Diquafosol sodium eye drops and preparation method thereof

Abstract

The invention relates to the technical field of preparation of eye drops, in particular to diquafosol sodium eye drops and a preparation method thereof, and the diquafosol sodium eye drops comprise diquafosol sodium, disodium hydrogen phosphate, sodium chloride, potassium chloride, a preservative, a pH regulator and water for injection; wherein the preservative is a combination of boric acid, disodium ethylene diamine tetraacetate and polyvinylpyrrolidone. The diquafosol sodium eye drops can achieve the antibacterial efficacy meeting the standard, meanwhile, the damage of a preservative to the ocular surface of eyes can be effectively weakened, and the diquafosol sodium eye drops are prevented from causing secondary damage to the eye tissues of patients suffering from glaucoma, xerophthalmia and the like which need to be taken for a long time; the diquafosol sodium eye drop solves the problems that in the prior art, an existing diquafosol sodium eye drop is added with a preservative which greatly damages eyes, so that eye tissues are easily damaged or secondarily damaged, and potential risks are caused to the eyes due to the large addition amount of the preservative.

Description

Technical Field

[0001] The invention relates to the technical field of eye drop preparation, and in particular to diquafosol sodium eye drops and a preparation method thereof. Background Art

[0002] Diquafosol sodium is a dinucleotide derivative with the molecular formula C 18 H 22 N4Na4O 23 P4; Diquafosol sodium, as one of the P2Y2 receptor agonists, activates the P2Y2 receptors on the conjunctival tissue and goblet cell membrane to increase the intracellular calcium ion concentration, thereby promoting the secretion of tears containing water and mucin, making the tear layer close to normal in both quality and quantity, improving corneal and conjunctival epithelial damage, and relieving the symptoms of dry eye; therefore, diquafosol sodium eye drops are usually suitable for patients diagnosed with dry eye with corneal and conjunctival epithelial damage accompanied by abnormal tears. Eye drops, especially multi-dose eye drops, if their main drug ingredients themselves do not have sufficient antibacterial activity, must be added with appropriate preservatives to kill microorganisms contaminated during normal storage and use of the eye drops; at the same time, prevent and limit the growth and reproduction of microorganisms; avoid harm to the eyes caused by microbial contamination during the use of eye drops. At present, benzalkonium chloride, chlorobutanol, boric acid and borax are all commonly used preservatives in ophthalmic preparations; however, the damage to the ocular surface caused by long-term use of eye drops containing preservatives has been fully confirmed from in vivo, in vitro experiments and clinical studies; for example, when benzalkonium chloride is used as a preservative, it will destroy the tear film and damage the ocular surface epithelial cells; although chlorobutanol has a broad antibacterial spectrum, it is easy to evaporate. When it is used as a preservative in eye drops, in order to better exert the antibacterial effect, the pH value of the eye drops cannot exceed 5, which limits the application scope of chlorobutanol, and chlorobutanol can also cause damage to the cornea; when boric acid, borax, etc. are used as preservatives in eye drops, the amount of boric acid and borax added is large, and there are still potential risks. In addition, the damaging effects of preservatives such as benzalkonium chloride and chlorobutanol on the tear film and cornea will increase with the extension of medication time. For patients with glaucoma and dry eye disease who need long-term medication, the use of eye drops containing preservatives may cause "secondary" damage to their eye tissues. Controlling microbial contamination in eye drops and reducing the damage of preservatives to the ocular surface is a multi-faceted systematic project; this requires drug regulatory authorities to strictly perform their duties to ensure drug safety; it also requires medical staff to use drugs rationally to protect the health of patients' ocular surfaces; at the same time, it is inseparable from the innovative research of scientific researchers to provide stronger scientific support for the development and application of eye drops. In order to allow the majority of patients with eye diseases to obtain greater benefits, in the process of preparing eye drops, it is necessary to focus on the selection of preservative types and the dosage of preservatives.

[0003] The invention provides a diquafosol sodium eye drops and a preparation method thereof, so as to solve the problems in the prior art that a preservative which is highly damaging to the eye is added to the existing diquafosol sodium eye drops, which is easy to cause secondary damage to the eye tissue, and the amount of preservative added is large, which makes the eye drops have greater potential risks. Summary of the invention

[0004] The purpose of the present invention is to provide a diquafosol sodium eye drops and a preparation method thereof, so as to solve the problems in the prior art that the existing diquafosol sodium eye drops contain a preservative that is highly damaging to the eye, which is likely to cause secondary damage to eye tissue, and the amount of preservative added is large, which makes the eye drops have greater potential risks.

[0005] The technical scheme of the present invention is: a diquafosol sodium eye drop, which comprises diquafosol sodium, disodium hydrogen phosphate, sodium chloride, potassium chloride, a preservative, a pH regulator and water for injection; wherein the preservative is a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone.

[0006] Preferably, in the diquafosol sodium eye drops, the mass concentration of diquafosol sodium is 3%;

[0007] The mass concentration of disodium oxalate tetraacetate is 0.005-0.01%;

[0008] The mass concentration of the boric acid is 2-3%;

[0009] The mass concentration of the polyvinyl pyrrolidone is 0.5-0.7%.

[0010] Preferably, the pH value of the diquafosol sodium eye drops is 7.2 to 7.8.

[0011] Preferably, in the diquafosol sodium eye drops, the mass concentration of disodium oxalate tetraacetate is 0.005% to 0.01%;

[0012] The mass concentration of the boric acid is 2% to 3%;

[0013] The mass concentration of the polyvinyl pyrrolidone is 0.5% to 0.6%.

[0014] The present invention also provides a method for preparing the diquafosol sodium eye drops, comprising the following steps:

[0015] S1. At a temperature of 20°C to 60°C, add 25% to 35% of water for injection into a batching tank, then add anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride and a preservative into the batching tank in sequence, and stir until completely dissolved to obtain a first solution;

[0016] S2, adding diquafosol sodium raw material to the first solution, stirring until completely dissolved, then adding injection water to the first solution to 90-98% of the total amount of the prepared solution, and continuing to stir and mix for 10-20 minutes to obtain a second solution;

[0017] S3, adding a pH adjusting agent to the second solution to adjust the pH value of the second solution to within the range of 7.2 to 7.8, then adding water for injection to the second solution and weighing to the total amount of the prepared solution, stirring for 20 to 40 minutes, mixing evenly, and obtaining a third solution;

[0018] S4, the third solution is first filtered through a 0.45um polyethersulfone filter for circulation, after filtering for 10 to 20 minutes, and then filtered through a 0.22um polyethersulfone filter for sterilization to obtain a batch of liquid medicine;

[0019] S5. Filling the batch of liquid medicine into the low-density polyethylene medicinal eye drop bottle that has been processed in advance, and after the filling is completed, performing a light inspection to obtain the diquafosol sodium eye drops.

[0020] Preferably, in step S4, the filter membranes of the 0.45um polyethersulfone filter and the 0.22um polyethersulfone filter need to be checked before performing the circulation filtration and the sterilization filtration;

[0021] In step S5, the filling volume of the diquafosol sodium eye drops is 5 mL / vial.

[0022] Preferably, the pH value of the diquafosol sodium eye drops is 7.5.

[0023] Compared with the prior art, the advantages of the present invention are:

[0024] (1) The present invention provides a diquafosol sodium eye drops and a preparation method thereof. The diquafosol sodium eye drops use a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone as a preservative, and the antibacterial efficacy of the diquafosol sodium eye drops is adjusted by adjusting the mass concentrations of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone in the diquafosol sodium eye drops, so that the diquafosol sodium eye drops can achieve an antibacterial efficacy that meets the A standard. At the same time, the damage of the preservative to the ocular surface of the eye can be effectively reduced, thereby preventing the diquafosol sodium eye drops from causing secondary damage to the eye tissue of patients with glaucoma and dry eye disease who need long-term medication. The invention solves the problems in the prior art that the existing diquafosol sodium eye drops contain preservatives that are highly damaging to the eye, which are likely to cause secondary damage to the eye tissue, and the amount of preservative added is large, which poses a potential risk to the eye.

[0025] (2) The present invention provides a diquafosol sodium eye drops and a preparation method thereof. The diquafosol sodium eye drops use a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone as a preservative, wherein the boric acid mainly plays an antibacterial role, and the disodium oxalate tetraacetate, polyvinyl pyrrolidone and boric acid work together to enable the boric acid to exert a greater antibacterial effect, thereby reducing the amount of boric acid used, thereby reducing the damage of the diquafosol sodium eye drops to the eyes and the secondary damage to the eyes when used for a long time, thereby reducing the potential risks of the diquafosol sodium eye drops; at the same time, polyvinyl pyrrolidone itself is a synthetic water-soluble polymer material with moisture retention, and has a better therapeutic effect on dry eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention will be further described below in conjunction with the accompanying drawings and embodiments:

[0027] Figure 1 This is a graph showing the antibacterial effect of the diquafosol sodium eye drops prepared in Example 4 of the present invention on Staphylococcus aureus over a 28-day period;

[0028] Figure 2 This is a graph showing the antibacterial effect of the diquafosol sodium eye drops prepared in Example 4 of the present invention on Aspergillus niger over a 28-day period;

[0029] Figure 3 This is a graph showing the antibacterial effect of the diquafosol sodium eye drops prepared in Example 4 of the present invention on Staphylococcus aureus over a 28-day period;

[0030] Figure 4 This is a graph showing the antibacterial effect of the diquafosol sodium eye drops prepared in Example 4 of the present invention on Pseudomonas aeruginosa over a period of 14 days. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below in conjunction with specific embodiments:

[0032] Disclosed is diquafosol sodium eye drops, which comprise a prescribed amount of diquafosol sodium, disodium hydrogen phosphate, sodium chloride, potassium chloride, a preservative, a pH regulator and water for injection; wherein the preservative is any one of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone or a combination of more than one thereof.

[0033] Furthermore, in order to enable the diquafosol sodium eye drops to better act on the P2Y2 receptors of the conjunctival tissue and goblet cell membrane, improve the damage of the corneal and conjunctival epithelium, and relieve the symptoms of dry eye, the mass concentration of diquafosol sodium in the diquafosol sodium eye drops needs to reach about 3%; in order to better kill microorganisms contaminated by the eye drops during normal storage and use, effectively prevent and limit the growth and reproduction of microorganisms, and avoid the harm of multiple doses of eye drops to the eyes caused by microbial contamination during use, the preservative added to the diquafosol sodium eye drops is preferably a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone; and, in the diquafosol sodium eye drops, the mass concentration of disodium oxalate tetraacetate needs to be controlled within the range of 0.005-0.01%; the mass concentration of boric acid needs to be controlled within the range of 2-3%; and the mass concentration of polyvinyl pyrrolidone needs to be controlled within the range of 0.5-0.7%.

[0034] Example 1

[0035] S1. At a temperature of 30°C, add 30% water for injection into a batching tank, then add the prescribed amount of anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride and a preservative into the batching tank in sequence, and stir until completely dissolved to obtain a first solution; wherein the preservative is boric acid;

[0036] S2, adding the prescribed amount of diquafosol sodium raw material to the first solution, stirring until completely dissolved, then adding injection water to the first solution to 95% of the total amount of the prepared solution, and continuing to stir and mix for 10 minutes to obtain a second solution;

[0037] S3, adding a pH adjuster to the second solution to adjust the pH value of the second solution to within the range of 7.2 to 7.8, then adding water for injection to the second solution and weighing to the total amount of the solution, stirring for 30 minutes, mixing evenly, to obtain a third solution;

[0038] S4, the third solution is first circulated and filtered through a 0.45um polyethersulfone filter, after filtering for 15 minutes, and then sterilized and filtered through a 0.22um polyethersulfone filter to obtain a batch of liquid medicine;

[0039] S5. Filling the batch of liquid medicine into a low-density polyethylene medicinal eye drop bottle that has been processed in advance, and after filling, performing a light inspection to obtain a diquafosol sodium eye drop solution with a mass concentration of 3% of diquafosol sodium, a mass concentration of 3% of boric acid, and a pH value of 7.45.

[0040] Boric acid, oxalic acid tetraacetic acid disodium, polyvinyl pyrrolidone or a combination of any two or three of boric acid, oxalic acid tetraacetic acid disodium, polyvinyl pyrrolidone are selected as preservatives to prepare diquafosol sodium eye drops, and the antibacterial efficacy of the prepared diquafosol sodium eye drops meets the standard by adjusting the addition amount and addition ratio of boric acid, oxalic acid tetraacetic acid disodium, and polyvinyl pyrrolidone; the specific selection and addition amount of the preservative are as shown in Examples 2-11, and the specific preparation method is the same as that in Example 1.

[0041] Comparative Example 1

[0042] S1. At a temperature of 40° C., add 30% water for injection into a batching tank, then add the prescribed amount of anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride and a preservative into the batching tank in sequence, and stir until completely dissolved to obtain a first solution; wherein the preservative is benzalkonium chloride;

[0043] S2, adding the prescribed amount of diquafosol sodium raw material to the first solution, stirring until completely dissolved, then adding injection water to the first solution to 95% of the total amount of the prepared solution, and continuing to stir and mix for 10 minutes to obtain a second solution;

[0044] S3, adding a pH adjusting agent to the second solution to adjust the pH value of the second solution to within the range of 7.2 to 7.8, then adding water for injection to the second solution and weighing to the total amount of the solution, stirring for 20 minutes, mixing evenly, to obtain a third solution;

[0045] S4, the third solution is first circulated and filtered through a 0.45um polyethersulfone filter, after filtering for 15 minutes, and then sterilized and filtered through a 0.22um polyethersulfone filter to obtain a batch of liquid medicine;

[0046] S5. Filling the batch of liquid medicine into a low-density polyethylene medicinal eye drop bottle that has been processed in advance, and after filling, performing a light inspection to obtain diquafosol sodium eye drops with a mass concentration of 3% of diquafosol sodium, a mass concentration of 0.01% of benzalkonium chloride, and a pH value of 7.47.

[0047] Comparative Example 2

[0048] S1. At a temperature of 40° C., add 30% water for injection into a batching tank, then add the prescribed amount of anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride and a preservative into the batching tank in sequence, and stir until completely dissolved to obtain a first solution; wherein the preservative is chlorobutanol;

[0049] S2, adding the prescribed amount of diquafosol sodium raw material to the first solution, stirring until completely dissolved, then adding injection water to the first solution to 95% of the total amount of the prepared solution, and continuing to stir and mix for 10 minutes to obtain a second solution;

[0050] S3, adding a pH adjusting agent to the second solution to adjust the pH value of the second solution to within the range of 7.2 to 7.8, then adding water for injection to the second solution and weighing to the total amount of the solution, stirring for 20 minutes, mixing evenly, to obtain a third solution;

[0051] S4, the third solution is first circulated and filtered through a 0.45um polyethersulfone filter, after filtering for 15 minutes, and then sterilized and filtered through a 0.22um polyethersulfone filter to obtain a batch of liquid medicine;

[0052] S5. Filling the batch of liquid medicine into a low-density polyethylene medicinal eye drop bottle that has been processed in advance, and after filling, performing a light inspection to obtain a diquafosol sodium eye drop solution with a mass concentration of 3% of diquafosol sodium, a mass concentration of 0.01% of chlorobutanol, and a pH value of 7.51.

[0053] The antibacterial efficacy evaluation standard of the diquafosol sodium eye drops prepared in this application refers to the antibacterial efficacy judgment standard of injections, ophthalmic preparations, and preparations for the uterus and breast, as shown in Table 1; the "reduced lg value" in the table refers to the difference between the lg value of the bacterial count measured at each time interval and the lg value of the bacterial count inoculated in 1ml of the test sample; NR means that the test bacteria have not resumed growth; NI means no increase, which means that the number of test bacteria increased by no more than 0.5lg for the previous measurement time. "A" in the table refers to the antibacterial efficacy standard that should be achieved; in special cases, such as antibacterial agents may increase the risk of adverse reactions, at least the antibacterial efficacy standard of "B' should be achieved.

[0054] Table 1. Criteria for judging the antibacterial efficacy of ophthalmic preparations and other preparations

[0055]

[0056] The antibacterial efficacy of the diquafosol sodium eye drops prepared in Examples 1-11 and Comparative Examples 1-2 was evaluated by detecting the inhibitory efficacy of the eye drops against strains such as Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. The test results are shown in Table 2.

[0057] Table 2. Antibacterial efficacy test results of diquafosol sodium eye drops prepared in Examples 1-11

[0058]

[0059]

[0060] According to the data analysis recorded in Table 2, the addition of boric acid as a preservative in Example 1-2 can make the diquafosol sodium eye drops have a higher antibacterial effect; and Figure 1 , Figure 2 As shown, no obvious Staphylococcus aureus and Aspergillus niger were found in the culture dish; further indicating that the antibacterial efficacy of the sodium diquafosol eye drops was high; however, when the mass concentration of boric acid in the eye drops was 3%, its antibacterial efficacy only met the requirements of the B standard; when the mass concentration of boric acid was increased to 4.5%, the eye drops could achieve the antibacterial efficacy that met the A standard; indicating that when boric acid was used alone as a preservative, more boric acid needed to be added to make the prepared eye drops achieve the antibacterial efficacy that met the A standard. However, since boric acid is a weak acidic substance, when the content of boric acid in the eye drops is high, it may irritate the cornea and conjunctiva of the eye; and boric acid is also corrosive to a certain extent, and long-term use may cause damage to corneal epithelial cells, and even cause serious consequences such as perforation; that is, when the content of boric acid in the eye drops is high, the eye drops will have a greater potential risk; therefore, it is necessary to further explore the selection of preservatives, and use boric acid with other additives to increase its antibacterial effect through synergistic effects.

[0061] In Example 3 and Example 4, disodium tetraacetate is used alone as a preservative. Although the addition of disodium tetraacetate to the eye drops can make the eye drops have a certain antibacterial effect and help maintain the stability and safety of the eye drops; however, its antibacterial effect is relatively poor and cannot meet the antibacterial requirements. Even if the addition amount of disodium tetraacetate is increased, the eye drops cannot achieve the antibacterial effect required by the standard; Figure 3 , Figure 4 As shown, the antibacterial effect of the diquafosol sodium eye drops prepared in Example 4 on Staphylococcus aureus and Pseudomonas aeruginosa was poor, and could not reach the antibacterial efficacy that met the B standard. In addition, a larger amount of disodium tetraacetate added may also cause the eye drops to irritate the conjunctiva and cornea; experimental studies have found that disodium tetraacetate can destroy the cell walls of bacteria by binding to metal ions, and can be used to enhance the antibacterial effect of other preservatives. Therefore, it is considered to use disodium tetraacetate in combination with other preservatives to enhance the antiseptic effect and reduce the amount of other preservatives through mutual synergy; as shown in Example 5; in Example 5, boric acid and disodium tetraacetate are used as preservatives, which can make the prepared quafosol sodium eye drops reach the antibacterial efficacy that meets the A standard; the antibacterial effect is mainly exerted by boric acid, and disodium tetraacetate plays an auxiliary antibacterial role, and the two work together to enable the eye drops to achieve the antibacterial efficacy that meets the A standard; however, the amount of boric acid and disodium tetraacetate added in the quafosol sodium eye drops is still relatively large, which will make the eye drops have a greater potential risk.

[0062] It has been found that polyvinyl pyrrolidone can be added to eye drops as a thickener and stabilizer to increase the viscosity of the aqueous composition containing diquafosol or its salt, which can prolong the residence time of the drug on the ocular surface, thereby enhancing the efficacy of diquafosol or its salt; however, the polyvinyl pyrrolidone does not have a direct preservative effect; when polyvinyl pyrrolidone is used alone as a preservative, the antibacterial efficacy of the eye drops prepared therefrom is very poor, and it is difficult to make the eye drops reach the antibacterial efficacy that meets the B standard, as shown in Example 6; however, when polyvinyl pyrrolidone is combined with boric acid or disodium oxalate tetraacetate as a preservative, the synergistic effect between polyvinyl pyrrolidone and boric acid or disodium oxalate tetraacetate, and the thickening and stabilizing effect of polyvinyl pyrrolidone, the added boric acid and / or disodium oxalate tetraacetate with a preservative function can better exert an antibacterial effect, thereby significantly improving the antibacterial efficacy of the eye drops, as shown in Examples 7 and 8. Through a large number of experimental explorations, the invention uses a combination of polyvinyl pyrrolidone, disodium tetraacetate and boric acid as a preservative, and by adjusting the amount of polyvinyl pyrrolidone, boric acid and disodium tetraacetate added, as in Examples 9-11, the prepared diquafosol sodium eye drops can achieve an antibacterial effect that meets the B standard or the A standard. In addition, by comparing Example 9 with Example 10, it can be seen that when a combination of polyvinyl pyrrolidone, boric acid and disodium tetraacetate is selected as a preservative, under the synergistic effect between polyvinyl pyrrolidone, boric acid and disodium tetraacetate, the eye drops prepared can still achieve an antibacterial effect that meets the A standard while appropriately reducing the amount of boric acid and disodium tetraacetate added, thereby effectively reducing the potential risks of the diquafosol sodium eye drops; at the same time, polyvinyl pyrrolidone can increase the retention time of the drug in the eye, thereby improving the efficacy of the eye drops; the added polyvinyl pyrrolidone can also improve the comfort of the patient when taking the drug. Among them, the specific antibacterial efficacy test results (reduced lg value) of the diquafosol sodium eye drops prepared in Example 10 are shown in Table 3, and the specific antibacterial efficacy test results (reduced lg value) of the diquafosol sodium eye drops prepared in Example 11 are shown in Table 4.

[0063] Table 3. Antibacterial efficacy test results of diquafosol sodium eye drops prepared in Example 10

[0064]

[0065]

[0066] Table 4. Antibacterial efficacy test results of diquafosol sodium eye drops prepared in Example 11

[0067] Testing time Staphylococcus aureus Pseudomonas aeruginosa Candida albicans Aspergillus niger 6h ＞4.3 0.2 N / A N / A 24h ＞4.3 1.0 N / A N / A 7d ＞4.3 ＞4.4 ＞4.0 2.7 14d N / A N / A ＞4.0 ＞3.0 28d NI NI NI NI

[0068] As shown in Table 3, the diquafosol sodium eye drops prepared in Example 10 have good inhibitory effects on Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger at different time periods such as 6h, 24h, 7d, 14d, and 28d, which further illustrates that the addition of a combination of polyvinyl pyrrolidone, boric acid, and disodium oxalate tetraacetate as a preservative in the eye drops, and controlling the mass concentration of polyvinyl pyrrolidone in the diquafosol sodium eye drops to 0.6%, the mass concentration of boric acid to 3%, and the mass concentration of disodium oxalate tetraacetate to 0.01%, can make the diquafosol sodium eye drops have excellent antibacterial effects; however, as shown in Table 4, the diquafosol sodium eye drops prepared in Example 11 have good inhibitory effects at different time periods such as 6h, 24h, and 14d. The antibacterial effect of the diquafosol sodium eye drops was poor against Pseudomonas aeruginosa at different time periods of 6h, 24h, 7d, 14d, 28d, etc., while the inhibitory effects on Staphylococcus aureus, Candida albicans and Aspergillus niger were good at different time periods such as 6h, 24h, 7d, 14d, and 28d, which further indicated that reducing the mass concentrations of polyvinyl pyrrolidone, boric acid and disodium oxalate tetraacetate in the eye drops would affect the antibacterial effect of the diquafosol sodium eye drops; therefore, in order to ensure that the prepared diquafosol sodium eye drops have excellent antibacterial efficacy, the mass concentration of polyvinyl pyrrolidone in the diquafosol sodium eye drops needs to be controlled within the range of 0.5% to 0.6%, the mass concentration of boric acid needs to be controlled within the range of 2% to 3%, and the mass concentration of disodium oxalate tetraacetate needs to be controlled within the range of 0.005% to 0.01%.

[0069] In addition, by comparing Example 9 and Example 10 with Comparative Example 1 and Comparative Example 2, it can be seen that the antibacterial efficacy of the diquafosol sodium eye drops prepared with a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone as a preservative is equivalent to or better than the antibacterial efficacy of the diquafosol sodium eye drops prepared with benzalkonium chloride or chlorobutanol as a preservative; however, the use of the combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone provided in the present application as a preservative to prepare diquafosol sodium eye drops can kill microorganisms contaminated during normal storage and use of the eye drops, prevent and limit the growth and reproduction of microorganisms, and avoid or reduce the damage to the ocular surface caused by long-term use of eye drops containing preservatives, and avoid the eye drops for patients with glaucoma and dry eye diseases who need long-term medication. "Secondary" damage to the eye tissue.

[0070] Boric acid, disodium tetraacetate and polyvinyl pyrrolidone are all relatively low in irritation and are suitable for use in eye drops. The combination of boric acid, disodium tetraacetate and polyvinyl pyrrolidone as a preservative can enable boric acid to exert a greater antibacterial effect through the synergistic effect of the three, thereby making the prepared diquafosol sodium eye drops have excellent antibacterial effect. At the same time, a large number of experiments have verified that the diquafosol sodium eye drops prepared in the present application have high safety and effectiveness, and comply with the regulations of pharmacopoeias and drug regulatory agencies of various countries.

[0071] In other embodiments, other metal chelating agents may be used to replace the disodium tetraacetate in the present application; other additives having the same effect as polyvinyl pyrrolidone and boric acid may also be used to replace the polyvinyl pyrrolidone and boric acid in the present application.

[0072] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the scope of protection of the present invention. For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic features of the present invention. Therefore, no matter from which point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is limited by the attached claims rather than the above description, and it is intended to include all changes within the meaning and scope of the equivalent elements of the claims in the present invention.

Claims

1. A diquafosol sodium eye drop, comprising diquafosol sodium, disodium hydrogen phosphate, sodium chloride, potassium chloride, a preservative, a pH regulator and water for injection; characterized in that: The preservative is a combination of boric acid, disodium oxalate tetraacetate and polyvinyl pyrrolidone.

2. The diquafosol sodium eye drops according to claim 1, characterized in that: In the diquafosol sodium eye drops, the mass concentration of diquafosol sodium is 3%; The mass concentration of disodium oxalate tetraacetate is 0.005-0.01%; The mass concentration of the boric acid is 2-3%; The mass concentration of the polyvinyl pyrrolidone is 0.5-0.7%.

3. The diquafosol sodium eye drops according to claim 2, characterized in that: The pH value of the diquafosol sodium eye drops is 7.2-7.

8.

4. The diquafosol sodium eye drops according to claim 2, characterized in that: In the diquafosol sodium eye drops, the mass concentration of disodium oxalate tetraacetate is 0.005% to 0.01%; The mass concentration of the boric acid is 2% to 3%; The mass concentration of the polyvinyl pyrrolidone is 0.5% to 0.6%.

5. A method for preparing the diquafosol sodium eye drops according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1. At a temperature of 20°C to 60°C, add 25% to 35% of water for injection into a batching tank, then add anhydrous disodium hydrogen phosphate, sodium chloride, potassium chloride and a preservative into the batching tank in sequence, and stir until completely dissolved to obtain a first solution; S2, adding diquafosol sodium raw material to the first solution, stirring until completely dissolved, then adding injection water to the first solution to 90-98% of the total amount of the prepared solution, and continuing to stir and mix for 10-20 minutes to obtain a second solution; S3, adding a pH adjusting agent to the second solution to adjust the pH value of the second solution to within the range of 7.2 to 7.8, then adding water for injection to the second solution and weighing to the total amount of the prepared solution, stirring for 20 to 40 minutes, mixing evenly, and obtaining a third solution; S4, the third solution is first filtered through a 0.45um polyethersulfone filter for circulation, after filtering for 10 to 20 minutes, and then filtered through a 0.22um polyethersulfone filter for sterilization to obtain a batch of liquid medicine; S5. Filling the batch of liquid medicine into the low-density polyethylene medicinal eye drop bottle that has been processed in advance, and after the filling is completed, performing a light inspection to obtain the diquafosol sodium eye drops.

6. The method for preparing diquafosol sodium eye drops according to claim 5, characterized in that: In step S4, the filter membranes of the 0.45um polyethersulfone filter and the 0.22um polyethersulfone filter need to be checked before performing the circulation filtration and the sterilization filtration; In step S5, the filling volume of the diquafosol sodium eye drops is 5 mL / vial.

7. The method for preparing diquafosol sodium eye drops according to claim 5, characterized in that: The pH value of the diquafosol sodium eye drops is 7.5.

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