VISCOELASTIC AGENT MATERIAL

Abstract

The present invention relates to a viscoelastic agent that is suitable for ophthalmic surgery and can avoid the problem of intraocular lens opacity after ophthalmic surgery (such as cataract surgery). The viscoelastic agent comprises viscoelastic substance(s), pH buffering agent(s), wherein the pH buffering agent is selected from pH buffering agent(s) based on boric acid and/or borate, osmotic pressure regulator(s), and water. The viscoelastic agent may further optionally comprise substances with oxidizing and/or reducing properties.

Claims

1. Viscoelastic agent, comprising the following substances: viscoelastic substance, wherein the viscoelastic substance is selected from sodium hyaluronate, chondroitin sulfate, and/or carboxymethylcellulose sodium; pH buffering agent, wherein the pH buffering agent is selected from pH buffering agent based on boric acid and/or borate; osmotic pressure regulator; and water.

2. The viscoelastic agent according to claim 1, wherein the viscoelastic substance is selected from collagen.

3. The viscoelastic agent according to claim 1, wherein the molar concentration of the boron element in the pH buffering agent based on boric acid and/or borate is no higher than 0.44 mol/L.

4. The viscoelastic agent according to claim 1, wherein the osmotic pressure regulator is selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride.

5. (canceled)

6. The viscoelastic agent according to claim 1, consisting of the following components: sodium hyaluronate: 1%-2.5% w/v; boric acid: 0.7%-0.85% w/v; borax: 0.04%-0.07% w/v; sodium chloride: 0.3%-0.7% w/v; and water.

7. (canceled)

8. An ophthalmic implant comprising a viscoelastic agent, the viscoelastic agent comprising: viscoelastic substance, wherein the viscoelastic substance is selected from sodium hyaluronate, chondroitin sulfate, and/or carboxymethylcellulose sodium; pH buffering agent, wherein the pH buffering agent is selected from pH buffering agent based on boric acid and/or borate; osmotic pressure regulator; and water.

9. (canceled)

10. (canceled)

11. The viscoelastic agent according to claim 1, wherein the content of the viscoelastic substance ranges from 0.1% to 4% w/v.

12. The viscoelastic agent according to claim 1, wherein the content of the viscoelastic substance ranges from 1.5% to 2.5% w/v.

13. The viscoelastic agent according to claim 1, wherein the pH buffering agent based on boric acid and/or borate is selected from boric acid and/or borax; boric acid and sodium hydroxide; borax and hydrochloric acid.

14. The viscoelastic agent according to claim 1, wherein the pH buffering agent based on boric acid and/or borate is selected from boric acid and/or borax.

15. The viscoelastic agent according to claim 1, wherein the content of boric acid in the pH buffering agent based on boric acid and/or borate is 0.5%-1.0% w/v.

16. The viscoelastic agent according to claim 13, wherein the content of borax in the pH buffering agent based on boric acid and/or borate is 0.02%-0.1% w/v.

17. The viscoelastic agent according to claim 1, wherein the osmotic pressure regulator is sodium chloride, its content being 0.3%-0.7% w/v.

18. The viscoelastic agent according to claim 1, wherein the pH range of the viscoelastic agent is 6.8-7.6.

19. The viscoelastic agent according to claim 1, wherein the viscoelastic agent further comprises a treatment-related drug, selected from: anti-inflammatory drugs required for surgery, sterilization drugs, hemostatic drugs, fluorescent agents, and photosensitizers

20. The ophthalmic implant according to claim 8, wherein the viscoelastic substance is selected from collagen.

21. The ophthalmic implant according to claim 8, wherein the content of the viscoelastic substance ranges from 0.1% to 4% w/v.

22. The ophthalmic implant according to claim 8, wherein the content of the viscoelastic substance ranges from 1.5% to 2.5% w/v.

23. The ophthalmic implant according to claim 8, wherein the pH buffering agent based on boric acid and/or borate is selected from boric acid and/or borax; boric acid and sodium hydroxide; borax and hydrochloric acid.

24. The ophthalmic implant according to claim 8, wherein the pH buffering agent based on boric acid and/or borate is selected from boric acid and/or borax.

25. The ophthalmic implant according to claim 8, wherein the molar concentration of the boron element in the pH buffering agent based on boric acid and/or borate is no higher than 0.44 mol/L.

26. The ophthalmic implant according to claim 8, wherein the content of boric acid in the pH buffering agent based on boric acid and/or borate is 0.5%-1.0% w/v.

27. The ophthalmic implant according to claim 23, wherein the content of borax in the pH buffering agent based on boric acid and/or borate is 0.02%-0.1% w/v.

28. The ophthalmic implant according to claim 8, wherein the osmotic pressure regulator is selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride.

29. The ophthalmic implant according to claim 8, wherein the osmotic pressure regulator is sodium chloride, its content being 0.3%-0.7% w/v.

30. The ophthalmic implant according to claim 8, wherein the pH range of the viscoelastic agent is 6.8-7.6.

31. The ophthalmic implant according to claim 8, wherein the viscoelastic agent further comprises a treatment-related drug, selected from: anti-inflammatory drugs required for surgery, sterilization drugs, hemostatic drugs, fluorescent agents, and photosensitizers.

32. The ophthalmic implant according to claim 8, consisting of the following components: sodium hyaluronate: 1%-2.5% w/v; boric acid: 0.7%-0.85% w/v; borax: 0.04%-0.07% w/v; sodium chloride: 0.3%-0.7% w/v; and water.

Description

DESCRIPTION OF THE DRAWINGS

[0102] FIG. 1 is a graph of rheological properties of formulation 1 of Example 1.

[0103] FIG. 2 is a graph of rheological properties of formulation 2 of Example 1.

[0104] FIG. 3 is a graph of rheological properties of formulation 3 of Example 1.

[0105] FIG. 4 is a graph showing the rheological properties of the viscoelastic agent formed by adding oxidized glutathione in Example 4.

[0106] FIG. 5 is a graph showing the rheological properties of the viscoelastic agent formed by adding reduced glutathione in Example 6.

[0107] FIG. 6 is a graph showing the modulus being varied as a function of frequency of the viscoelastic agent formed by adding reduced glutathione in Example 6.

EXAMPLES

[0108] Hereinafter, the present invention will be described in more detail through specific examples, but the provided examples are only illustrative and not intended to limit the present invention.

Example 1

[0109] According to Table 1 below, the viscoelastic agents of the present invention having formulations 1-9 were prepared according to the following steps. First, the pH buffer and the osmotic pressure regulator powder were dispersed and dissolved in water for injection, and filtered through aqueous filter membrane with 0.22 μm to obtain a sterile buffer. In a dynamic 100-level environment, added the viscoelastic substance weighed according to the corresponding formula to the sterile buffer, shacked and mixed, and then standed at 2-8° C. to remove bubbles. The mixed and bubble-free liquid is filled into the prefilled syringe through the prefilled syringe filling machine under the protection of the oRABS aseptic isolation system, and sterilized by moist heat.

TABLE-US-00001 TABLE 1 Formula Formula Formula Formula Formula Formula Formula Formula Formula 1 2 3 4 5 6 7 8 9 HA 1.0% — — 1.5% — — —  2.0% — (hyaluronic acid) (molecular weight 1.2 million) HA — — — — —  1.5% — — — (hyaluronic acid) (molecular weight 1.5 million) HA — 2.0% 2.5% — 1.7% —  1.7% —  1.5% (hyaluronic acid) (molecular weight is 2 million) CS — — — — —   4%   2% — — (chondroitin sulfate) HPMC — — — — — — —   2%   3% (hydroxypropyl methylcellulose) Boric acid 0.75% 0.76% 0.650% —  0.5%  0.9% 0.80% 0.65% Borax 0.09% 0.053% 0.05% 0.09% 0.1% 0.02% 0.04% 0.053%  — Sodium — — — — — — — — 0.12% hydroxide HCl 0.45% — — — 0.5% — — — — Sodium 0.55% 0.45% 0.37% 0.520% 0.500% 0.40% 0.60% 0.38% 0.50% chloride Magnesium — — — — — — — — 0.05% chloride Calcium — — — — — — — — 0.04% chloride Potassium — — — — — — — 0.04% — chloride pH — — — 7.60 7.22   7.31   7.10   6.98   7.02 Osmotic 310 298 302 305 300 280  330  287  315  pressure Shear 80 290 430 100 240 200  255  160  252  viscosity(0.25 s.sup.−1) .

[0110] Placed the viscoelastic agent of the above formulae encapsulated in a prefilled syringe in a moist heat sterilization cabinet with pressure compensation, setted the sterilization temperature at 121° C. and F0=8, tested by using a rheometer (Supplier: TA, Model: DHR-1) before and after sterilization. As shown in the above examples and FIGS. 1-3, the viscoelastic agent of the present invention may withstand moist heat sterilization. After conventional final moist heat sterilization, the viscoelastic agent of the present invention still has excellent viscosity, the viscoelastic agent comprising pH buffering agent based on boric acid and/or borate of the present invention still has the required viscoelastic property and so on.

Example 2: Rabbit Eye Implantation Test

[0111] Before surgery, evaluated and recorded the eyeball by using a rebound tonometer, slit lamp microscope and UBM. Eliminated animals with abnormal eyeballs, chosen 6 groups of control (comparative) eyes and 6 groups of test eyes. About 25% of the anterior chamber fluid in one eye of the test animal were replaced by using the same amount of the viscoelastic agent Formula 2 of Example 1 of the present invention (the test OVD), and the another eye in other side was operated in the same way with the control OVD. Before starting the next animal, operated on one eyeball and then the other eyeball in a random order. At 24 h and 7 days, the verification reactions that occurred during the operation were recorded, as shown in Table 2.

TABLE-US-00002 TABLE 2 Observation item Test eye Control eye Corneal transparency 24 h normal normal 7 d normal normal Cells 24 h normal normal 7 d normal normal Fibrin 24 h normal normal 7 d normal normal Tyndall (flash) 24 h Non Non 7 d Non Non Iritis 24 h Non Non 7 d Non Non Transparency of 24 h normal normal intraocular lens 7 d normal normal

[0112] The viscoelastic agent of the present invention passed the rabbit eye implantation test and verified its biological safety. There were no differences in rabbit corneal transparency, transparency of intraocular lens, cells number, etc. between before and after implantation, and there was no anterior chamber flash (Tyndall), iritis, and proliferation of fibrin etc., or complications, and the viscoelastic agent of the present invention had good biological safety.

Example 3 Rabbit Eye Cell Endothelial Technology Test

[0113] The 6 groups of test groups underwent phacoemulsification and lens implantation, a 3 mm transparent corneal tunnel incision was made by cutting, and 0.2 ml of the viscoelastic agent of Example 1 of the present invention (after moist heat sterilization) was injected through the anterior chamber, and continuous circular capsulorhexis and then ultrasonic emulsified, and aspirated the cortex. The folded intraocular lens was placed in the capsular bag, and applied anti-inflammatory syrup after the operation. The 6 groups of Control groups 1 were subjected to the same operations, and the phosphate pH buffering agent was used by replacing the pH buffering agent in the viscoelastic agent of the formulation 2 of Example 1 of the present invention. The 6 groups of Control groups 2 were subjected to the same operation replaced the viscoelastic agent with a pH buffer of sodium dihydrogen phosphate, so that the pH of the viscoelastic agent was 6.9. The density of corneal endothelial cells was checked by non-contact corneal endothelial microscope before and after surgery, and the average loss rate of corneal endothelial cells was calculated.

TABLE-US-00003 TABLE 3 Test Control Control Observation items group group 1 group 2 the average loss rate of 2% 4.9% 4% corneal endothelial cells before and after surgery (%)

[0114] The viscoelastic agent of the present invention had a higher protective effect on the corneal endothelium than that of the viscoelastic agent comprising phosphate system. The loss rate of corneal endothelial cells before and after surgery was small, and the viscoelastic agent of the present invention had an excellent protective effect on corneal endothelial cells.

Example 4

[0115] Weighted 0.0092 g of oxidized glutathione, 0.75 g of boric acid, 0.053 g of borax, 0.4 g of sodium chloride, then added appropriate amount of water for injection to dissolve them, added 3.0 g of dry sodium hyaluronate powder into the above, added water for injection to make up the weight to 100 g, placed a shaker and stirred thoroughly until uniform, formulated concentration of sodium hyaluronate solution was 3.0%, and formulated the concentration of oxidized glutathione solution was 0.15 mmol/L, left to stand at a low temperature and sterilized under high temperature and high pressure at 121° C. for 12 minutes.

Example 5

[0116] Weighted 0.0092 g of oxidized glutathione, 0.01 g of vitamin C, 0.75 g of boric acid, 0.053 g of borax, 0.4 g of sodium chloride, added appropriate amount of water for injection to dissolve them, then added 3.4 g of dry sodium hyaluronate powder into the above, added water for injection to make up the weight to 100 g, placed a shaker and stirred thoroughly until uniform, formulated concentration of sodium hyaluronate solution was 3.0%, formulated concentration of oxidized glutathione solution was 0.15 mmol/L, and formulated concentration of vitamin C solution was 0.01%, left to stand at a low temperature and sterilized under high temperature and high pressure at 121° C. for 12 minutes.

Example 6

[0117] Weighted 0.0092 g of reduced glutathione, 0.75 g of boric acid, 0.053 g of borax, 0.4 g of sodium chloride, added appropriate amount of water for injection to dissolve them, then added 2.0 g of dry sodium hyaluronate powder into the above, added water for injection to make up the weight to 100 g, placed a shaker and stirred thoroughly until uniform, formulated concentration of sodium hyaluronate solution was 2.0%, formulated concentration of reduced glutathione solution was 0.3 mmol/L, left to stand at a low temperature and sterilized under high temperature and high pressure at 121° C. for 12 minutes.

Example 7

[0118] Weighted 0.0092 g of reduced glutathione, 0.01 g of vitamin C, 0.75 g of boric acid, 0.053 g of borax, 0.4 g of sodium chloride, added appropriate amount of water for injection to dissolve them, then added 2.4 g of dry sodium hyaluronate powder into the above, added water for injection to make up the weight to 100 g, placed a shaker and stirred thoroughly until uniform, formulated concentration of sodium hyaluronate solution was 2.4%, formulated concentration of reduced glutathione solution was 0.3 mmol/L, and formulated concentration of vitamin C solution was 0.01%, left to stand at a low temperature and sterilized under high temperature and high pressure at 121° C. for 12 minutes.

Example 8: Rabbit Eye Implantation Test

[0119] Before surgery, evaluated and recorded the eyeball by using a rebound tonometer, slit lamp microscope and UBM, eliminated animals with abnormal eyeballs, chosen 6 groups of control eyes and 6 groups of test eyes.

[0120] About 25% of the anterior chamber fluid in one eye of the test animal was replaced by using the same amount of the viscoelastic agent of Example 4 of the present invention, and the another eye in other side was operated in the same way with the control OVD. Before starting the next animal, operated on one eyeball and then the other eyeball in a random order. At 24 h and 7 days, the verification reactions that occurred during the operation were recorded, as shown in Table 4.

TABLE-US-00004 TABLE 4 project Evaluation Index Corneal Tyndall Transparency of transparency Fibrin (flash) Iritis intraocular lens Test Control Test Control Test Control Test Control Test Control Time group group group group group group group group group group Before Normal Normal Normal Normal None None None None Normal Normal surgery 6 h ± 1 h Normal Normal Normal Normal None None None None Normal Normal 24 h ± 2 h  Normal Normal Normal Normal None None None None Normal Normal 2 d ± 2 h Normal Normal Normal Normal None None None None Normal Normal 3 d ± 2 h Normal Normal Normal Normal None None None None Normal Normal 7 d ± 1 d Normal Normal Normal Normal None None None None Normal Normal

[0121] The viscoelastic agent of the present invention passed the rabbit eye implantation test and verified its biological safety. There were no differences in rabbit corneal transparency, transparency of intraocular lens, cells number, etc. between before and after implantation, and there was no anterior chamber flash (Tyndall), iritis, and proliferation of fibrin etc., or complications, and the viscoelastic agent of the present invention had good biological safety.

Example 9: Rabbit Eye Cell Endothelial Technology Test

[0122] The 6 groups of test groups underwent phacoemulsification and lens implantation, a 3 mm transparent corneal tunnel incision was made by cutting, and 0.2 ml of the viscoelastic agent of Example 1 of the present invention (after moist heat sterilization) was injected through the anterior chamber, and continuous circular capsulorhexis and then ultrasonic emulsified, and aspirated the cortex. The folded intraocular lens was placed in the capsular bag, and applied anti-inflammatory syrup after the operation. The 6 groups of Control groups 1 were subjected to the same operations, and the phosphate pH buffering agent was used by replacing the pH buffering agent in the viscoelastic agent of Example 7 of the present invention. The 6 groups of Control groups 2 were subjected to the same operation replaced the viscoelastic agent with a pH buffer of sodium dihydrogen phosphate/hydrochloric acid/sodium hydroxide buffer system, so that the pH of the viscoelastic agent was 7.2. The density of corneal endothelial cells was checked by non-contact corneal endothelial microscope before and after surgery, and the average loss rate of corneal endothelial cells was calculated.

TABLE-US-00005 TABLE 5 Test Control Control Observation items group group 1 group 2 Average loss rate of 2.45 ± 0.74% 4.12 + 1.36% 4.93 ± 1.92% corneal endothelial cells before and after surgery (%)

[0123] The viscoelastic agent of the present invention had a higher protective effect on the corneal endothelium than that of the viscoelastic agent comprising phosphates system. The loss rate of corneal endothelial cells before and after surgery was small, and the viscoelastic agent of the present invention had an excellent protective effect on corneal endothelial cells.

Example 10: Rabbit Eye Cell Endothelial Technology Test

[0124] The 6 groups of test groups underwent phacoemulsification and lens implantation, a 3 mm transparent corneal tunnel incision was made by cutting, and 0.2 ml of the viscoelastic agent of Example 6 of the present invention (after moist heat sterilization) was injected through the anterior chamber, and continuous circular capsulorhexis and then ultrasonic emulsified, and aspirated the cortex. The folded intraocular lens was placed in the capsular bag, and applied anti-inflammatory syrup after the operation. The 6 groups of Control groups 1 were subjected to the same operations, made a control viscoelastic agent by only removing the reduced glutathione from the viscoelastic agent of Example 7 of the present invention. The density of corneal endothelial cells was checked by non-contact corneal endothelial microscope before and after surgery, and the average loss rate of corneal endothelial cells was calculated.

TABLE-US-00006 TABLE 6 Observation items Test group Control group 1 Average loss rate of 2.74 ± 0.88% 4.65 ± 1.05% corneal endothelial cells before and after surgery (%) .

[0125] When the viscoelastic agent of the present invention comprises a substance with oxidizing and/or reducing properties, the viscoelastic agent of the present invention has a higher protective effect on the corneal endothelium than that of a viscoelastic agent that does not comprise the substance with oxidizing and/or reducing properties of the present invention. The loss rate of corneal endothelial cells is small between before and after surgery, and it has excellent protection of corneal endothelial cells.