Emedastine fumarate eye drops and a method for preparing the same

Abstract

The application discloses a kind of emedastine fumarate eye drops and preparation method thereof, belong to ophthalmic drug technical field.The emedastine fumarate eye drops include the following concentration components: emedastine fumarate 0.3~1.0mg / mL, osmotic pressure regulator 12.0~25.0mg / mL, antibacterial agent 0.05~0.1mg / mL, thickening agent 2~6mg / mL, pH regulator is adjusted to 7.2~7.6 pH.The application improves thickening agent and osmotic pressure regulator, improves the retention time of emedastine fumarate on ocular surface, prevents being washed away by tear flow, hydroxypropyl methyl cellulose and sodium hyaluronate compound, form hydrogen bond-electrostatic double adhesion network, so that ocular surface retention time is significantly prolonged, mannitol can reduce the damage of NaCl to hydroxypropyl methyl cellulose viscosity, further prolong ocular surface retention time.Mannitol and glycerol can form hydrogen bond network to inhibit NaCl crystallization, the product still maintains clear and transparent at low temperature, and the nonionic property can neutralize the ionic strength of NaCl, reduce the salting-out effect of emedastine fumarate drug.

Description

Technical Field

[0001] This invention belongs to the field of ophthalmic drug technology, specifically relating to an emesitin fumarate eye drop and its preparation method. Background Technology

[0002] Emestin fumarate is a highly selective histamine H1 receptor antagonist. Clinically, it is used as eye drops to rapidly relieve symptoms such as itchy eyes and conjunctival congestion caused by allergic conjunctivitis. The original formulation, emestin, uses sodium chloride as an osmotic regulator and a small amount of hydroxypropyl methylcellulose for slight thickening, achieving only static isotonicity in the finished product, and is currently the mainstream clinical formulation. Due to the physiological structure of the eye, ordinary aqueous eye drops are easily diluted by the continuously circulating tear film after being instilled into the conjunctival sac and drained through the lacrimal puncta. The drug has a short adhesion time to the ocular surface, and the ocular surface bioavailability is only 1% to 5%. Multiple daily doses are required to maintain effective efficacy, resulting in poor patient compliance.

[0003] Current emesitin fumarate eye drops systems rely solely on sodium chloride for osmotic adjustment, focusing only on achieving the required osmotic pressure value for the finished product. They fail to construct a synergistic buffering system of electrolytes and polyols that matches healthy tears. After mixing and diluting the medication with tears, the osmotic pressure shift generally exceeds 10%. This significant deviation from the physiological range easily irritates the ocular surface, inducing reflexive excessive tearing and further accelerating medication loss. It also causes eye discomfort such as burning, dryness, and stinging. Long-term use can damage the corneal mucosa, limiting the potential for improving drug duration and user comfort. Conventional industry improvements often rely on adding polymeric thickeners to prolong retention, lacking technical solutions that synergistically improve tear compatibility and reduce washout through an osmotic pressure buffer matrix. Summary of the Invention

[0004] To address the problems existing in the prior art, the present invention provides an emesitin fumarate eye drop and its preparation method. By improving the thickener and osmotic pressure regulator, the retention time of emesitin fumarate on the ocular surface is increased, the efficacy is improved, and the stability of the product at low temperatures is also improved.

[0005] This invention is achieved through the following technical solution: In a first aspect, the present invention provides an emesitin fumarate eye drop, comprising the following components in mass concentrations: emesitin fumarate 0.3~1.0 mg / mL, osmotic pressure regulator 12.0~25.0 mg / mL, antibacterial agent 0.05~0.1 mg / mL, thickener 2~6 mg / mL, and pH adjuster adjusted to pH 7.2~7.6; The osmotic pressure regulator is a mixed solution of sodium chloride, mannitol, and glycerol; The thickeners are hydroxypropyl methylcellulose and sodium hyaluronate.

[0006] Furthermore, the pH adjuster is tromethamine, which adjusts the pH of emestin fumarate eye drops to 7.4-7.5.

[0007] Furthermore, the mass ratio of sodium chloride, mannitol, and glycerol is 5:1~2:0.5~1.

[0008] Furthermore, the mass ratio of hydroxypropyl methylcellulose to sodium hyaluronate is 1:0.01~0.1; the molecular weight of sodium hyaluronate is 1.5 million to 2.5 million Daltons.

[0009] Furthermore, the antibacterial agent is benzalkonium chloride or polyhexamethylene biguanide.

[0010] Furthermore, the solvent component of the emesitin fumarate eye drops is water for injection.

[0011] In a second aspect, the present invention provides a method for preparing the aforementioned emesitin fumarate eye drops, comprising the following steps: (1) At 50~80℃, add the thickener to part of the water for injection, stir and disperse evenly until dissolved, cool down to 20~25℃, add the osmotic pressure regulator and antibacterial agent and stir until completely dissolved, then add emestin fumarate and stir until completely dissolved; (2) Add pH adjuster to adjust pH to 7.2~7.6 to the system of step (1), and add the remaining water for injection to make up the volume; (3) Filling and sterilizing to obtain emestin fumarate eye drops.

[0012] Furthermore, in step (1), the water for injection is 1 / 3 to 2 / 3 of the total amount of water for injection; in step (2), the pH adjuster is an aqueous solution with a concentration of 0.5 wt%.

[0013] Furthermore, in step (1), vacuum degassing is activated during the operation.

[0014] Furthermore, the sterilization in step (3) is heat sterilization.

[0015] Hydroxypropyl methylcellulose (HMC) acts as a thickener, serving as a carrier and homogenizer, resulting in well-encapsulated active ingredients in the solution and a uniform distribution of their content. When instilled into the eye, HMC adheres to the corneal surface, mimicking the mucin layer of the natural tear film, reducing ocular surface friction and relieving dryness and stinging caused by insufficient tear secretion or excessive evaporation. However, while HMC alone increases viscosity and prolongs drug retention time, its bioadhesion is insufficient, leading to a relatively high rate of drug loss during blinking. Combining HMC with sodium hyaluronate forms a hydrogen-bonded-electrostatic dual adhesion network, significantly extending the ocular surface retention time.

[0016] Sodium chloride is used as an osmotic pressure regulator. A certain proportion of sodium chloride in an aqueous solution can mimic tear components to directly replenish the ocular surface moisture, achieving osmotic pressure balance and facilitating drug absorption. However, prolonged use of sodium chloride alone as an osmotic pressure regulator can disrupt the electrolyte balance of tears, leading to decreased tear film stability. Long-term use of sodium chloride solution can also damage the hydrogen bond network of the ocular surface mucus layer, causing mucin loss and exposing the corneal epithelium directly to external stimuli. Combining sodium chloride with mannitol and glycerol mimics the electrolyte composition of healthy tears, automatically adjusting the water molecule binding state according to changes in ocular surface osmotic pressure to maintain tear homeostasis. This results in smaller osmotic pressure fluctuations and significantly improved ocular surface comfort. The nonionic properties of mannitol and glycerol neutralize the ionic strength of NaCl, reducing the salting-out effect of emesthetine fumarate. Furthermore, mannitol can reduce the destructive effect of NaCl on the viscosity of hydroxypropyl methylcellulose, further prolonging the retention time on the ocular surface. Mannitol and glycerol can form a hydrogen bond network to inhibit NaCl crystallization, ensuring the product remains clear and transparent even at low temperatures.

[0017] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: (1) This invention improves the thickener and osmotic pressure regulator to increase the retention time of emesitin fumarate on the ocular surface and prevent it from being washed away by tears. Hydroxypropyl methylcellulose and sodium hyaluronate are combined to form a hydrogen bond-electrostatic double adhesion network, which significantly prolongs the retention time on the ocular surface. The nonionic properties of mannitol and glycerol can neutralize the ionic strength of NaCl, reduce the salting-out effect of emesitin fumarate, and mannitol can reduce the damage of NaCl to the viscosity of hydroxypropyl methylcellulose, further prolonging the retention time on the ocular surface.

[0018] (2) This invention uses sodium chloride, mannitol, and glycerol to simulate the electrolyte composition of healthy tears. It automatically adjusts the binding state of water molecules according to the changes in ocular surface osmotic pressure, maintains tear stability, has a small range of osmotic pressure fluctuations, and significantly improves ocular surface comfort. At the same time, mannitol and glycerol can form a hydrogen bond network to inhibit NaCl crystallization, and the product remains clear and transparent at low temperatures. Detailed Implementation

[0019] The present invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods not specifically described in the following examples are generally performed under conventional conditions or as recommended by the manufacturer.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. All reagents and materials used in this invention are readily available through conventional means, and unless otherwise specified, they shall be used in accordance with conventional methods in the art or as per the product instructions.

[0021] Example 1 The preparation method of emesitin fumarate eye drops in this embodiment is as follows: (1) At 65°C, add 5g of hydroxypropyl methylcellulose and sodium hyaluronate (150~250 million Daltons) in a mass ratio of 1:0.5 as thickeners to 650mL of water for injection, stir and disperse evenly until dissolved, cool to 20°C, add 18g of sodium chloride, mannitol and glycerol in a mass ratio of 5:1:0.8 as osmotic pressure regulators and 0.06g of benzalkonium chloride and stir until completely dissolved, then add 0.5g of emestin fumarate and stir until completely dissolved; vacuum is turned on to remove bubbles during the above operation. (2) Add 0.5 wt% tromethamine aqueous solution to the system in step (1) to adjust the pH to 7.4, and add water for injection to make up to 1000 mL; (3) Filling and heat-pressing sterilize to obtain emestin fumarate eye drops.

[0022] Example 2 (1) At 65°C, add 5g of hydroxypropyl methylcellulose and sodium hyaluronate (150~250 million Daltons) in a mass ratio of 1:0.1 as thickeners to 650mL of water for injection, stir and disperse evenly until dissolved, cool to 20°C, add 18g of sodium chloride, mannitol and glycerol in a mass ratio of 5:1:1 as osmotic pressure regulators and 0.08g of polyhexamethylene biguanide and stir until completely dissolved, then add 0.5g of emestin fumarate and stir until completely dissolved; vacuum is turned on to remove bubbles during the above operation. (2) Add 0.5 wt% tromethamine aqueous solution to the system in step (1) to adjust the pH to 7.4, and add water for injection to make up to 1000 mL; (3) Filling and heat-pressing sterilize to obtain emestin fumarate eye drops.

[0023] Example 3 (1) At 65°C, 5g of hydroxypropyl methylcellulose and sodium hyaluronate (150-250 million Daltons) in a mass ratio of 1:0.8 were added as thickeners to 650mL of water for injection. The mixture was stirred and dispersed until dissolved. The temperature was lowered to 20°C. 18g of sodium chloride in a mass ratio of 5:1.5:0.5, mannitol and glycerol were added as osmotic pressure regulators, and 0.06g of benzalkonium chloride was added and stirred until completely dissolved. Then, 0.5g of emestin fumarate was added and stirred until completely dissolved. Vacuum was turned on to remove bubbles during the above operation. (2) Add 0.5 wt% tromethamine aqueous solution to the system in step (1) to adjust the pH to 7.4, and add water for injection to make up to 1000 mL; (3) Filling and heat-pressing sterilize to obtain emestin fumarate eye drops.

[0024] Comparative Example 1 Compared with Example 1, the thickener component of Comparative Example 1 is only hydroxypropyl methylcellulose (the amount of hydroxypropyl methylcellulose added is the sum of hydroxypropyl methylcellulose and sodium hyaluronate in Example 1), and the other raw materials and preparation methods are the same as in Example 1.

[0025] Comparative Example 2 Compared with Example 1, the osmotic pressure regulator in Comparative Example 2 consists only of sodium chloride (the amount of sodium chloride added is the sum of sodium chloride, mannitol and glycerol in Example 1), and the other raw materials and preparation methods are the same as in Example 1.

[0026] Comparative Example 3 Compared with Example 1, the osmotic pressure regulator in Comparative Example 2 is a mixture of sodium chloride and mannitol in a mass ratio of 5:1 (the amount of sodium chloride and mannitol added is the sum of sodium chloride, mannitol and glycerol in Example 1), and the other raw materials and preparation methods are the same as in Example 1. Comparative Example 4 Compared with Example 1, the osmotic pressure regulator in Comparative Example 2 is only a mixture of sodium chloride and glycerol in a mass ratio of 5:0.8 (the amount of sodium chloride and glycerol added is the sum of sodium chloride, mannitol and glycerol in Example 1), and the other raw materials and preparation methods are the same as in Example 1.

[0027] Performance testing 1. Stability Testing The emesitin fumarate eye drops prepared in the embodiments and comparative examples of this invention were subjected to storage stability tests (1 year) at a temperature of 40±2℃ and a humidity of 25±5%. The results are shown in Table 1 below: Table 1. Stability test results of emesitin fumarate eye drops at 40±2℃ (1 year) The emesitin fumarate eye drops prepared in the embodiments and comparative examples of the present invention were subjected to storage stability tests (1 year) at a temperature of 5±2℃ and a humidity of 25±5%. The results are shown in Table 1 below: As shown in Tables 1 and 2, the emesitin fumarate eye drops prepared by the method of this invention maintain a relatively stable state at both low and relatively high temperatures. The absence of mannitol and / or glycerol in the osmotic pressure regulator would compromise this stability, especially at low temperatures. This may be because mannitol and glycerol can form a hydrogen bond network to inhibit NaCl crystallization, and their nonionic properties can neutralize the ionic strength of NaCl, reducing the salting-out effect of emesitin fumarate. The product remains clear and transparent even at low temperatures. 2. Ocular surface retention time test Sodium fluorescein was added as a chromogenic material (0.1% sodium fluorescein content) to the emesthetine fumarate eye drops prepared in Examples 1-3 and Comparative Examples 1-4. 100 μL of emesthetine fumarate eye drops containing sodium fluorescein was instilled into the left eye of rabbits, and an equal volume of pH 7.4 buffer solution was instilled into the right eye. After administration, the rabbits' eyes were passively closed for 30 seconds, and the fluorescence decay time on the ocular surface was observed using a slit lamp. The results are shown in Table 3. Table 3. Fluorescence fading time of emestin fumarate eye drops on the ocular surface As shown in Table 3, this invention improves the ocular surface retention time of emestin fumarate by using thickeners and osmotic pressure regulators, preventing it from being washed away by tears. The combination of hydroxypropyl methylcellulose and sodium hyaluronate forms a hydrogen bond-electrostatic dual adhesion network, which significantly prolongs the ocular surface retention time. Mannitol can reduce the damage of NaCl to the viscosity of hydroxypropyl methylcellulose, further prolonging the ocular surface retention time.

[0028] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention are included within the protection scope of the present invention.

Claims

1. An eye drop containing emesitin fumarate, characterized in that, It includes the following components in the following mass concentrations: emesitin fumarate 0.3~1.0 mg / mL, osmotic pressure regulator 12.0~25.0 mg / mL, antibacterial agent 0.05~0.1 mg / mL, thickener 2~6 mg / mL, and pH adjuster to adjust the pH to 7.2~7.6; The osmotic pressure regulator is a mixed solution of sodium chloride, mannitol, and glycerol; The thickeners are hydroxypropyl methylcellulose and sodium hyaluronate.

2. The emesitin fumarate eye drops according to claim 1, characterized in that, The pH adjuster is tromethamine, which adjusts the pH of emestin fumarate eye drops to 7.4-7.

5.

3. The emesitin fumarate eye drops according to claim 1, characterized in that, The mass ratio of sodium chloride, mannitol, and glycerol is 5:1~2:0.5~1.

4. The emesitin fumarate eye drops according to claim 1, characterized in that, The mass ratio of hydroxypropyl methylcellulose to sodium hyaluronate is 1:0.01~0.1; the molecular weight of sodium hyaluronate is 1.5 million to 2.5 million Daltons.

5. The emesitin fumarate eye drops according to claim 1, characterized in that, The antibacterial agent is benzalkonium chloride or polyhexamethylene biguanide.

6. The emesitin fumarate eye drops according to claim 1, characterized in that, The solvent component of the emesitin fumarate eye drops is water for injection.

7. A method for preparing emesine fumarate eye drops according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) At 50~80℃, add the thickener to part of the water for injection, stir and disperse evenly until dissolved, cool down to 20~25℃, add the osmotic pressure regulator and antibacterial agent and stir until completely dissolved, then add emestin fumarate and stir until completely dissolved; (2) Add pH adjuster to adjust pH to 7.2~7.6 to the system of step (1), and add the remaining water for injection to make up the volume; (3) Filling and sterilizing to obtain emestin fumarate eye drops.

8. The method for preparing emesine fumarate eye drops according to claim 7, characterized in that, In step (1), the water for injection is 1 / 3 to 2 / 3 of the total amount of water for injection; in step (2), the pH adjuster is an aqueous solution with a concentration of 0.5 wt%.

9. The method for preparing emesine fumarate eye drops according to claim 7, characterized in that, Step (1) During the operation, the vacuum is turned on to remove air bubbles.

10. The method for preparing emesine fumarate eye drops according to claim 7, characterized in that, The sterilization in step (3) is heat sterilization.

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