CN103893742B - Containing the application of the outer albumen 1 of vitellinae membrana in preparation treatment dry eye drug - Google Patents
Containing the application of the outer albumen 1 of vitellinae membrana in preparation treatment dry eye drug Download PDFInfo
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- CN103893742B CN103893742B CN201410075266.2A CN201410075266A CN103893742B CN 103893742 B CN103893742 B CN 103893742B CN 201410075266 A CN201410075266 A CN 201410075266A CN 103893742 B CN103893742 B CN 103893742B
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Abstract
The invention discloses containing the application of the outer albumen 1 of vitellinae membrana in preparation treatment dry eye drug.The present invention found through experiments, and the outer albumen 1 of vitellinae membrana can extend the time of the tear film rupture of Mouse and rat, therefore may be used for treating xerophthalmia.The outer albumen 1 of vitellinae membrana of the present invention can extend the time of the tear film rupture of Mouse and rat, therefore may be used for prevention and therapy xerophthalmia, has broad application prospects.
Description
Technical field:
The invention belongs to field of pharmaceutical preparations, be specifically related to containing the application of the outer albumen 1 of vitellinae membrana in preparation treatment dry eye drug.
Background technology:
Normal eye surface coverage one deck tear film, stable tear film maintains healthy basis, eye surface.Xerophthalmia is because tear amount or matter cause tear film instability and ocular surface injury extremely, thus the class disease caused; For one of modal eye surface diseases, the quality of life of people can be had a strong impact on.Its sickness rate the whole world reach 5-30%(50 year more than), China report then higher (Beijing: more than 40 years old be 21%; Shanghai: more than 20 years old be 30%; The Inner Mongol: have symptom 50% for more than 40 years old, breakup time of tear film shortens 37%).The existing treatment means of xerophthalmia comprises non-drug therapy, Drug therapy and operative treatment etc., and etiological treatment is preferred plan.Owing to causing the reason of xerophthalmia very complicated, for the patient being difficult to find the etiological cause of the disease, alleviating dry eye symptom is the important goal of its treatment.The xerophthalmia that different reason causes and dissimilar xerophthalmia, its Therapeutic Method is different, and current most convenient, the effectively Therapeutic Method of alleviating dry eye symptom are external eye drop formulation.And artificial tears's replacement therapy is the Primary Care measure for the treatment of any type xerophthalmia.Select during artificial tears's preparation and should consider following factor: first, its chemical composition should be consistent with physiology tear with Wuli-Shili-Renli system approach.Such as pH value is neutral, and osmotic pressure is identical with physiology tear, otherwise may produce stimulation, pain and other discomforts to eyes after using.Secondly, should, containing the composition of simulating mucin layer effect in physiology tear, make the water liquid layer longer time depend on eyeball surface, reach long-time and alleviate the dry and astringent effect of eye.Again, its viscosity should be close with physiology tear, can not feel sticky or make blurred vision, and can not affect wearing of recessive glasse after using.Finally, artificial tears is not preferably containing antibiotic, and contained preservative agent diagonal angle conjunctiva impact is minimum or not impact.Long-term or frequent artificial tears's preparation person of use (such as medication every day is more than 4-6 time) answers first-selection not contain antiseptic, and at least contained antiseptic does not affect the artificial tears of cornea, to prevent its toxic and side effects.
The vitellinae membrana that VMO1 is found in egg is the earliest outer, is a kind of water soluble protein.The present invention uses people to recombinate the nucleotide sequence of encoding gene of aminoacid sequence of vmo1, vmo1 as shown in 51 ~ 659 of SEQIDNO.1, the Genbank:BC104195.1 of the sequence shown in SEQIDNO.1.
Summary of the invention:
First object of the present invention is to provide containing the outer albumen 1(VMO1 of vitellinae membrana) treat the application in dry eye drug in preparation.
We find that VMO1 high abundance is expressed in the tear of camel, also there is this kind of albumen, and there is not this kind of albumen in the tear of people and rabbit in the tear of sheep and mice.Protein in tear plays a significant role in stable tear film, defence infected by microbes, the healing of promotion conjunctival epithelium etc.For the situation of change of tear protein express spectra in associated ophthalmopathy (xerophthalmia), someone attempts lysozyme, lactoferrin to introduce in the development of artificial tears, for the protein that supplementary concentration reduces, to maintain the infection of the stable of tear film and the microorganism of defence eye table.
The present invention found through experiments, and the nucleotide sequence of its encoding gene of the outer albumen 1(of vitellinae membrana is as shown in 51 ~ 659 of SEQIDNO.1) time of the tear film rupture of Mouse and rat can be extended, therefore may be used for treating xerophthalmia.
Second object of the present invention is to provide a kind of external eye drop formulation for the treatment of xerophthalmia, it is characterized in that, containing effective dose containing the outer albumen 1 of vitellinae membrana and adjuvant.
The described aminoacid sequence containing the outer albumen 1 of vitellinae membrana, the nucleotide sequence of its encoding gene is as shown in 51 ~ 659 of SEQIDNO.1.
Described contains the outer albumen 1 of vitellinae membrana, and its content is containing the outer protein 10 .3 ~ 0.75g of vitellinae membrana in every 100ml eye drop formulation.Be dissolved in eye drop formulation containing the outer albumen 1 of vitellinae membrana, it can be pure protein, compound protein or its mixture.
External eye drop formulation, according to the resistance to requirement that receive certain limit of eye to osmotic pressure and pH value, adds a certain amount of adjuvant if osmotic pressure regulator, pH value regulator are to reduce the zest of eye drop formulation, improves compliance, ensures the smooth enforcement for the treatment of.Be multiple dosing preparation according to eye drop formulation, one or more a certain amount of antiseptic can be added.
Described adjuvant comprises hyaluronic acid or its salt, osmotic pressure regulator and pH value regulator.
Described hyaluronic acid or its salt account for the 0.1-0.5% of eye drop formulation gross mass, are preferably hyaluronate sodium.Hyaluronic acid or its salt are used for increasing the viscosity of eye drop formulation, and its viscosity can be regulated by adjustment concentration, wherein hyaluronate sodium best results.
Osmotic pressure the best of eye drop formulation is isotonic, but eye can tolerate the hypotonic of certain limit or hyperosmotic solution.Because the osmotic pressure of tear is under normal circumstances 295-309mOsm/l, so osmotic pressure controls between 295-309mOsm/l by external eye drop formulation of the present invention, keep the concordance with tear, reduce the stimulation to eyes as far as possible.
Described osmotic pressure regulator can be selected from sodium chloride, potassium chloride, glucose, mannitol, Polyethylene Glycol or its mixture.
The present invention adopts and adds pH value regulator and regulate pH value, and the pH value of eye drop formulation maintains in the scope that eyes can tolerate, and is generally 5-9.Because the pH value of tear is under normal circumstances generally between 5.20-8.35, so pH value controls between 5.20-8.35 by external eye drop formulation of the present invention, keep the concordance with tear, reduce the stimulation to eyes as far as possible.
Described pH value regulator can be selected from hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, tartaric acid, lactic acid, glycolic, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, boric acid, Borax, dihydric phosphate, phosphoric acid hydrogen disalt or its mixture.
Eye drop formulation of the present invention can add or not adding preservative agent.As needed adding preservative agent, by choosing to the less antiseptic of the zest of eyes, parabens, benzoic acids, Pyrusussuriensis acids, alcohols, organic acid, ammonium class antiseptic or its mixture can be selected from.
The external eye drop formulation for the treatment of xerophthalmia of the present invention is by the preparation of this area conventional method.
The outer albumen 1 of vitellinae membrana of the present invention can extend the time of the tear film rupture of Mouse and rat, therefore may be used for prevention and therapy xerophthalmia, has broad application prospects.
Detailed description of the invention:
Following examples further illustrate of the present invention, instead of limitation of the present invention.
Embodiment 1:
By the external eye drop formulation of following prescription proportioning preparation treatment xerophthalmia
In 100ml, the nucleotide sequence of its encoding gene of VMO1(is as shown in 51 ~ 659 of SEQIDNO.1, can be bought by Novoprotein company, its article No. is C650) 0.75g, hyaluronate sodium 0.3g, dextran-70 0.1g, L-carnitine 0.25g, boric acid 0.7g, sodium borate 0.2g, sodium chloride 0.4g and potassium chloride 0.04g.
A. by 45ml pure water and 0.3g hyaluronate sodium stirring and dissolving, 120-130 degrees Centigrade sterilization 30-60 minute, makes solution 1;
B. the pure water of 45ml autoclave sterilization and 0.75gVMO1,0.25g L-carnitine, 0.1g dextran-70 and boric acid, sodium borate, sodium chloride, potassium chloride are mixed, through 0.45um, 0.22um filtering with microporous membrane after stirring, make solution 2;
C. A is mixed until evenly become a phase with the solution 1 that step B makes with 2, add hydrochloric acid or sodium hydroxide to regulate between acid-base value to 5.20-8.35, add sodium chloride or potassium chloride to regulate between osmotic pressure to 295-309mOsm/l, with the pure water of autoclave sterilization, volume is adjusted to 100ml, through 0.45um, 0.22um filtering with microporous membrane after stirring, sterile filling, obtains the external eye drop formulation of the treatment xerophthalmia of the present embodiment thus.
Embodiment 2:
By the external eye drop formulation of following prescription proportioning preparation treatment xerophthalmia
In 100ml, VMO10.3g, hyaluronate sodium 0.3g, dextran-70 0.1g, L-carnitine 0.25g, boric acid 0.7g, sodium borate 0.2g, sodium chloride 0.4g and potassium chloride 0.04g.
A. by 45ml pure water and 0.3g hyaluronate sodium stirring and dissolving, 120-130 degrees Centigrade sterilization 30-60 minute, makes solution 1;
B. the pure water of 45ml autoclave sterilization and 0.3gVMO1,0.25g L-carnitine, 0.1g dextran-70 and boric acid, sodium borate, sodium chloride, potassium chloride are mixed, through 0.45um, 0.22um filtering with microporous membrane after stirring, make solution 2;
C. A is mixed until evenly become a phase with the solution 1 that step B makes with 2, add hydrochloric acid or sodium hydroxide to regulate between acid-base value to 5.20-8.35, add sodium chloride or potassium chloride to regulate between osmotic pressure to 295-309mOsm/l, with the pure water of autoclave sterilization, volume is adjusted to 100ml, through 0.45um, 0.22um filtering with microporous membrane after stirring, sterile filling, obtains the external eye drop formulation of the treatment xerophthalmia of the present embodiment thus.
Embodiment 3:
Containing the external eye drop formulation of the treatment xerophthalmia of VMO1 on the impact of C57 mice breakup time of tear film.
The C57 mice 240 that concrete grammar: 6-8 week male and female are not limit, is divided into 2 groups at random.Wherein A group 120 mices are matched group, and B group 120 mices are experimental group.All mices are only tested with right eye, and left eye does not do any process.The A group mice water-soluble drop right eye containing final concentration being only the fluorescein sodium of mass fraction 0.25%, and under slit lamp, observe, record the time of its tear film rupture.With the aqueous solution of to be the VMO1 of 0.75ug/ul and final concentration containing final concentration the be fluorescein sodium of 0.25%, (to B group mice it add fluorescein sodium in the external eye drop formulation of the treatment xerophthalmia of embodiment 1, the content of fluorescein sodium is mass fraction 0.25%) drip right eye, and under slit lamp, observe, record the time of its tear film rupture.Experiment adopts blind process.
Result is as shown in table 1, and experimental group and control group mice breakup time of tear film have significant difference (P<0.001) as can be seen from Table 1.Namely the breakup time of tear film of experimental mice occurs significantly to change.Confirm that Topical can extend the time of mice tear film rupture containing the eye drop of VMO1.
Table 1: the statistical result of the breakup time of tear film of control group mice and experimental mice.
| Group | Breakup time of tear film (s) |
| Matched group | 2.04±0.33 |
| Experimental group | 3.56±0.75 |
| P value | <0.001 |
Embodiment 4:
Containing the external eye drop formulation of the treatment xerophthalmia of VMO1 on the impact of SD rat breakup time of tear film.
The SD rat 240 that concrete grammar: 6-8 week male and female are not limit, is divided into 2 groups at random.Wherein A group 120 rats are matched group, and B group 120 rats are experimental group.All rats are only tested with right eye, and left eye does not do any process.The A group rat water-soluble drop right eye containing final concentration being only the fluorescein sodium of mass fraction 0.25%, and under slit lamp, observe, record the time of its tear film rupture.With the aqueous solution of to be the VMO1 of 0.75ug/ul and final concentration containing final concentration the be fluorescein sodium of 0.25%, (to B group rat it add fluorescein sodium in the external eye drop formulation of the treatment xerophthalmia of embodiment 1, the content of fluorescein sodium is mass fraction 0.25%) drip right eye, and under slit lamp, observe, record the time of its tear film rupture.Experiment adopts blind process.
Result is as shown in table 2, and table 2 result shows that experimental group and control rats breakup time of tear film have significant difference (P<0.001).Namely the breakup time of tear film of experimental group rat occurs significantly to change.Confirm that Topical can time of prolong rats tear film rupture containing the eye drop of VMO1.
Table 2: the statistical result of the breakup time of tear film of control rats and experimental group rat.
| Group | Breakup time of tear film (s) |
| Matched group | 6.09±1.10 |
| Experimental group | 8.24±0.95 |
| P value | <0.001 |
The above is only preferred embodiment of the present invention, not imposes any restrictions the present invention, every above embodiment is done according to essence of the present invention any simple modification, change and equivalent structure change, all still belong in protection scope of the present invention.
Claims (8)
1. the application of the outer albumen 1 of vitellinae membrana in preparation treatment dry eye drug, the outer albumen 1 of described vitellinae membrana, the nucleotide sequence of its encoding gene is as shown in 51 ~ 659 of SEQIDNO.1.
2. treat an external eye drop formulation for xerophthalmia, it is characterized in that, the outer albumen 1 of the vitellinae membrana containing effective dose and adjuvant, the outer albumen 1 of described vitellinae membrana, the nucleotide sequence of its encoding gene is as shown in 51 ~ 659 of SEQIDNO.1.
3. external eye drop formulation according to claim 2, is characterized in that, the outer albumen 1 of described vitellinae membrana, and its content is containing the outer protein 10 .3 ~ 0.75g of vitellinae membrana in every 100ml eye drop formulation.
4. external eye drop formulation according to claim 2, is characterized in that, described adjuvant comprises hyaluronic acid or its salt, osmotic pressure regulator and pH value regulator.
5. external eye drop formulation according to claim 4, is characterized in that, described hyaluronic acid or its salt account for the 0.1-0.5% of eye drop formulation gross mass.
6. external eye drop formulation according to claim 4, is characterized in that, described osmotic pressure regulator is selected from sodium chloride, potassium chloride, glucose, mannitol, Polyethylene Glycol or its mixture.
7. external eye drop formulation according to claim 4, it is characterized in that, described pH value regulator is selected from hydrochloric acid, sulphuric acid, phosphoric acid, citric acid, tartaric acid, lactic acid, glycolic, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, boric acid, Borax, dihydric phosphate, phosphoric acid hydrogen disalt or its mixture.
8. external eye drop formulation according to claim 4, it is characterized in that, described external eye drop formulation is also containing antiseptic, and described antiseptic is selected from parabens, benzoic acids, Pyrusussuriensis acids, alcohols, organic acid, ammonium class antiseptic or its mixture.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1392355B1 (en) * | 2001-05-21 | 2007-02-14 | Alcon, Inc. | Use of proteasome inhibitors to treat dry eye disorders |
| CN102579492A (en) * | 2012-03-05 | 2012-07-18 | 兆科药业（广州）有限公司 | Sodium hyaluronate eyedrop containing deproteinized calf blood extractive and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100004163A1 (en) * | 2004-04-13 | 2010-01-07 | Tufts University | Composition and Uses of a Galectin for Treatment of Dry Eye Syndrome |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1392355B1 (en) * | 2001-05-21 | 2007-02-14 | Alcon, Inc. | Use of proteasome inhibitors to treat dry eye disorders |
| CN102579492A (en) * | 2012-03-05 | 2012-07-18 | 兆科药业（广州）有限公司 | Sodium hyaluronate eyedrop containing deproteinized calf blood extractive and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Comparison of camel tear proteins between summer and winter;Ziyan Chen等;《Molecular Vision》;20110201;第17卷;323-331 * |
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