Atropine sulfate eye drops and preparation method thereof

Abstract

The invention relates to the technical field of eye medicine, and particularly discloses atropine sulfate eye drops and a preparation method thereof. The atropine sulfate eye drops comprise the following raw materials in percentage: 0.01-2% of atropine sulfate, 0.5-3% of an osmotic pressure regulator, a pH buffer agent, 3-5% of edetate disodium, 1-3% of sodium hyaluronate and the balance of pure water, the pH buffer agent is used for adjusting the pH value of the eye drops to 5.0-7.6; according to the eye drops, the molecular structure of atropine sulfate can be kept stable by adjusting the pH value of the eye drops to be 5.0-7.6, meanwhile, edetate disodium is adopted for reducing catalytic degradation of metal ions, and the stability of atropine sulfate is further improved; the sodium hyaluronate can form a three-dimensional network with mucoprotein in tears, the viscosity of the eye drops is increased, the residence time of the eye drops in eyes is prolonged, and the availability of medicine components of the eye drops is improved.

Description

Technical Field

[0001] The present application relates to the technical field of ocular medication, and in particular to atropine sulfate eye drops and a preparation method thereof. Background Art

[0002] In the pharmaceutical field, the research, development, and production of ophthalmic medications have always been a key research area. With changing lifestyles, such as prolonged use of electronic devices, the incidence of eye diseases has gradually increased, and the demand for ophthalmic medications has also grown. Ophthalmic medications play a vital role in treating various eye diseases, alleviating eye discomfort symptoms, and protecting eye health. Effective drug treatments for common eye conditions, such as myopia and astigmatism, can improve patients' vision and enhance their quality of life.

[0003] Atropine is an alkaloid M receptor antagonist with peripheral and central M receptor antagonist effects. Atropine sulfate has been used in the field of ophthalmology for more than a hundred years. Traditionally, it is mainly used for fundus examination and mydriasis before cataract surgery, and for the treatment of iridocyclitis and iridocyclitis.

[0004] However, atropine's chemical structure is relatively unstable, the ester bonds in the structural molecules are easily hydrolyzed, and conventional eye drops have a short mydriatic effect, lasting only 6-8 hours. Therefore, it needs to be administered twice a day for myopia prevention and control. Summary of the Invention

[0005] In order to improve the stability and medication effect of existing atropine sulfate eye drops, the present application provides an atropine sulfate eye drops and a preparation method thereof.

[0006] In the first aspect, the present application provides an atropine sulfate eye drop, which adopts the following technical solution: Atropine sulfate eye drops comprise the following raw materials in the following percentages: 0.01-2% atropine sulfate, 0.5-3% osmotic pressure regulator, 3-5% pH buffering agent, 1-3% sodium hyaluronate, and the balance being pure water; the pH buffering agent is used to adjust the pH value of the eye drops to 5.0-7.6.

[0007] By adopting the above technical solution, the pH of the eye drops is adjusted within the range of 5.0-7.6, which can maintain the stability of the molecular structure of atropine sulfate. At the same time, the concentration range of atropine sulfate of 0.01-2% can meet the low-concentration requirements for myopia prevention and control and the high-concentration needs for therapeutic mydriasis. Disodium edetate reduces the catalytic degradation of metal ions, further improving the stability of atropine sulfate. Sodium hyaluronate can form a three-dimensional network with mucin in tears, while increasing the viscosity of the eye drops, prolonging the retention time of the eye drops in the eye, and improving the utilization of the drug ingredients in the eye drops. At the same time, sodium hyaluronate can compensate for the effects of atropine sulfate on glandular secretion, reduce dry eyes, adapt to the physiological needs of the ocular surface, and improve the comfort of medication.

[0008] Preferably, the pH buffering agents are citric acid and sodium citrate.

[0009] Preferably, the sodium hyaluronate is cross-linked and modified in advance using mercaptopolyethylene glycol and divinyl sulfone.

[0010] By adopting the above technical solution, mercaptopolyethylene glycol grafts thiol groups onto sodium hyaluronate. At body temperature, the thiol groups in sodium hyaluronate react with double bonds on the surface of ocular tissue, thereby immobilizing the sodium hyaluronate. This further prolongs the residence time of atropine sulfate eye drops in the eyeball and reduces the number of times patients need to apply the eye drops. Furthermore, mercaptopolyethylene glycol improves the biocompatibility of atropine sulfate and reduces eye irritation.

[0011] Divinyl sulfone can form a uniform cross-linking network with sodium hyaluronate and mercaptopolyethylene glycol, thereby increasing the viscosity of the eye drops, thereby delaying the residence time of the eye drops in the eyeball and improving the medication effect of the eye drops.

[0012] Preferably, the cross-linking modification method of sodium hyaluronate comprises the following specific steps: mixing sodium hyaluronate, divinyl sulfone and water to form a sodium hyaluronate mixed solution, adjusting the pH of the sodium hyaluronate mixed solution to neutral or weakly acidic, and then adding mercapto polyethylene glycol and heating the mixture to obtain cross-linked modified sodium hyaluronate.

[0013] Preferably, the heating temperature is 40-50°C.

[0014] Preferably, the mass ratio of the mercaptopolyethylene glycol, divinyl sulfone and sodium hyaluronate is (1-3): (5-8):10.

[0015] Preferably, the osmotic pressure regulator is at least one of sodium chloride, boric acid, borax, and glucose.

[0016] In the second aspect, the present application provides a method for preparing atropine sulfate eye drops, adopting the following technical solution: a method for preparing atropine sulfate eye drops, comprising the following specific steps: mixing sulfuric acid, an osmotic pressure regulator, disodium edetate, sodium hyaluronate, and pure water, adding a pH buffer to adjust the pH, filtering, and filling to obtain atropine sulfate eye drops.

[0017] By adopting the above technical solution, the structural molecules of atropine sulfate are kept in a stable pH environment, the viscosity of the eye drops is increased, the retention time of the eye drops in the eyes is prolonged, and the number of times the patient applies eye drops is reduced.

[0018] In summary, this application has the following beneficial effects: 1. Since the pH of the eye drops is adjusted within the range of 5.0-7.6, the molecular structure of atropine sulfate can be kept stable. Disodium edetate is used to reduce the catalytic degradation of metal ions, further improving the stability of atropine sulfate. Sodium hyaluronate can form a three-dimensional network with mucin in tears, while increasing the viscosity of the eye drops, prolonging the retention time of the eye drops in the eye, improving the utilization of the eye drops' drug components, and reducing the number of times the patient needs to apply the eye drops.

[0019] 2. In this application, mercaptopolyethylene glycol and divinyl sulfone are used to crosslink and modify sodium hyaluronate. The thiol group of mercaptopolyethylene glycol is grafted onto sodium hyaluronate to enable sodium hyaluronate to be fixed on the surface of the eye tissue. DETAILED DESCRIPTION

[0020] The present application is further described in detail below with reference to the embodiments.

[0021] All raw materials in the examples are commercially available. Example

[0022] Example 1 This embodiment provides an atropine sulfate eye drop comprising the following raw materials in percentage by weight: 1.5% atropine sulfate, 1.7% osmotic pressure regulator, 4% disodium edetate, 2% sodium hyaluronate, a pH buffer to adjust the pH of the eye drop, and the balance being pure water. The pH buffer is citric acid and sodium citrate, and the osmotic pressure regulator is sodium chloride.

[0023] The preparation method of atropine sulfate eye drops comprises the following specific steps: mixing sulfuric acid, an osmotic pressure regulator, disodium edetate, sodium hyaluronate and pure water, adding a pH buffer to adjust the pH value to 5, filtering and then filling to prepare the atropine sulfate eye drops.

[0024] Example 2 The difference between Example 2 and Example 1 is that the atropine sulfate eye drops include the following raw materials in weight percentage: 0.01% atropine sulfate, 0.5% osmotic pressure regulator, 3% disodium edetate, 3% sodium hyaluronate, a pH buffer for adjusting the pH value of the eye drops, and the balance is pure water.

[0025] Example 3 The difference between Example 3 and Example 1 is that the atropine sulfate eye drops include the following raw materials in percentage by weight: 2% atropine sulfate, 3% osmotic pressure regulator, 5% disodium edetate, 1% sodium hyaluronate, a pH buffer for adjusting the pH value of the eye drops, and the balance is pure water.

[0026] Example 4 The difference between Example 4 and Example 1 is that the preparation method of atropine sulfate eye drops includes the following specific steps: mixing sulfuric acid, an osmotic pressure regulator, disodium edetate, sodium hyaluronate, and pure water, adding a pH buffer to adjust the pH to 7.6, filtering, and filling to obtain atropine sulfate eye drops.

[0027] Example 5 The difference between Example 5 and Example 1 is that the sodium hyaluronate is pre-crosslinked and modified using mercaptopolyethylene glycol and divinyl sulfone in the raw materials of atropine sulfate eye drops. The mercaptopolyethylene glycol is purchased from Ruixi Biotechnology R-1502-2k.

[0028] The preparation method of atropine sulfate eye drops comprises the following specific steps: S1: Sodium hyaluronate, divinyl sulfone and water are mixed, and the mass ratio of the total amount of sodium hyaluronate and divinyl sulfone to water is 1:10. The mixture is reacted for 15 minutes to form a sodium hyaluronate mixture. Citric acid and sodium citrate are then used to adjust the pH of the sodium hyaluronate mixture to 5. Mercapto polyethylene glycol is then added and heated to 40°C for 20 hours. The mass ratio of mercapto polyethylene glycol, divinyl sulfone and sodium hyaluronate is 2:7:10 to obtain cross-linked modified sodium hyaluronate.

[0029] S2: Sulfuric acid, an osmotic pressure regulator, disodium edetate, cross-linked modified sodium hyaluronate and pure water are mixed, a pH buffer is added to adjust the pH value to 5, and the mixture is filtered and bottled to prepare atropine sulfate eye drops.

[0030] Example 6 The difference between Example 6 and Example 5 is that the preparation method of atropine sulfate eye drops comprises the following specific steps: S1: Sodium hyaluronate, divinyl sulfone and water are mixed, and the mass ratio of the total amount of sodium hyaluronate and divinyl sulfone to water is 1:10. The mixture is reacted for 15 minutes to form a sodium hyaluronate mixture. Citric acid and sodium citrate are then used to adjust the pH of the sodium hyaluronate mixture to 5. Mercapto polyethylene glycol is then added and heated to 40°C for 20 hours. The mass ratio of mercapto polyethylene glycol, divinyl sulfone and sodium hyaluronate is 1:8:10 to obtain cross-linked modified sodium hyaluronate.

[0031] S2: Sulfuric acid, an osmotic pressure regulator, disodium edetate, cross-linked modified sodium hyaluronate and pure water are mixed, a pH buffer is added to adjust the pH value to 5, and the mixture is filtered and bottled to prepare atropine sulfate eye drops.

[0032] Example 7 The difference between Example 7 and Example 5 is that the preparation method of atropine sulfate eye drops comprises the following specific steps: S1: Sodium hyaluronate, divinyl sulfone and water are mixed, and the mass ratio of the total amount of sodium hyaluronate and divinyl sulfone to water is 1:10. The mixture is reacted for 15 minutes to form a sodium hyaluronate mixture. Citric acid and sodium citrate are then used to adjust the pH of the sodium hyaluronate mixture to 5. Mercapto polyethylene glycol is then added and heated to 40°C for 20 hours. The mass ratio of mercapto polyethylene glycol, divinyl sulfone and sodium hyaluronate is 3:5:10 to obtain cross-linked modified sodium hyaluronate.

[0033] S2: Sulfuric acid, an osmotic pressure regulator, disodium edetate, cross-linked modified sodium hyaluronate and pure water are mixed, a pH buffer is added to adjust the pH value to 5, and the mixture is filtered and bottled to prepare atropine sulfate eye drops.

[0034] Example 8 The difference between Example 8 and Example 5 is that the preparation method of atropine sulfate eye drops comprises the following specific steps: S1: Sodium hyaluronate, divinyl sulfone and water are mixed, and the mass ratio of the total amount of sodium hyaluronate and divinyl sulfone to water is 1:10. The mixture is reacted for 15 minutes to form a sodium hyaluronate mixture. Citric acid and sodium citrate are then used to adjust the pH of the sodium hyaluronate mixture to 5. Mercapto polyethylene glycol is then added and heated to 50°C for 20 hours. The mass ratio of mercapto polyethylene glycol, divinyl sulfone and sodium hyaluronate is 1:8:10 to obtain cross-linked modified sodium hyaluronate.

[0035] S2: Sulfuric acid, an osmotic pressure regulator, disodium edetate, cross-linked modified sodium hyaluronate and pure water are mixed, a pH buffer is added to adjust the pH value to 5, and the mixture is filtered and bottled to prepare atropine sulfate eye drops.

[0036] Example 9 The difference between Example 9 and Example 5 is that the preparation method of atropine sulfate eye drops comprises the following specific steps: S1: Sodium hyaluronate, mercapto polyethylene glycol and water are mixed, and the mass ratio of the total amount of sodium hyaluronate and mercapto polyethylene glycol to water is 1:10. The mixture is heated to 50° C. and reacted for 20 hours. The mass ratio of mercapto polyethylene glycol to sodium hyaluronate is 1:10 to obtain cross-linked modified sodium hyaluronate.

[0037] S2: Sulfuric acid, an osmotic pressure regulator, disodium edetate, cross-linked modified sodium hyaluronate and pure water are mixed, a pH buffer is added to adjust the pH value to 5, and the mixture is filtered and bottled to prepare atropine sulfate eye drops.

[0038] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that sodium hyaluronate is not used in the raw materials of atropine sulfate eye drops.

[0039] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that disodium edetate is not used in the raw materials of atropine sulfate eye drops.

[0040] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the preparation method of atropine sulfate eye drops comprises the following specific steps: mixing sulfuric acid, an osmotic pressure regulator, disodium edetate, sodium hyaluronate, and pure water, adding a pH buffer to adjust the pH value to 8, filtering, and filling to obtain atropine sulfate eye drops.

[0041] Performance testing The following performance tests were performed on the atropine sulfate eye drops provided in Examples 1-9 and Comparative Examples 1-3 of the present application. The specific test results are shown in Table 1.

[0042] Detection method 1. Stability The atropine sulfate eye drops prepared in the present application were subjected to content tracking detection by high performance liquid chromatography, with an injection volume of 20 μL; the detection wavelength was 225 nm, and the samples were injected at different times under room temperature. The chromatograms were recorded to detect the total impurity content of the atropine sulfate eye drops after 15 and 30 days.

[0043] 2. Viscosity test The viscosity of the atropine sulfate eye drops prepared in this application was tested using a rotational viscometer.

[0044] Table 1: Performance test results data table The performance test results show that the atropine sulfate eye drops prepared in the present application have good stability and low impurity content, while also being able to maintain a high viscosity, which can prolong the retention time of the eye drops in the eyes, improve the utilization of the drug components of the eye drops, and reduce the number of times patients use the drug.

[0045] Comparison of Comparative Example 1 with Example 1 shows that, in Comparative Example 1, sodium hyaluronate is not used. Performance test results show that the stability and drug utilization of the prepared atropine sulfate eye drops are significantly reduced. This further demonstrates that sodium hyaluronate forms a three-dimensional network with mucin in tears, increasing the viscosity of the eye drops. This dual approach prolongs the retention time of the eye drops in the eye and improves the utilization of the drug components of the eye drops. At the same time, sodium hyaluronate can compensate for the effects of atropine sulfate on glandular secretion, reduce dry eye symptoms, and improve medication comfort.

[0046] The difference between Comparative Example 2 and Example 1 is that edetate disodium is not used in the raw materials of the atropine sulfate eye drops prepared in Comparative Example 2. As shown in the performance test results, the stability of the prepared atropine sulfate eye drops is reduced. This further demonstrates that edetate disodium can reduce the catalytic degradation of metal ions and further improve the stability of atropine sulfate.

[0047] The difference between Comparative Example 3 and Example 1 is that the pH of the atropine sulfate eye drops prepared in Comparative Example 3 is weakly alkaline. From the performance test results, it can be seen that the stability of the prepared atropine sulfate eye drops is significantly reduced, further indicating that adjusting the pH of the eye drops within the range of 5.0-7.6 is beneficial to maintaining the stability of the molecular structure of atropine sulfate.

[0048] As can be seen from Examples 5-8, the cross-linking modification of sodium hyaluronate using mercaptopolyethylene glycol and divinyl sulfone in advance increases the viscosity and stability of the eye drops, prolongs the residence time of atropine sulfate eye drops in the eyeball, and reduces the number of times the patient needs to apply eye drops. As can be seen from Example 9, the absence of divinyl sulfone in Example 9 reduces the viscosity-increasing effect of the eye drops, further demonstrating that the synergistic effect of divinyl sulfone, sodium hyaluronate, and mercaptopolyethylene glycol can form a uniform cross-linked network, increase the viscosity of the eye drops, and thus delay the residence time of the eye drops in the eyeball.

[0049] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. Atropine sulfate eye drops, characterized in that: The eye drops include the following raw materials in the following percentages: 0.01-2% atropine sulfate, 0.5-3% osmotic pressure regulator, 3-5% disodium edetate, 1-3% sodium hyaluronate, and the balance is pure water; the pH buffer is used to adjust the pH value of the eye drops to 5.0-7.

6.

2. Atropine sulfate eye drops according to claim 1, characterized in that, The pH buffers are citric acid and sodium citrate.

3. Atropine sulfate eye drops according to claim 1, characterized in that, The sodium hyaluronate is cross-linked and modified in advance using mercapto polyethylene glycol and divinyl sulfone.

4. Atropine sulfate eye drops according to claim 3, characterized in that, The cross-linking modification method of sodium hyaluronate comprises the following specific steps: mixing sodium hyaluronate, divinyl sulfone and water to form a sodium hyaluronate mixed solution, adjusting the pH of the sodium hyaluronate mixed solution to neutral or weakly acidic, and then adding mercapto polyethylene glycol and heating the solution to react to obtain cross-linked modified sodium hyaluronate.

5. Atropine sulfate eye drops according to claim 4, characterized in that, The heating temperature is 40-50°C.

6. Atropine sulfate eye drops according to claim 4, characterized in that, The mass ratio of the mercapto polyethylene glycol, divinyl sulfone and sodium hyaluronate is (1-3): (5-8):

10.

7. Atropine sulfate eye drops according to claim 1, characterized in that, The osmotic pressure regulator is at least one of sodium chloride, boric acid, borax and glucose.

8. A method for preparing the atropine sulfate eye drops according to any one of claims 1 to 7, characterized in that: The method comprises the following specific steps: mixing sulfuric acid, an osmotic pressure regulator, disodium edetate, sodium hyaluronate and pure water, adding a pH buffer to adjust the pH, filtering and then filling to prepare atropine sulfate eye drops.

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