulation 30min, be chilled to 40～50 ℃ as <2> liquid, <1> liquid and <2> liquid are merged, the water for injection that adds surplus.The eye drop pH modulating is 6.7.
Embodiment 3
The benzalkonium chloride of getting recipe quantity is dissolved in the water for injection of recipe quantity 50%, the sodium dihydrogen phosphate that adds recipe quantity, sodium hydrogen phosphate, sodium chloride makes to dissolve, with the sodium hydroxide solution of 1N, pH is adjusted to 6.5, be heated to 80～90 ℃ to dissolving, be cooled to room temperature, with No. 3 sintered filter funnels, filter, stand-by as <1> liquid, sodium carboxymethylcellulose pyce is dissolved in the water for injection of recipe quantity 30%, with the buchner funnel that is lined with 200 order nylon cloths, filter, be heated to 80～90 ℃, the gellan gum that adds recipe quantity, Rimexolone stirs evenly, insulation 30min, be chilled to 40～50 ℃ as <2> liquid, <1> liquid and <2> liquid are merged, the water for injection that adds surplus.
Embodiment 4
The benzalkonium chloride of getting recipe quantity is dissolved in 500ml water for injection, add sodium dihydrogen phosphate, the sodium chloride of recipe quantity to make to dissolve, with the sodium hydroxide solution of 1N, adjust pH to 7.0, add propylene glycol, add again gellan gum, the dexamethasone sodium phosphate of recipe quantity to be heated to 80～90 ℃ to dissolving, be cooled to room temperature, with No. 3 sintered filter funnels, filter, add the water for injection of surplus.
Embodiment 6
Get the water for injection of recipe quantity 50%, add recipe quantity sodium dihydrogen phosphate,, sodium chloride makes dissolving, propylene glycol, ethyl hydroxybenzoate, propylparaben, with the sodium hydroxide solution of 1N, pH is adjusted to 7.0, add again Travoprost, the dexamethasone sodium phosphate of recipe quantity to be heated to 80～90 ℃ to dissolving, be cooled to room temperature, with No. 3 sintered filter funnels, filter, add the water for injection of surplus.
Embodiment 5
By the benzalkonium chloride of recipe quantity, dexamethasone, inject water 20ml furnishing suspension <1>, by the vaseline of recipe quantity, liquid Paraffin, lanoline mixes makes Eye ointments substrate, after being dissolved in to 10ml water for injection, mixes with <1> gellan gum, after mixing, rapidly appropriate substrate is joined in suspension <1> gradually, stir evenly until water adds the substrate of surplus to mix after exhausting, sterilizing, multiple dose loading amount, content 2g/ props up subpackage and get final product.
Embodiment 6
Under nitrogen protection, get sodium sulfite, the EDTA-Na of recipe quantity
2, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, benzalkonium chloride is dissolved in the water for injection of recipe quantity 50%, with the sodium hydroxide solution of 1N, pH is adjusted to 6.4 if desired, with No. 3 sintered filter funnels, filter, stand-by as <1> liquid, gellan gum, hydroxypropyl emthylcellulose is dissolved in the water for injection of recipe quantity 30%, with the buchner funnel that is lined with 200 order nylon cloths, filter, be heated to 80～90 ℃, add the prednisolone of recipe quantity to stir evenly, insulation 30min, be chilled to 40～50 ℃ as <2> liquid, <1> liquid and <2> liquid are merged, add water for injection to 1000ml.After stirring and evenly mixing, sterilizing, subpackage, obtains.
Pharmaceutical biology is tested 1 cell toxicity test
Experiment material:
People's corneal epithelial cell, with Eagle ' S (BME) culture fluid, adds 10% calf serum, 0.3mg/ml paddy ammonia phthalein amine, 20 units/ml gentamycin, pH7.2 cultivates in 37C incubator, cell concentration 1.5X105ml, add in 24 hole plastic culture plates, cultivate 36～48 hours, stand-by.
Experimentation and grading:
First cell culture fluid is sucked, add tested aqueous solution 0.5ml, every group of 4 holes after dosing 15,30,60 and 120 minutes, are observed under inverted microscope.Acute cytotoxicity evaluation criterion: normal person is " 0 " level, occurs that granule is "+" in cytoplasm, and cytoplasm and nucleus occur that granule is " ++ ", also occurs that except " ++ " changes cell shrinkage, gap broaden as " +++ ".
After dosing 2 hours, medicinal liquid is sucked, with normal saline, clean, then add culture fluid, in 37C incubator, cultivate 24 hours, with 0.4% Trypan Blue 4min, examine under a microscope dead cell number, to determine the toxicity of cell in late period.As dead cell accounts for below 25%, be "+", dead cell accounts for 50% for " ++ ", and surpassing 50% is " +++ ".Each group is used tested aqueous solution situation as follows.
| Grouping serial number | Tested aqueous solution is detailed | Grouping serial number | Tested aqueous solution is detailed |
| 1-1 | 0.1% ethyl hydroxybenzoate | 1-2 | 0.1% ethyl hydroxybenzoate, 0.02% gellan gum |
| 2-1 | 0.02% thimerosal | 2-2 | 0.02% thimerosal, 0.05% gellan gum |
| 3-1 | 0.05% chlorhexidine acetate | 3-2 | 0.05% chlorhexidine acetate, 0.07% gellan gum |
| 4-1 | 2% boric acid | 4-2 | 2% boric acid, 0.09% gellan gum |
| 5-1 | 0.01% benzalkonium chloride | 5-2 | 0.01% benzalkonium chloride, 0.07% gellan gum |
| 6 | Normal saline |
Experimental result
| Grouping serial number | 15 minutes | 30 minutes | 60 minutes | 120 minutes | 24 hours |
| 1-1 | + | + | +～++ | ++ | +～++ |
| 2-1 | 0～+ | + | + | + | ++ |
| 3-1 | +～++ | ++～+++ | +++ | +++ | +++ |
| 4-1 | ++ | ++～+++ | ++～+++ | +++ | +++ |
| 5-1 | ++ | ++～+++ | ++～+++ | +++ | +++ |
| 1-2 | 0 | 0～+ | 0～+ | + | + |
| 2-2 | 0 | 0～+ | 0～+ | + | + |
| 3-2 | + | + | +～++ | ++ | ++ |
| 4-2 | +～++ | ++ | ++ | ++～+++ | ++～+++ |
| 5-2 | 0～+ | + | +～++ | +～++ | ++ |
| 6 | 0 | 0 | 0 | 0 | 0 |
Claims (6)
1. the application of gellan gum antibacterial toxicity in reducing eye externally-applied medicinal composition.
2. application as claimed in claim 1, is characterized in that antibacterial is parabens, alcohols, organic acid, phenols, ammonium class, hibitane, one or more in thimerosal.
3. application as claimed in claim 1, it is characterized in that antibacterial is ethyl hydroxybenzoate, methyl hydroxybenzoate, propylparaben, benzyl alcohol, ethanol, phenethanol, chlorobutanol, benzoic acid, sorbic acid, dehydroacetic acid, phenol, Moschus phenol, chlorocresol, benzalkonium bromide, benzalkonium chloride, hibitane, one or more in thimerosal.
4. application as claimed in claim 1, is characterized in that antibacterial is one or more in cationic antibacterial.
5. application as claimed in claim 1, is characterized in that antibacterial is one or more in polyquaternary ammonium salt.
6. application as claimed in claim 1, is characterized in that antibacterial is one or more in benzalkonium chloride, benzalkonium bromide.
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