CN104906037A - Recombinant hirudin eye drop and preparation method thereof - Google Patents
Recombinant hirudin eye drop and preparation method thereof Download PDFInfo
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- CN104906037A CN104906037A CN201510345194.3A CN201510345194A CN104906037A CN 104906037 A CN104906037 A CN 104906037A CN 201510345194 A CN201510345194 A CN 201510345194A CN 104906037 A CN104906037 A CN 104906037A
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Abstract
The invention discloses a recombinant hirudin eye drop. The recombinant hirudin eye drop takes recombinant hirudin as an effective component and sodium hyaluronate as a thickening agent, and also contains an isoosmotic adjusting agent, a metal complexing agent, a preservative and a pharmaceutically acceptable carrier; and the mass ratio of the sodium hyaluronate to the recombinant hirudin to the isoosmotic adjusting agent to the metal complexing agent to the preservative in the eye drop is 10 to 2 to 15.27 to 50 to 3. The preparation method comprises the following steps: dissolving the sodium hyaluronate, the isoosmotic adjusting agent, the metal complexing agent and the preservative into the pharmaceutically acceptable carrier to prepare a blank matrix of the eye drop, dissolving the recombinant hirudin into the blank matrix of the eye drop, mixing evenly, filtering, degerming and sub-packaging to prepare the recombinant hirudin eye drop. According to the eye drop disclosed by the invention, on one hand, the recombinant hirudin can be retainedin a focal zone for a long period of time; on the other hand, irritation is not generated to sensitive eye tissues; and meanwhile, the storage stability of the recombinant hirudin eye drop can also be ensured.
Description
Technical field
The invention belongs to pharmaceutical field, be specially a kind of lepirudin 023 ludon eye drop and preparation method thereof.
Background technology
Hirudin is that a class is separated the peptide material be made up of 65 ~ 66 aminoacid obtained at first from Hementaria officianalis salivary gland, mainly contains the isomer (Hirudin variant) that HV1, HV2, HV3 tri-kinds of homologys are very high.Hirudin can suppress formation and the disseminated inravascular coagulation (DIC) of Artery, Vein blood bolt effectively by the activity of direct Trombin inhibiting, therefore, hirudin has high using value in the diseases such as prevention and therapy DVT, coronary artery thrombosis and angina pectoris.
At present, external existing two lepirudin 023 ludon products approval listing: 1.Desirudin (trade name: Revasc, Switzerland Novartis product); 2.Lepirudin (trade name: Refludan, Britain Pharmion and U.S. BerlexLaboratories product).Both structures only exist fine difference at N-end, and Desirudin is Val1-Val2, and Lepirudin is Leu1-Tyr2.The prevention of DVT (DVT) and treatment when Desirudin is for performing the operation, Lepirudin is used for the anticoagulant therapy of heparin-induced thrombocytopenic disease patient.In addition, hirudin all has huge potential clinical value in control unstable angina pectoris, disseminated inravascular coagulation, brain blood coagulation, thrombophlebitis and coronary artery thrombosis etc.
(the Chinese invention patent such as Wu Wutong, the patent No.: 03132224.7) pharmacological testing proves that the cataract of lepirudin 023 ludon to D-galactose and sodium selenite induction all has remarkable prevention effect, the lepirudin 023 ludon eye drop of its invention, employing chitosan is thickening agent, is mainly used in treating cataract.But; chitosan macromole has active hydroxyl and amino; under certain conditions; easily to be hydrolyzed, alkylation, acyl group, carboxy methylation, sulfonation, nitrated, halogenation, oxidation, reduction, the chemical reaction such as condensation and complexation, and generate the uncertain chitosan derivatives of various character.
Thickening agent great majority to improve the bioavailability of medicine with the principle of physics thickening, and must reach finite concentration and just can work.But the potentiation that physics thickening plays is more limited, and when viscosity reaches certain value, drug effect would not increase along with the increase of viscosity.Conventional the having of this kind of thickening agent: poloxamer, carbomer, hypromellose etc.In addition, in these thickening agents, some is Newtonian fluid, has pain during nictation, and to pH and/or responsive to temperature, other also has more incompatibility.Such as, poloxamer temperature-sensitive gel, although can be semi-solid by liquid phase more than 25 DEG C, when getting back to low temperature, semi-solid gel be but difficult to get back to liquid condition, is therefore difficult to control for producing greatly its technique.In addition, carbomer gel can make its viscosity decline due to salt electrolyte, and alkaline-earth metal ions and cationic polymer etc. also can be combined into it insoluble salt, and strong acid also can make it lose viscosity, and therefore, carbomer has more incompatibility.The cellulose derivatives such as hypromellose, polyvinyl alcohol and polyvinylpyrrolidone etc. are as the thickening agent of eye drop, mainly they belong to Newtonian fluid to its shortcoming, viscosity improves with the increase of concentration but is not subject to the impact of shearforce (shearforce as during nictation), sometimes in order to produce obvious thickening power, must be added it to finite concentration, but when viscosity reaches certain degree, eyelid can be made not easily to blink and produce the ocular tissue of sensitivity to stimulate, make user be difficult to tolerance.
Summary of the invention
The object of the present invention is to provide a kind of lepirudin 023 ludon eye drop and preparation method thereof, this eye drop can make lepirudin 023 ludon be detained focal zone for a long time on the one hand, stimulation can not be produced to the ocular tissue of sensitivity again, the storage stability of lepirudin 023 ludon eye drop can also be ensured simultaneously.
For achieving the above object, technical scheme of the present invention is as follows:
Of the present inventionly prevent and treat cataractous lepirudin 023 ludon eye drop, take lepirudin 023 ludon as effective ingredient, hyaluronate sodium is thickening agent, also containing isoosmotic adjusting agent, metal chelating agent, antiseptic and pharmaceutically acceptable carrier; In eye drop, the mass ratio of hyaluronate sodium, lepirudin 023 ludon, isoosmotic adjusting agent, metal complex and antiseptic is 10:2:15.27:50:3.
Preferably, described isoosmotic adjusting agent is selected from one or more in sodium chloride, borate buffer solution or phosphate buffer.
Preferably, the pH value of described buffer solution is 7.4.
Preferably, described metal chelating agent is disodiumedetate.
Preferably, described antiseptic is one or more in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzalkonium bromide or thimerosal.
Further, described pharmaceutically acceptable carrier is water for injection.
The present invention also provides a kind of preparation method of preventing and treating cataractous eye drop to be: hyaluronate sodium, isoosmotic adjusting agent, metal chelating agent and antiseptic are dissolved in pharmaceutically acceptable carrier and make eye drop bare substrate, then lepirudin 023 ludon is dissolved in this eye drop bare substrate, mixing, filtration, degerming subpackage, obtained lepirudin 023 ludon eye drop.
Effective ingredient hirudin of the present invention is relative molecular mass be 7000 macromolecular substances, must could preferably by eye mucosal absorption by the effect of absorption enhancers.Disodiumedetate and chitosan have stronger molten cell ability as absorption enhancers, and to eye without direct stimulation, and disodiumedetate also can metal ion in chelate solution simultaneously, plays the effect of stabilize proteins.Lepirudin 023 ludon eye drop, by improving SOD vigor, reduces MDA content, alleviates oxygen-derived free radicals and play it to cataractous therapeutical effect to the damage of lens cell.
Hyaluronate sodium of the present invention (SH) is thickening agent, and hyaluronate sodium is the sodium-salt form of hyaluronic acid (HA).Hyaluronic acid is also known as Hyaluronic Acid, and be the mucopolysaccharide material formed for disaccharidase repetitive with 2-Acetamido-2-deoxy-D-glucose and glucuronic acid, usually exist with its sodium-salt form, mean molecule quantity can be 60 ~ 2,800,000.The hyaluronate sodium viscosity of different molecular weight is different, and therefore its purposes is also different.The molecular weight of hyaluronate sodium of the present invention is approximately 1,300,000, belongs to eye drop rank.Hyaluronate sodium is extensively present in animal tissue cell's interstitial and vitreum, and main physiological function keeps organizing moisture and lubrication etc.Hyaluronate sodium not only has the advantage of carbomer, poloxamer, hypromellose, the contour molecular viscosity material of chitosan, also there is good biocompatibility, while increase medicine viscosity, overcome the shortcoming that eyelid not easily blinks, become the good carrier of eye drop.Hyaluronate sodium can also reduce the untoward reaction of preservative in eye drops.Under normal circumstances, when using the eye drop containing hyaluronate sodium, the hyaluronate sodium that eye table nature exists forms a skim and is covered in corneal epithelial surfaces, corneal epithelium has and hyaluronate sodium specific binding site, so eye table can be retained in for a long time containing the medicine of hyaluronate sodium, be conducive to ocular tissue and medicine is for a long time effectively absorbed.Therefore, hyaluronate sodium biocompatibility is fabulous, not only can thickening, and can moisturizing, thus can keep the moistening of eye long period while improving vision, serves assosting effect to improving vision.
Hirudin is a kind of highly stable protein, the rising of temperature and the change of pH do not affect its vigor, this dropping liquid preparation adds metal chelating agent and antiseptic agent, inhibits the metal ion that may exist to the impact of protein stability and antibacterial to the Degradation of albumen.Therefore this eye drop shows metastable character, can preserve 1 year and have no vigor loss.
The preparation method of lepirudin 023 ludon eye drop of the present invention is very simple, and conventional eye drop production technology can be adopted to produce, and simple physical mixes.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail.
Embodiment 1
The formula of eye drop of the present invention:
Lepirudin 023 ludon 0.02g
Hyaluronate sodium 0.1g
Borax 0.19g
Sodium chloride 0.22g
Disodiumedetate 0.5g
Methyl parahydroxybenzoate 0.03g
Water for injection is settled to 100ml
Preparation technology:
1., under the water bath condition of 60-80 DEG C, 0.1g hyaluronate sodium also slowly joins in 70ml water for injection by rapid stirring, makes it disperse completely, fully swelling, does not make bonding agglomerating, stirs and can dissolve completely for about 30 minutes.
2. respectively Borax, sodium chloride, sodium ethylene diamine tetracetate and methyl parahydroxybenzoate are joined in above-mentioned sodium hyaluronate solution, stir evenly dissolving, be then settled to 100ml, obtain the eye drop bare substrate of pH7.0.
3. joined by lepirudin 023 ludon in above-mentioned eye drop bare substrate, stir evenly dissolving, degerming by 0.22um frit, then subpackage, obtains lepirudin 023 ludon eye drop.
Embodiment 2
The formula of eye drop of the present invention:
Lepirudin 023 ludon 0.02g
Hyaluronate sodium 0.1g
Borax 1.5g
Disodiumedetate 0.5g
Ethylparaben 0.03g
Water for injection is settled to 100ml
Preparation technology:
1., under the water bath condition of 60-80 DEG C, 0.1g hyaluronate sodium also slowly joins in 70ml water for injection by rapid stirring, makes it disperse completely, fully swelling, does not make bonding agglomerating, stirs and can dissolve completely for about 30 minutes.
2. respectively Borax, sodium ethylene diamine tetracetate and ethylparaben are joined in above-mentioned sodium hyaluronate solution, stir evenly dissolving, be then settled to 100ml, obtain the eye drop bare substrate of pH7.1.
3. joined by lepirudin 023 ludon in above-mentioned eye drop bare substrate, stir evenly dissolving, degerming by 0.22um frit, then subpackage, obtains lepirudin 023 ludon eye drop.
Embodiment 3
The formula of eye drop of the present invention:
Lepirudin 023 ludon 0.02g
Hyaluronate sodium 0.1g
Phosphate buffer 1 .0g
Sodium chloride 0.5g
Disodiumedetate 0.5g
Benzalkonium bromide 0.03g
Water for injection is settled to 100ml
Preparation technology:
1., under the water bath condition of 60-80 DEG C, 0.1g hyaluronate sodium also slowly joins in 70ml water for injection by rapid stirring, makes it disperse completely, fully swelling, does not make bonding agglomerating, stirs and can dissolve completely for about 30 minutes.
2. respectively phosphoric acid, sodium chloride, sodium ethylene diamine tetracetate and benzalkonium bromide are joined in above-mentioned sodium hyaluronate solution, stir evenly dissolving, be then settled to 100ml, obtain the eye drop bare substrate of pH7.2.
3. joined by lepirudin 023 ludon in above-mentioned eye drop bare substrate, stir evenly dissolving, degerming by 0.22um frit, then subpackage, obtains lepirudin 023 ludon eye drop.
Embodiment 4
The formula of eye drop of the present invention:
Lepirudin 023 ludon 0.02g
Hyaluronate sodium 0.1g
Phosphatase 11 .0g
Borax 0.5g
Disodiumedetate 0.5g
Benzalkonium bromide 0.02g
Thimerosal 0.01g
Water for injection is settled to 100ml
Preparation technology:
1., under the water bath condition of 60-80 DEG C, 0.1g hyaluronate sodium also slowly joins in 70ml water for injection by rapid stirring, makes it disperse completely, fully swelling, does not make bonding agglomerating, stirs and can dissolve completely for about 30 minutes.
2. respectively phosphoric acid, Borax, sodium ethylene diamine tetracetate and benzalkonium bromide are joined in above-mentioned sodium hyaluronate solution, stir evenly dissolving, be then settled to 100ml, obtain the eye drop bare substrate of pH7.4.
3. joined by lepirudin 023 ludon in above-mentioned eye drop bare substrate, stir evenly dissolving, degerming by 0.22um frit, then subpackage, obtains lepirudin 023 ludon eye drop.
Embodiment 5
Lagophthalmos stimulation test
Lepirudin 023 ludon eye drop in embodiment 1 ~ 4 is carried out zest investigation according to the clinical front guideline method of new drug, select healthy new zealand rabbit 8, be divided into 4 groups, left eye every day is to the embodiment of the present invention 1 ~ 4 lepirudin 023 ludon eye drop 5 times, right eye does blank to normal saline respectively, 1,24,48,72h carries out examination of eyes, observe conjunctiva, cornea, iris and other visible damage, Continuous Observation 7d, according to the score value (the results are shown in Table 1) of Eye irritation reaction score criteria record eye reaction.
Each observing time respectively organized eyes final score by table 1
| Laboratory animal group | 1h | 24h | 48h | 72h | 4d | 5d | 6d | 7d |
| Embodiment 1 left eye | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Embodiment 2 left eye | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Embodiment 3 left eye | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Embodiment 4 left eye | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| All right eyes | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
As shown in Table 1, there is not zest in lepirudin 023 ludon eye drop administration side eye cornea, iris and conjunctiva, the same with contrast side eyes, proves that lepirudin 023 ludon III eye drop is without eye irritation thus.
Embodiment 6
Stability experiment
After lepirudin 023 ludon eye drop measures anticoagulant vigor, be placed in 4 DEG C of refrigerators and room temperature respectively, in placement 1,2,4 weeks and 3, after 6,12 months, the not change of its anticoagulant vigor and pH value, face shaping, clarity and sterility test all meet Pharmacopoeia of People's Republic of China (two) annex IIIA to the requirement of eye drop.
Embodiment 7
Pharmacodynamic experiment is to the therapeutical effect of the cataract rat that D-galactose is induced
Experimental agents: the lepirudin 023 ludon eye drop in embodiment 1 ~ 4
Laboratory animal: SD rat, male and female half and half, 130 ± 20g
Experimental technique and result:
1.SD rat cataract model is set up
Get 42 SD rats and be divided into 7 groups at random, often group is 6 (male and female half and half), is respectively Normal group, model control group, catalin matched group and lepirudin 023 ludon eye drop (2000ATU/ml) group.Except Normal group, the D-galactose solution 25mL/kg of the equal lumbar injection 0.08% of other group SD rat, be equivalent to 20mg/kg, 2 administrations of every bu, each 1 time of morning and afternoon, give 14d continuously, and drink 10%D-galactose solution, Normal group presses the normal saline of the same manner lumbar injection same volume.After modeling success, respectively group eyes drop administration respectively, each group administration volume is 100uL//time, 3 administrations of every bu, continuous 30 days.
2. lepirudin 023 ludon III eye drop is to the therapeutical effect of cataract rat
Administration, after 30 days, uses compound tropicamide eye drops mydriasis, with the turbidity of slit lamp microscope routine observation rat lens, records result after observation.Lenticular opacity degree gives different score value respectively by table 3 standard, t inspection between organizing.Model group rats without Drug therapy, along with its lenticular turbidity of prolongation of time is more and more higher.Lepirudin 023 ludon eye drop group, compared with model group lenticular opacity degree, has pole significant difference (p < 0.01), shows that lepirudin 023 ludon eye drop significantly can alleviate lenticular opacity (see table 2).
Table 2 rHVIII eye drop is on the impact (n=6) of SD rat lens turbidity
Note A: without muddy; B: slight haze; C: medium muddiness; D: seriously muddy; Vs model group, * p < 0.05, * * p < 0.01.
Rat, after 30 days, is put to death and gets eyeball, isolate crystalline lens by administration.Detect rat lens SOD activity, MDA content and AR respectively active.Compare with model group, catalin matched group and lepirudin 023 ludon eye drop group all can extremely remarkable increased SOD activity (p < 0.01) and extremely significantly reduce MDA content (p < 0.01), and significantly can reduce AR activity (see table 3).
Table 3 lepirudin 023 ludon III eye drop is on the impact (n=6) of SD rat lens SOD activity, MDA content and AR activity
| Group | n | MAD content (nmol/mg prot) | SOD activity (U/mg prot) | AR activity (U/mg prot) |
| Normal group | 6 | 3.27±0.37** | 13.15±2.79** | 1.05±0.47** |
| Model control group | 6 | 4.65±2.33 | 9.08±1.26 | 1.32±0.77 |
| Catalin group | 6 | 3.59±0.95* | 12.99±1.52** | 1.24±0.55* |
| Embodiment 1 | 6 | 3.42±0.83** | 11.66±2.55* | 1.17±0.79* |
| Embodiment 2 | 6 | 3.41±0.76** | 11.65±2.34* | 1.16±0.39* |
| Embodiment 3 | 6 | 3.41±0.44** | 11.67±2.78* | 1.17±0.33* |
| Embodiment 4 | 6 | 3.43±0.12** | 11.66±2.22* | 1.18±0.21* |
Note: vs model group, * p < 0.05, * * p < 0.01.
Experiment conclusion:
Lepirudin 023 ludon eye drop obviously can alleviate len's opacity, alleviates the development of galactose cataract symptom, and can increase SOD activity, reduces MDA content, reduces AR active, significantly improves the rat galactose-cataract order of severity.
Claims (7)
1. a lepirudin 023 ludon eye drop, is characterized in that: take lepirudin 023 ludon as effective ingredient, and hyaluronate sodium is thickening agent, also containing isoosmotic adjusting agent, metal chelating agent, antiseptic and pharmaceutically acceptable carrier; In eye drop, the mass ratio of hyaluronate sodium, lepirudin 023 ludon, isoosmotic adjusting agent, metal complex and antiseptic is 10:2:15.27:50:3.
2. according to the eye drop described in claim 1, it is characterized in that: described isoosmotic adjusting agent is selected from one or more in sodium chloride, borate buffer solution or phosphate buffer.
3. eye drop according to claim 2, is characterized in that: the pH value of described buffer solution is 4.0 ~ 7.5.
4. eye drop according to claim 1, is characterized in that: described metal chelating agent is disodiumedetate.
5. eye drop according to claim 1, is characterized in that: described antiseptic is one or more in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzalkonium bromide or thimerosal.
6. eye drop according to claim 1, is characterized in that: described pharmaceutically acceptable carrier is water for injection.
7. eye drop according to claim 1, it is characterized in that, its preparation method is: hyaluronate sodium, isoosmotic adjusting agent, metal chelating agent and antiseptic are dissolved in pharmaceutically acceptable carrier and make eye drop bare substrate, then lepirudin 023 ludon is dissolved in this eye drop bare substrate, mixing, filtration, degerming subpackage, obtained lepirudin 023 ludon eye drop.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110639010A (en) * | 2019-11-15 | 2020-01-03 | 云山化妆品研究开发(广州)有限公司 | Traditional Chinese medicine composition containing recombinant hirudin suitable for eyes and preparation method thereof |
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| CN1183302A (en) * | 1996-11-22 | 1998-06-03 | 凌沛学 | Eye drops contg. sodium hyaluronate and preparing method thereof |
| CN1483473A (en) * | 2003-08-04 | 2004-03-24 | 中国药科大学 | New use of recombinated hirudin |
| US20050233966A1 (en) * | 2004-04-12 | 2005-10-20 | Yu Cheng-Der T | Methods for controlling angiogenesis and cell proliferation |
| CN102727874A (en) * | 2012-07-18 | 2012-10-17 | 中国药科大学 | Recombinant hirudin eye drops and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1183302A (en) * | 1996-11-22 | 1998-06-03 | 凌沛学 | Eye drops contg. sodium hyaluronate and preparing method thereof |
| CN1483473A (en) * | 2003-08-04 | 2004-03-24 | 中国药科大学 | New use of recombinated hirudin |
| US20050233966A1 (en) * | 2004-04-12 | 2005-10-20 | Yu Cheng-Der T | Methods for controlling angiogenesis and cell proliferation |
| CN102727874A (en) * | 2012-07-18 | 2012-10-17 | 中国药科大学 | Recombinant hirudin eye drops and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110639010A (en) * | 2019-11-15 | 2020-01-03 | 云山化妆品研究开发(广州)有限公司 | Traditional Chinese medicine composition containing recombinant hirudin suitable for eyes and preparation method thereof |
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