CN103976946A - Rebamipide suspension eye drop containing water soluble high-molecular polymers and preparation method thereof - Google Patents
Rebamipide suspension eye drop containing water soluble high-molecular polymers and preparation method thereof Download PDFInfo
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- CN103976946A CN103976946A CN201410213148.3A CN201410213148A CN103976946A CN 103976946 A CN103976946 A CN 103976946A CN 201410213148 A CN201410213148 A CN 201410213148A CN 103976946 A CN103976946 A CN 103976946A
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Abstract
The invention provides rebamipide suspension eye drop containing water soluble high-molecular polymers and a preparation method thereof. The rebamipide suspension eye drop can be used for treating dry eyes. The main components of the eye drop comprise the water soluble high-molecular polymers, active pharmaceutical ingredients, a deflocculating agent, a pH regulator and an osmotic pressure regulator; the eye drop is prepared by sterilizing and filtering or high temperature sterilizing. The rebamipide suspension eye drop provided by the invention has the characteristics of being fine and uniform and free of settlement and agglomeration of particles, the sizes of the particles are kept to be consistent in a long term storage process, no particle is felt during eye dropping and no stimulation is generated, so that the rebamipide suspension eye drop is accepted by patients easily.
Description
Technical field
The present invention relates to a kind of suspension type eye drop that contains rebamipide and preparation method thereof, rebamipide fine particles can be suspended in medium for a long time, make suspensoid keep for a long time suspension, be used for the treatment of xerophthalmia, belong to medical technical field.
Background technology
Xerophthalmia (Keratoconjuetivitis sicca, KCS) refer to that tear produces minimizing, the absolute and relative shortage of the tear film fluidity composition that a variety of causes such as mucus diacrisis and meibomian gland dysfunction cause, eye table tear abnormal distribution, tear evaporation increase to the syndrome of common trait.Nineteen forty-six Wolf finds that the structure of tear film is divided into lipid layer, water layer, slime layer.Lipid layer can reduce tear evaporation, prevent that tear from overflowing margo palpebrae, the viscosity that increases tear film and lubricate; Water layer, mainly by lacrimal secretion, is secreted by accessory lacrimal glands on a small quantity; Slime layer is mainly from the goblet cell of conjunctival epithelium, and effect is the tension force that reduces eye surface, and tear film is shaped and is stable.It is essential that tear maintains constant humidity by film, corneal nutrition and maintain Corneal transparency and play an important role.
Rebamipide (Rebamipide) Chinese another name is Rebamipide, Rui Ba meter Te, Rebamipide; Chemistry 2-(4-chloro-benzoyl amino)-3-(1,2-dihydro-2-oxo--4-quinolyl) propanoic acid by name.
Rebamipide structural formula
Rebamipide is a kind of mucosa protection agent; can be by increasing the synthetic defence capability that strengthens gastric mucosa of gastric mucosa prostaglandin; by the expression of induction COX-2, increase the generation of PGE2; raise the level of cell growth factor (HGF); accelerate the reparation of gastric mucosa; can suppress the neutrophil activation of various impairment factor inductions and reduce inflammatory cytokine to discharge, thus the inflammatory reaction that alleviates tissue.The clinical test results carrying out in recent years shows, rebamipide can improve cornea-conjunctival damage and subjective symptoms due to xerophthalmia (comprise in ocular pain, eye have sand sensation and blurred vision), promote that Cornea and conjunctiva produces mucoprotein, promote to increase eyes goblet cell density, increase tear concentration, make ophthalmic aqueous layer stable, be used to treat at present xerophthalmia.
Due to rebamipide poorly water-soluble, almost insoluble in water or dilute hydrochloric acid, cannot make the eye drop of transparent clarification.And common ultra-fine grain that rebamipide is made, add suspensoid, thickening agent etc. directly to prepare ophthalmic suspension, along with the storage life extends, rebamipide microgranule still can sedimentation, microgranule can be assembled in put procedure, and it is large that particle diameter becomes, and splashes into and in eyes, has grains of sand sense, have stimulation, it is uncomfortable that patient feels.
Under such prior art background, need exploitation little to the zest of eyes, the better suspendible of stability is put drops in one's eyes, and has better safety and compliance.Suspensoid unstability is mainly manifested in two aspects: the acceleration of gravity of particle causes particle to sink; The surface free energy of particle causes particle to have coalescent and sedimentation.
Summary of the invention
The object of the invention is prepared a kind of collyrium, and it has the advantages that fine and even, not sedimentation, microgranule are not lumpd, particle size remains unchanged in long-term storage, and during eye drip, numbness is less than granule, non-stimulated, and patient is easy to knot and is subject to.
In order to overcome the problem of above-mentioned prior art, in water, add high molecular weight water soluble polymer and deflocculant, increase the stability of suspension.Suspendible eye drop need to be controlled particle diameter and distribution thereof, increases solution viscosity, controls sedimentation volumn ratio, keeps good redispersibility.
Summary of the invention
Described a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer, it is characterized in that being made in following ratio, in 100ml eye drop, high molecular weight water soluble polymer 0.2～0.8g wherein, rebamipide 2.0g, osmotic pressure regulator 0.1-0.9g, deflocculant 0～1, pH adjusting agent 0.01-0.5g, complexing of metal ion agent 0～0.1g, all the other are water for injection.Wherein preferably the weight ratio of high molecular weight water soluble polymer and rebamipide is 0.2～0.8: 2.
High molecular weight water soluble polymer comprises: carbomer, sodium carboxymethyl cellulose.
Deflocculant of the present invention is: dextran sulfate sodium, citric acid, sodium citrate, tartrate, phosphate, glycinate.
Osmotic pressure regulator of the present invention is sodium chloride, potassium chloride.
PH adjusting agent in the present invention is boric acid, hydrochloric acid and sodium hydroxide.
Complexing of metal ion agent in the present invention is disodiumedetate, calcio-disodium edetate.
Eye drop pH is controlled between 6.0-7.5.
The effect of high molecular polymer is the viscosity that increases disperse medium in suspensoid; thereby reduce the sedimentation velocity of drug microparticles; it can be formed mechanicalness or electrical protecting film by drug microparticles surface adsorption again, thereby prevents from assembling mutually between microgranule or transition of crystallization, and suspensoid stability is increased.Carbomer (carbomer) this product is the copolymer of poly-alkyl sucrose or poly-alkyl tetramethylolmethane and acrylic crosslinking polymer, need to add alkaline matter could form viscous solution while being used as solubilizing agent.Sodium carboxymethyl cellulose (Carboxymethyl Cellulose) is the sodium salt of carboxymethyl cellulose ether, belongs to anionic cellulose ether.
The invention provides a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer.By rebamipide microgranule mean diameter D after superfine grinding
avebelow 30 μ m.Particle size determination before and after pulverizing the results are shown in accompanying drawing 1 and Fig. 2, can find out, after superfine grinding, grain diameter obviously diminishes, distribution narrow.
As the preparation method of rebamipide suspendible eye drop of the present invention, realize as follows:
(1) high molecular weight water soluble polymer is dissolved in water for injection, then other adjuvant is added wherein and dissolved, with 0.2 μ m microporous filter membrane aseptic filtration or flowing steam sterilization, obtain clear and bright solution A;
(2) rebamipide is made to superfine grinding granule (mean diameter D
avebelow 30 μ m), after aseptic process, be scattered in clear and bright solution A obtained in the previous step, stir, obtain the suspension B that contains rebamipide;
(3) by suspension B sterile filling in eye-drop liquid bottle, sealing, obtain rebamipide suspendible eye drop.
Through optimizing the rebamipide suspendible eye drop of formula preparation, its pH value, granularity, settling volume such as compare at the requirement that every inspection all meets the suspension type eye drop of Chinese Pharmacopoeia version regulation in 2010.Study on the stability and irritant experiment show, this eye drop steady quality, to eye nonirritant.The feature of rebamipide suspendible eye drop provided by the invention is that production technology is simple and easy to control, favorable reproducibility, and adjuvant source is easy to get, and is applicable to industrialized great production.
Inventive point of the present invention is that in rebamipide suspendible eye drop, high molecular weight water soluble polymer is carbomer, sodium carboxymethyl cellulose, and in addition, the weight ratio of high molecular weight water soluble polymer and rebamipide is 0.2～0.8: 2, mean diameter D after superfine grinding
avebelow 30 μ m.The weight ratio that particularly points out soluble macromolecular polymer and rebamipide is 0.2～0.8: 2 is most important, inventor has screened different macromolecules, or carbomer, sodium carboxymethyl cellulose and rebamipide different proportion, it is to prepare collyrium at 0.2～0.8: 2 that discovery only has the weight ratio of carbomer or sodium carboxymethyl cellulose and rebamipide, can realize the collyrium preparing and have that fine and even, not sedimentation, microgranule are not lumpd, the particle size feature that remains unchanged in long-term storage.
Beneficial effect of the present invention is mainly:
(1) rebamipide is insoluble in water, and commonsense method is prepared suspendible eye drop cannot reach steady quality, and zest is stronger, cannot use clinically, and eye drop fine size prepared by this method, steady quality, not sedimentation, do not assemble, thereby reduce zest, safety is provided.
(2) suspensoid preparation method mild condition of the present invention, simply controlled, do not need to use the methods such as high pressure homogenization or grinding, is suitable for large-scale production, and preparation cost is low.
(3) in nano suspension prescription of the present invention, because sodium carboxymethyl cellulose and carbomer all have anionic group, by hydrogen bond and the structural carboxyl of rebamipide by adsorption by hydrogen bond at particle surface, solvation and the hydrogen bond action of the charged terminal functionality forming, make rebamipide particle surface form the hydrated sheath that one deck is combined closely, the hydrated sheath closely being fettered by surface has produced the obstacle on physics and energy, there are double electrical layers and zeta potential, weight ratio 0.1～0.8 when high molecular weight water soluble polymer and rebamipide: in the time of 1～2, microgranule electric double layer and zeta potential are of moderate size, make intergranular repulsion be greater than captivation, suspensoid is stablized to the good effect of playing.And higher or lower than aforementioned proportion gained suspensoid, can not realize long-term stability.
Accompanying drawing explanation
Fig. 1 pulverizes the particle size distribution typical figure of rear rebamipide superfine grinding granule;
Fig. 2 does not pulverize the particle size distribution typical figure of rebamipide.
The specific embodiment
By following examples, further understand the present invention, but following examples are not construed as limiting the invention.
Embodiment 1
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take sodium carboxymethyl cellulose and be scattered in wherein, after stirring and dissolving, add disodiumedetate, sodium chloride, be stirred to dissolve, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, with 0.2 μ m microporous filter membrane aseptic filtration, add aseptic rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, add water for injection to full dose, shake up, under aseptic condition, be sub-packed in eye drop bottle in and get final product.
Embodiment 2
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take sodium carboxymethyl cellulose and be scattered in wherein, after stirring and dissolving, add disodiumedetate, sodium chloride, be stirred to dissolve, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, with 0.2 μ m microporous filter membrane aseptic filtration, add aseptic rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, add water for injection to full dose, shake up, under aseptic condition, be sub-packed in eye drop bottle in and get final product.
Embodiment 3
Prescription
With reference to embodiment 1 method preparation.
Embodiment 4
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take carbomer and be scattered in wherein, after stirring and dissolving, add sodium citrate, disodiumedetate, potassium chloride, be stirred to dissolve, cooling after, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, adds water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Embodiment 5
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take carbomer and be scattered in wherein, after stirring and dissolving, add sodium citrate, potassium chloride, be stirred to dissolve, after cooling, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, add water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Embodiment 6
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take carbomer and be scattered in wherein, after stirring and dissolving, add sodium citrate, disodiumedetate, sodium chloride, be stirred to dissolve, after cooling, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.0～7.0, add water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Comparative example 1
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take hyaluronic acid sodium and be scattered in wherein, after stirring and dissolving, add citric acid, sodium chloride, be stirred to dissolve, cooling after, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, adds water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Comparative example 2
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, weighing polyvinyl alcohol is scattered in wherein, after stirring and dissolving, add citric acid, sodium chloride, be stirred to dissolve, cooling after, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, adds water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Comparative example 3
Prescription
Get appropriate water for injection, be heated to 80 ℃～90 ℃, take PVP K30 and be scattered in wherein, after stirring and dissolving, add sodium dihydrogen phosphate, sodium chloride, be stirred to dissolve, cooling after, add rebamipide superfine grinding granule (0.1～50 μ m), agitation as appropriate, mix homogeneously, with sodium hydroxide/salt acid for adjusting pH value 6.5～7.5, adds water for injection to full dose, 100 ℃ of sterilizing 30min, are sub-packed in eye drop bottle and get final product.
Embodiment 7
Rebamipide thermally-stabilised
Get embodiment write out a prescription 1-6 and comparative example 1,2,3, be respectively charged in vial, sealing, with flowing steam sterilization, 121 ℃ and 115 ℃ 30 minutes, found that embodiment 1-6 prescription is without clustering phenomena, and suspendible is good, and product is stablized.Comparative example 1-3 shows suspension appearance poor, layering, the phenomenon that particle granule increases.
Embodiment 8
Settling volume is than investigating
Get embodiment and write out a prescription 1～6, and comparative example 1-3, apparatus plug graduated cylinder measures this product 50ml, close plug, and jolting 1min firmly, writes down the beginning height (H of suspended matter
0), standing 3h, writes down the final height (H) of suspended matter, by formula, calculates, and settling volume ratio should be not less than 0.90.
Settling volume ratio=H/H
0
Result shows, the embodiment comparison of writing out a prescription has better stability, hardly sedimentation than prescription.
Embodiment 9
Study on the stability
By 2010 editions Chinese Pharmacopoeia XIXC crude drug and pharmaceutical preparation stability test guideline, get embodiment 1-6 and comparative example 1-3, be placed in 40 ℃, 75% climatic chamber, carry out study on the stability 6 months, monthly sample, entirely examine.As a result, rebamipide is after 6 months, and outward appearance, content, particle diameter etc. all change not quite, and outward appearance, the change of size of contrast prescription are larger.
Embodiment 10
Irritant experiment
Chemicals zest, anaphylaxis and hemolytic investigative technique guideline, get 10 of healthy new zealand rabbits, toward every rabbit left eye, splash into 1 of embodiment 2 product respectively, make lagophthalmos passive closed 10 seconds, right eye splashes into 1 normal saline and compares, and records after administration 1,4,8,12,24,48h eye local response situation.Result medication Rabbits Before And After eyes no significant difference, eyes are all normal to luminous reflectance, nictation, and without photophobia, the phenomenon such as shed tears, conjunctiva, without phenomenons such as hyperemia, edema, shows that this eye drop is to eye nonirritant.And after comparative example 2 administrations, frequency of wink increases, conjunctiva is slightly hemorrhage, illustrates that 2 pairs of eyes of comparative example have weak zest.
It is good that this product is used for the treatment of xerophthalmia curative effect, and nonirritant has good application prospect.
Claims (7)
1. a rebamipide suspendible eye drop that contains high molecular weight water soluble polymer.
2. a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer as claimed in claim 1, it is characterized in that being made in following ratio, in 100ml eye drop, high molecular weight water soluble polymer 0.2～0.8g wherein, rebamipide 2.0g, osmotic pressure regulator 0.1-0.9g, deflocculant 0～1, pH adjusting agent 0.01-0.5g, complexing of metal ion agent 0～0.1g, all the other are water for injection.
3. a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer as claimed in claim 2, is characterized in that high molecular weight water soluble polymer is carbomer, sodium carboxymethyl cellulose.
4. a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer as claimed in claim 2, is characterized in that rebamipide microgranule mean diameter D after superfine grinding
avebelow 30 μ m.
5. a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer as claimed in claim 2, is characterized in that deflocculant is dextran sulfate sodium, citric acid, sodium citrate, tartrate, phosphate, glycinate.
6. a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer as claimed in claim 2, is characterized in that deflocculant is preferably citric acid, sodium citrate, phosphate.
7. a method of preparing a kind of rebamipide suspendible eye drop that contains high molecular weight water soluble polymer described in claim 1-6, the method comprises:
(1) high molecular weight water soluble polymer is dissolved in water for injection, then other adjuvant is added wherein and dissolved, with 0.2 μ m microporous filter membrane aseptic filtration or flowing steam sterilization, obtain clear and bright solution A;
(2) rebamipide is made to superfine grinding granule, after aseptic process, be scattered in clear and bright solution A obtained in the previous step, stir, obtain the suspension B that contains rebamipide;
(3) by suspension B sterile filling in eye-drop liquid bottle, sealing, obtain rebamipide suspendible eye drop.
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Cited By (5)
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| CN104274402A (en) * | 2014-09-10 | 2015-01-14 | 南京华威医药科技开发有限公司 | Medicine water suspended emulsion containing rebamipide and preparation method of medicine water suspended emulsion |
| CN105878245A (en) * | 2015-01-07 | 2016-08-24 | 珠海亿胜生物制药有限公司 | Preparation method of rebamipide aqueous suspension |
| CN107349181A (en) * | 2016-05-09 | 2017-11-17 | 四川科伦药物研究院有限公司 | Ophthalmology water slurry containing Rebamipide and PVP and preparation method thereof |
| CN111107838A (en) * | 2017-09-21 | 2020-05-05 | 大宇制药株式会社 | Novel eye drop composition containing rebamipide for treating xerophthalmia and method for solubilizing and stabilizing the same |
| WO2021199813A1 (en) * | 2020-03-31 | 2021-10-07 | 参天製薬株式会社 | Aqueous suspension containing rebamipide or salt thereof and polymer |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104274402A (en) * | 2014-09-10 | 2015-01-14 | 南京华威医药科技开发有限公司 | Medicine water suspended emulsion containing rebamipide and preparation method of medicine water suspended emulsion |
| CN105878245A (en) * | 2015-01-07 | 2016-08-24 | 珠海亿胜生物制药有限公司 | Preparation method of rebamipide aqueous suspension |
| CN105878245B (en) * | 2015-01-07 | 2017-12-15 | 珠海亿胜生物制药有限公司 | A kind of preparation method of Rebamipide water slurry |
| CN107349181A (en) * | 2016-05-09 | 2017-11-17 | 四川科伦药物研究院有限公司 | Ophthalmology water slurry containing Rebamipide and PVP and preparation method thereof |
| CN107349181B (en) * | 2016-05-09 | 2021-02-19 | 四川科伦药物研究院有限公司 | Ophthalmic aqueous suspension containing rebamipide and povidone, and process for producing the same |
| CN111107838A (en) * | 2017-09-21 | 2020-05-05 | 大宇制药株式会社 | Novel eye drop composition containing rebamipide for treating xerophthalmia and method for solubilizing and stabilizing the same |
| CN111107838B (en) * | 2017-09-21 | 2023-06-30 | 大宇制药株式会社 | Eye drop composition containing rebamipide for treating dry eye and solubilization and stabilization method thereof |
| WO2021199813A1 (en) * | 2020-03-31 | 2021-10-07 | 参天製薬株式会社 | Aqueous suspension containing rebamipide or salt thereof and polymer |
| JP7008886B1 (en) * | 2020-03-31 | 2022-01-25 | 参天製薬株式会社 | Aqueous suspension containing rebamipide or a salt thereof and a polymer |
| JP2022050562A (en) * | 2020-03-31 | 2022-03-30 | 参天製薬株式会社 | Aqueous suspension comprising rebamipide or salt thereof and polymer |
| JP7144630B2 (en) | 2020-03-31 | 2022-09-29 | 参天製薬株式会社 | Aqueous suspension containing rebamipide or its salt and polymer |
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Application publication date: 20140813 |