CN101658491B - Amnion eye drops for curing cornea alkali burn - Google Patents
Amnion eye drops for curing cornea alkali burn Download PDFInfo
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- CN101658491B CN101658491B CN2009101784227A CN200910178422A CN101658491B CN 101658491 B CN101658491 B CN 101658491B CN 2009101784227 A CN2009101784227 A CN 2009101784227A CN 200910178422 A CN200910178422 A CN 200910178422A CN 101658491 B CN101658491 B CN 101658491B
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- amniotic membrane
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- 210000001691 amnion Anatomy 0.000 title claims abstract description 63
- 239000003889 eye drop Substances 0.000 title claims abstract description 38
- 239000003513 alkali Substances 0.000 title claims abstract description 12
- 229940012356 eye drops Drugs 0.000 title abstract 4
- 210000004087 cornea Anatomy 0.000 title abstract 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 30
- 229920000669 heparin Polymers 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 23
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 23
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 23
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- 229960002233 benzalkonium bromide Drugs 0.000 claims abstract description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides amnion eye drops for curing cornea alkali burn and a preparation method thereof. The preparation method comprises the steps of: taking amnion homogenate supernate as main active constituent; and adding with trehalose, hyaluronic acid or salt thereof, heparin or salt thereof, sodium chloride, benzalkonium bromide, vitamin, etc. The eye drops belongs to an ophthalmology drug delivery system, has a good lubrication function, and can provide a conglutination-resistant surface; and the drug delivery system is added with the other pharmacological active constituents, thereby being capable of increasing the viscocity of medical liquid, prolonging the residence time of the drug in eye surface, improving the bioavailability of the drug, reducing the side effect of the drug, reducing the drug irritation, and having a slow release effect. The amnion eye drops is an effective ophthalmology new drug, and has good clinic application foreground.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of ophthalmic remedy, relate in particular to a kind of amniotic membrane eye drop for the treatment of corneal alkali burn at corneal alkali burn.
Background technology
The crowd knows, amnion transplantation is as a new technique of ocular surface reconstruction, obtains applying gradually at home and abroad.Amnion transplantation has been widely used in corneal alkali burn and has obtained better therapeutic effect.But amniotic membrane is a kind of temporary biological covering, has the shortcoming of following several respects:
(1) in 1-2 week after transplanting, the amnion transplantation sheet dissolves voluntarily, comes off, is shifted, infects;
(2) be attached at anterior corneal surface more for a long time, be deposited on bowman's lamina, continued three months for slight muddy;
(3) the postoperative profile is not good enough, influences attractive in appearance;
(4) can the amniotic membrane long-term existence after transplanting become receptor tissue's ingredient and still lack positive evidence.
A kind of method of production for the treatment of people's amniotic membrane homogenate supernatant of rabbit corneal alkali burn sketched in " pathological study of people's amniotic membrane homogenate supernatant treatment rabbit corneal alkali burn " this piece article from " modern medicine health ", and amniotic membrane homogenate supernatant is better than amnion transplantation economy, convenience, effect.Its preparation method is on the super-clean bench amniotic membrane to be cleaned 3 times in PBS liquid, about 10～15 minutes, and get suitable size and claim weight in wet base, add PBS liquid by 1: 1 and put into refiner, per minute 5000 changes, and 10 strokes grind homogenate, every stroke 30 seconds.Take out homogenate and added PBS liquid centrifugal 2000r/min in centrifuge tube, 10 minutes, get supernatant standby (using in 1 hour) by 1: 5.Add cells frozen storing liquid subsequently and put into-80 ℃ of refrigerator overnight, it is frozen to put into liquid nitrogen again.But because amniotic membrane homogenate instability can only be used in the short time, also be not used for clinical at present.
Glass acid is present in human body, the direct mucopolysaccharide of being made up of for disaccharidase unit general alduronic acid and N-n acetylglucosamine n.Glass acid is many to be that (English: form sodium hyaluronate) exists and uses hyaluronic acid sodium with its sodium salt.The glass acidic group originally is a chemically inert material, and it has the unique viscoelasticity and the characteristic of non-Newtonian fluid, and has important pharmacological action and physiological function, as:
1. intelligent moisture-keeping function: glass acid is called as ideal nature moisturizing factor, and the carboxyl in its molecule and other polar group can form hydrogen bond and combine a large amount of water with water.And glass acid can also be regulated water absorption automatically according to the humidity of environment.This intelligent moisture-keeping function can make the eye table remain optimum humidity;
2. lubrication: the glass acid solution has good viscoelasticity, and hitting frequency in low building is that solution is stickiness under the shearing, can reduce the friction between tissue, is that solution is elasticity under the high shearing at the high-light window unit frequency, can avoid tissue injury;
3. repair, promote the healing effect: glass acid is that wound does not have indispensable material in the cicatrix reparation, but its inflammation-inhibiting reaction is repaired the eye table and damaged;
4. bioadhesive: glass acid is compared with other high molecular polymer, identical solution viscosity even lower viscosity but can make medicine obtain high bioavailability, its reason is that glass acid and eyeball surface are mucoprotein and has a kind of special affinity, i.e. a bio-adhesive.Hydrophilic functional group in the glass acid molecule can with mucoprotein interaction, thereby delay the elimination of medicine;
5. spreading wetting ability: glass acid is as a kind of mucopolysaccharide, and the viscous glycoprotein in its molecular structure, character and the tear has similarity, easily with and tear have an effect.When increasing the medicinal liquid viscosity, because of having the surface tension close, mix with tear thereby help medicine with tear, medicinal liquid is sprawled equably at anterior corneal surface, strengthen the effect of medicine;
6. slow releasing function: glass acid has the effect that makes medicament slow release, is determined by its molecular specificity.Medicine can be embedded in the macromolecular network structure of glass acid by non-covalent mode, and the glass acid molecule is just as a dynamic molecular sieve, is attached to eyeball surface together with the medicine long period;
7. non-Newton fluid characteristic: though materials such as synthesising macromolecule copolymer can increase the viscosity of medicinal liquid, thereby prolong medicinal liquid and improve curative effect in the holdup time of eye table, yet used synthesising macromolecule copolymer solution is essentially Newtonian fluid, when viscosity increases to a certain degree, can make eyes produce the sensation of sticky discomfort.And the glass acid solution is a non-Newtonian fluid, has unique viscoelasticity, and when eyes blinked, the viscosity reduction owing to high shearing had overcome the deficiency that viscosifier such as synthesising macromolecule copolymer exist.
Trehalose has multiple biological nature; for example: 1. resist drying characteristic (" water substitute " effect): trehalose is a kind of disaccharidase that plays crucial protective effect in dehydration; it can make many biologies under abnormal condition; still can keep original activity as high temperature, dehydration, when freezing, dry, improve the resist drying ability of cell.Discover that trehalose can suppress the In vitro culture people corneal epithelial cell death that causes because of drying;
2. the effect of stabilate film: people's eye table also is a biomembrane, and trehalose can make the film fat under dehydration conditions still can be in mesomorphic state by reducing phase transition temperature, thereby plays the biomembranous effect of protection;
3. to the protective effect of biomolecule such as protein: trehalose has significant protective effect to the living matter of dehydrate, even in exsiccant environment extremely, it is biomolecule such as stable protein well, and it is not damaged;
4. the effect of preparation stabilization agent and antistaling agent: trehalose is widely used as stabilizing agent and antistaling agent.
Summary of the invention
May plant the sheet rejection in order to overcome the amnion transplantation postoperative, plant the sheet shortcomings such as unstability, the retention time of complication such as dissolving, infection and amniotic membrane homogenate supernatant be short that come off, are shifted, the object of the present invention is to provide a kind of is the eye drop of main active with amniotic membrane homogenate supernatant.
In order to achieve the above object, the present invention adopts following technical scheme:
The invention provides a kind of amniotic membrane eye drop for the treatment of corneal alkali burn, it is to be main active with amniotic membrane homogenate supernatant, adds trehalose, glass acid or its salt, heparin or its salt, sodium chloride, benzalkonium bromide, vitamin again.
The prescription of described amniotic membrane eye drop is: in every 100ml water for injection, comprise trehalose 1-2g, glass acid or its salt 0.5-1.5g, heparin or its salt 4000-6000 unit, sodium chloride 0.3-0.9g, benzalkonium bromide 0.001-0.003g, vitamin E 0.05-0.15g, amniotic membrane homogenate supernatant 1-3 μ l.
Preferably, the prescription of described amniotic membrane eye drop is: in every 100ml water for injection, comprise trehalose 1.5g, glass acid or its salt 1.0g, heparin or its salt 5000 units, sodium chloride 0.6g, benzalkonium bromide 0.002g, vitamin E 0.1g, amniotic membrane homogenate supernatant 2 μ l.
The pH value of described amniotic membrane eye drop is 5.0-9.0, is preferably 6.5-7.5.Described eye drop can adopt phosphoric acid/phosphate-buffered that, boric acid/borate buffering is regulated pH value, preferred hydrochloric acid to, hydrochloric acid or sodium hydroxide.
Wherein, the glass acid that the present invention relates to comprises glass acid and salt thereof, and promptly the salt of hyaluronic acid sodium or other glass acid is preferably hyaluronic acid sodium.
Heparin involved in the present invention comprises heparin and salt thereof, is preferably heparin sodium or clarin.
The prescription of amniotic membrane eye drop of the present invention is reasonable, be mainly reflected in: the 1) water molecules of the preferential and protein surface of small-molecule substance such as trehalose, proteinic solvated layer radius is reduced, molecular structure is tightr, conformation is more stable, help resisting the influence of extraneous extreme environment, strengthen proteinic stability.2) glass acid and salt thereof have the effect that makes the corneal epithelial cell resist drying, are good wetting agents; Also can increase bioavailability of medicament, also can alleviate bioavailability of medicament, also can alleviate the stimulation of medicine, promote the healing of eye wound, alleviate the ophthalmic uncomfortable symptom rapidly eye.3) owing on the basic fibroblast growth factor functional areas heparin land is arranged, be the enrichment region of basic amino acid, these charged alkaline residues can combine with electronegative heparin and play a role.Behind the human bFGF heparin-binding molecular heparin, the conformation of its tertiary structure changes, and the protein solubility temperature is improved, and structure is more stable.And all right Profilin enzyme of heparin prolongs the half-life of bFGF to the hydrolysis of bFGF.In addition, heparin sodium or clarin have antiinflammatory action, can suppress the activation of immunostimulation or the inductive mastocyte of non-immunostimulation, suppress it and discharge the inflammatory material.Therefore, they can be used for treating chronic conjunctivitis and anaphylaxis conjunctivitis.In addition, heparin sodium or clarin also can suppress the absorption of antibacterial on the eye surface, can be used for the prevention of acute bacterial conjunctivitis.Compare with NSAID (non-steroidal anti-inflammatory drug) with adrenocortical hormone, heparin sodium has good biocompatibility, does not cause advantages such as intraocular pressure rising and life-time service safety, is a kind of comparatively ideal medicine.
The present invention also provides the preparation method of described amniotic membrane eye drop, is glass acid or the immersion of its salt are accounted in the water for injection of total amount 1/4, makes its dissolving standby; Get the water for injection that accounts for total amount 1/2, dissolve heparin or its salt, trehalose, sodium chloride, benzalkonium bromide, vitamin E successively, can heat in case of necessity, add the solution of described glass acid or its salt again, again amniotic membrane homogenate supernatant is added above-mentioned solution, add water for injection to volume, stir, adjust pH is 5.0-9.0 (being preferably 6.5-7.5), and reuse 0.22 μ m filtering with microporous membrane degerming promptly gets eye drop of the present invention after the packing.
Wherein, described amniotic membrane homogenate supernatant is to adopt following method to prepare: on the super-clean bench amniotic membrane is being cleaned 3 times about 10～15 minutes in PBS liquid, get suitable size and claim weight in wet base, added PBS liquid by 1: 1 and put into refiner, per minute 5000 changes, 10 strokes grind homogenate, every stroke 30 seconds.Take out homogenate and added PBS liquid centrifugal 2000r/min in centrifuge tube by 1: 5,10 minutes, it was standby to get supernatant;
Described adjust pH be adopt phosphoric acid/phosphate-buffered to, boric acid/borate buffering to, hydrochloric acid or sodium hydroxide, preferred hydrochloric acid.PH value is preferably between 6.5-7.5.
Amniotic membrane eye drop of the present invention can be used for the treatment of corneal alkali burn, treatment eye chemical injury, ocular disease such as treatment pterygium postoperative, glaucoma filtration postoperative, corneal epithelial defect.
The invention has the beneficial effects as follows with amnion transplantation and compare, easy to make, simple to operate, the not high advantage of technical difficulty that the amniotic membrane eye drop has.From patient's angle, this amniotic membrane eye drop portably uses conveniently, risk is little, expense is low.Further compare with existing amniotic membrane homogenate supernatant, eye drop of the present invention contains the various active material, has good stable and bioavailability: ophthalmic drug delivery of the present invention system has good lubrication, and the surface of anti can be provided; Add other pharmacological component as drug-supplying system, can increase the viscosity of medicinal liquid, prolong drug improves bioavailability of medicament in the retention time on eye surface, reduces the toxic and side effects of medicine, reduces the zest of medicine, and has slow releasing function.This eye drop is that an effective eye is used new drug, has good potential applicability in clinical practice.
The specific embodiment
The invention will be further described below in conjunction with embodiment, it should be understood that these embodiment only are used for the purpose of illustration, never limit protection scope of the present invention.
Trehalose is available from Peking blue Bo Site Bioisystech Co., Ltd; Model: CHLO7-25G; Specification: 50mg/ml.
Heparin sodium is available from the bright small stream economy and trade company limited in bright small stream sea, Shanghai; Model: JL011800278; Specification: 1g.
Hyaluronic acid sodium is available from Qisheng Biopreparations Co., Ltd., Shanghai; Product standard number: YZB/ state 0077-2005; Specification: 1.0ml/ props up; Indicate mass concentration: 15mg/ml.
Vitamin E is available from Wuhan Yuancheng Technology Development Co., Ltd.; Specification: food stage, pharmaceutical grade.
The preparation of amniotic membrane homogenate supernatant: on the super-clean bench amniotic membrane is being cleaned 3 times in PBS liquid, about 10～15 minutes, get suitable size and claim weight in wet base, add PBS liquid by 1: 1 and put into refiner, per minute 5000 changes, and 10 strokes grind homogenate, every stroke 30 seconds.Take out homogenate and added PBS liquid centrifugal 2000r/min in centrifuge tube by 1: 5,10 minutes, it was standby to get supernatant.
Embodiment 1
Prescription: trehalose 1.5g, hyaluronic acid sodium 1.0g, heparin sodium 5000 units, sodium chloride 0.6g, benzalkonium bromide 0.002g, vitamin E 0.1g, amniotic membrane homogenate supernatant 2 μ l, water for injection adds to 100ml.
Hyaluronic acid sodium is immersed in an amount of (account for total amount 1/4) water for injection, make its dissolving standby; Get the water for injection that accounts for total amount 1/2, dissolve heparin sodium, trehalose, sodium chloride, benzalkonium bromide, vitamin E successively, can heat in case of necessity, add hyaluronic acid sodium solution again, again the amniotic membrane homogenate supernatant for preparing is added above-mentioned solution, add water for injection to volume, stir, regulate pH to 6.5-7.5 with hydrochloric acid, reuse 0.22 μ m filtering with microporous membrane degerming promptly gets eye drop of the present invention after the packing.
Embodiment 2
Prescription: trehalose 1g, hyaluronic acid sodium 0.5g, clarin 4000 units, sodium chloride 0.3g, benzalkonium bromide 0.001g, vitamin E 0.05g, amniotic membrane homogenate supernatant 1 μ l, water for injection adds to 100ml.
Potassium hyaluronate is immersed in an amount of (account for total amount 1/4) water for injection, make its dissolving standby; Get the water for injection that accounts for total amount 1/2, dissolve clarin, trehalose, sodium chloride, benzalkonium bromide, vitamin successively, can heat in case of necessity, add potassium hyaluronate solution again, again the amniotic membrane homogenate supernatant for preparing is added above-mentioned solution, add water for injection to volume, stir, regulate pH to 5.0-6.5 with phosphoric acid/phosphate buffer, reuse 0.22 μ m filtering with microporous membrane degerming promptly gets eye drop of the present invention after the packing.
Embodiment 3
Prescription: trehalose 2g, hyaluronic acid sodium 1.5g, heparin sodium 6000 units, sodium chloride 0.9g, benzalkonium bromide 0.003g, vitamin E 0.15g, amniotic membrane homogenate supernatant 3 μ l, water for injection adds to 100ml.
Hyaluronic acid sodium is immersed in an amount of (account for total amount 1/4) water for injection, make its dissolving standby; Get the water for injection that accounts for total amount 1/2, dissolve heparin sodium, trehalose, sodium chloride, benzalkonium bromide, vitamin successively, can heat in case of necessity, add hyaluronic acid sodium solution again, again amniotic membrane homogenate supernatant is added above-mentioned solution, add water for injection to volume, stir, regulate pH to 7.5-9.0 with hydrochloric acid, reuse 0.22 μ m filtering with microporous membrane degerming promptly gets eye drop of the present invention after the packing.
The above only is preferred embodiment of the present invention, only is illustrative for the purpose of the present invention, and nonrestrictive.Those skilled in the art is understood, and can carry out many changes to it in the spirit and scope that claim of the present invention limited, revise, even equivalence, but all will fall within the scope of protection of the present invention.
Claims (12)
1. amniotic membrane eye drop for the treatment of corneal alkali burn is characterized in that being is main active with amniotic membrane homogenate supernatant, adds trehalose, glass acid or its salt, heparin or its salt, sodium chloride, benzalkonium bromide, vitamin E again;
Described amniotic membrane homogenate supernatant is to adopt following method to prepare: on the super-clean bench amniotic membrane is being cleaned 3 times in PBS liquid, 10～15 minutes, getting suitable size and claim weight in wet base, add PBS liquid by 1: 1 and put into refiner, per minute 5000 changes, and 10 strokes grind homogenate, every stroke 30 seconds; Take out homogenate and added PBS liquid centrifugal 2000r/min in centrifuge tube by 1: 5,10 minutes, it was standby to get supernatant.
2. amniotic membrane eye drop according to claim 1, it is characterized in that its prescription is: in every 100ml water for injection, comprise trehalose 1-2g, glass acid or its salt 0.5-1.5g, heparin or its salt 4000-6000 unit, sodium chloride 0.3-0.9g, benzalkonium bromide 0.001-0.003g, vitamin E 0.05-0.15g, amniotic membrane homogenate supernatant 1-3 μ l.
3. amniotic membrane eye drop according to claim 2, it is characterized in that its prescription is: in every 100ml water for injection, comprise trehalose 1.5g, glass acid or its salt 1.0g, heparin or its salt 5000 units, sodium chloride 0.6g, benzalkonium bromide 0.002g, vitamin E 0.1g, amniotic membrane homogenate supernatant 2 μ l.
4. according to each described amniotic membrane eye drop of claim 1-3, the pH value that it is characterized in that described eye drop is 5.0-9.0.
5. amniotic membrane eye drop according to claim 4, the pH value that it is characterized in that described eye drop is 6.5-7.5.
6. according to each described amniotic membrane eye drop of claim 1-3, it is characterized in that adopting phosphoric acid/phosphate-buffered to or boric acid/borate buffering to or hydrochloric acid or sodium hydroxide regulate pH.
7. amniotic membrane eye drop according to claim 6 is characterized in that adopting hydrochloric acid to regulate pH.
8. according to each described amniotic membrane eye drop of claim 1-3, it is characterized in that described glass acid or its salt are hyaluronic acid sodium; Described heparin or its salt are heparin sodium or clarin.
9. a method for preparing each described amniotic membrane eye drop of claim 1-3 is characterized in that it being that glass acid or the immersion of its salt are accounted in the water for injection of total amount 1/4, makes its dissolving standby; Get the water for injection that accounts for total amount 1/2, dissolve heparin or its salt, trehalose, sodium chloride, benzalkonium bromide, vitamin E successively, can heat in case of necessity, add the solution of described glass acid or its salt again, again amniotic membrane homogenate supernatant is added above-mentioned solution, add water for injection to volume, stir, adjust pH is at 5.0-9.0, and reuse 0.22 μ m filtering with microporous membrane degerming promptly gets eye drop after the packing.
10. the preparation method of amniotic membrane eye drop according to claim 9, it is characterized in that described adjust pH be adopt phosphoric acid/phosphate-buffered to, boric acid/borate buffering to, hydrochloric acid or sodium hydroxide; PH value is between 6.5-7.5.
11. the preparation method of amniotic membrane eye drop according to claim 10 is characterized in that described adjust pH is to adopt hydrochloric acid.
12. each described amniotic membrane eye drop of claim 1-3 is treated the eye chemical injury at preparation treatment corneal alkali burn, the application in the pharmaceutical preparation of treatment pterygium postoperative, glaucoma filtration postoperative, these ocular disease of corneal epithelial defect.
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| CN101947307B (en) * | 2010-08-19 | 2012-08-15 | 中山大学中山眼科中心 | Applications of human placenta peptide in preparing drugs for treating dry eye syndrome and other ocular surface diseases |
| CN102408467B (en) * | 2010-09-26 | 2014-03-05 | 海口维瑅瑷生物研究院 | Method for drying protein in vacuum, protein product prepared and kit |
| CN103006706B (en) * | 2012-12-21 | 2014-09-17 | 哈尔滨医科大学 | Amniotic membrane liposome for ocular surface reconstruction and preparation method and application thereof |
| CN104826166B (en) * | 2015-05-06 | 2017-06-06 | 广州优适清生物科技有限公司 | A kind of biomembrane for glaucoma treatment and preparation method thereof |
| KR102268319B1 (en) * | 2016-12-29 | 2021-06-23 | (주)휴온스 | Sustained release eyedrops |
| EP3643784A4 (en) | 2017-06-23 | 2021-05-05 | Zhuhai Essex Bio-pharmaceutical Co., Ltd. | Recombinant human-basic fibroblast growth factor (rh-bfgf) and pharmaceutical composition comprising rh-bfgf |
| GB201800909D0 (en) * | 2018-01-19 | 2018-03-07 | Biocel Ltd | Compositions and methods relating to amnion |
| CN108498514B (en) * | 2018-05-28 | 2020-01-17 | 南昌大学 | Application of Mdivi-1 in preparation of medicine for treating corneal alkali burn |
| CN111001010B (en) * | 2019-12-28 | 2022-09-02 | 潍坊医学院附属医院 | External eye operation flushing fluid and preparation method thereof |
| CN117442646B (en) * | 2023-12-21 | 2024-03-26 | 广州瑞泰生物科技有限公司 | Eye surface lubricating liquid and preparation process, quality control method and application thereof |
| CN117530961A (en) * | 2023-12-21 | 2024-02-09 | 广州瑞泰生物科技有限公司 | Preparation method and application of amniotic membrane extract |
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