Eye drops containing polyvinyl alcohol and preparation method thereof

Abstract

The invention discloses eye drops containing polyvinyl alcohol and a preparation method of the eye drops. The eye drops are prepared from the following components in percentage by mass: 1.2 to 1.6 percent of polyvinyl alcohol, 0.3 to 0.8 percent of a thickening agent, 0.3 to 0.8 percent of a surfactant, 0.1 to 0.6 percent of a dispersing agent, 1.0 to 5.0 percent of a cosolvent and the balance of water for injection. The preparation method comprises the following steps: premixing the polyvinyl alcohol and the cosolvent; mixing the dispersing agent with 40-60% of water for injection, and then adding the surfactant; mixing the thickening agent with 20-30% of water for injection; and combining the mixtures in sequence, finally adding an isotonic agent to adjust the pH and osmotic pressure, supplementing the balance of water for injection, and carrying out multi-stage sterilization and filtration to obtain a finished product. The preparation can be completed at the temperature of 30-59 DEG C without a high-temperature condition, the dissolving time is less than 60 minutes, and the product is good in stability, free of eye irritation and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, and in particular to an eye drop containing polyvinyl alcohol and a preparation method thereof. Background Art

[0002] Dry eye is a common ophthalmic disease, also known as keratoconjunctivitis sicca syndrome, which is characterized by the loss of tear film homeostasis and accompanied by ocular surface symptoms. According to the pathogenesis, dry eye can be divided into aqueous deficiency type, lipid abnormality type, mucin abnormality type, tear dynamics abnormality type and mixed dry eye.

[0003] Polyvinyl alcohol (PVA) is a high molecular polymer with good biocompatibility. At appropriate concentrations, polyvinyl alcohol can play a role similar to artificial tears and can be used to prevent or treat irritation symptoms such as dry eyes, foreign body sensation, eye fatigue, and improve dry eye symptoms. Its mechanism of action is mainly reflected in two aspects: on the one hand, the moisturizing and hydrating effect of polyvinyl alcohol can relieve water-deficient dry eyes caused by abnormal tear secretion; on the other hand, due to its hydrophilicity and film-forming properties, polyvinyl alcohol can be distributed on the surface of the tear film and maintain the stability of the oil on the surface of the tear film, thereby reducing the volatilization of tears. It is suitable for patients with lipid-abnormal dry eyes whose tear evaporation increases due to abnormal lipid layer.

[0004] Polyvinyl alcohol is a white to slightly yellow powder or translucent granules. It dissolves in hot water and is almost insoluble in ethanol or acetone. Factors such as alcoholysis degree, polymerization degree, and temperature have a significant effect on its solubility in water. The alcoholysis degree refers to the degree to which the acetate group in polyvinyl acetate is replaced by hydroxyl groups. The side groups of the completely alcoholyzed polyvinyl alcohol molecule only have hydroxyl groups, while the side groups of the partially alcoholyzed polyvinyl alcohol molecule have both hydroxyl groups and acetate groups. The effect of alcoholysis degree on the solubility of polyvinyl alcohol is mainly reflected in the changes in its molecular structure and intermolecular interactions. Within a certain range, the increase in alcoholysis degree will increase the water solubility of polyvinyl alcohol. The higher the alcoholysis degree, the higher the hydroxyl content in the polyvinyl alcohol molecule, the higher the hydrophilicity, and the higher the solubility in water. However, as the hydroxyl content increases, polyvinyl alcohol with a high alcoholysis degree may also reduce the dissolution rate due to the enhanced intermolecular forces. The degree of polymerization of polyvinyl alcohol is directly related to the molecular weight. Polyvinyl alcohol with a lower molecular weight has better water solubility, while polyvinyl alcohol with a high molecular weight has relatively poor solubility due to its long molecular chain and strong intermolecular forces. Polyvinyl alcohol has good solubility in hot water and complete dissolution usually requires 90 ～ Heat in 95℃ water for 30 ～ 60min, however, in the industrial production process, too high preparation temperature and too long reaction time may affect the stability of polyvinyl alcohol and even change its properties, which is not conducive to product quality control.

[0005] The preparation methods of polyvinyl alcohol eye drops in the prior art mainly include the following:

[0006] Chinese patent CN118453507A discloses a polyvinyl alcohol eye drop and its preparation method. The method is carried out under high temperature conditions of 92-95°C, and the specific steps include: adding the prescribed amount of sodium chloride and povidone K30 to 90%-95% of the total volume of water for injection, stirring and dissolving, adding the prescribed amount of polyvinyl alcohol, replenishing the amount of water, adjusting the pH value, and filtering through a multi-stage polyvinylidene fluoride filter element to obtain the finished product. This method has the disadvantages of inconvenient operation and high production cost.

[0007] Chinese patent CN106692048A discloses a single-dose eye drop containing polyvinyl alcohol and a preparation method thereof. The method needs to be carried out at a high temperature of 80-90°C, with polyvinyl alcohol as the main active ingredient, and isotonic agents and viscosity enhancers are added to improve osmotic pressure, viscosity and stability.

[0008] Chinese patent CN118490631A discloses a polyvinyl alcohol eye drop and its production process. The method controls the temperature of the injection water at 60-85°C and stirs and mixes it, and at the same time, thickeners, isotonicity regulators, and pH regulators are added to the injection water at 45-50°C, and the two solutions are mixed and filtered and filled.

[0009] Chinese patent CN104983786A discloses a method for preparing a polyvinyl alcohol composition. Although the method avoids the heating process, the main technical problem to be solved is that polyvinyl alcohol eye drops need to be used once after opening, and polyvinyl pyrrolidone is easy to agglomerate in the production process, which increases the blending time and labor cost. The technical solution adopted is: the formula uses polyvinyl alcohol, polyvinyl pyrrolidone, xanthan gum and non-ionic surfactant to solve the problem of polyvinyl pyrrolidone agglomeration. From a technical point of view, the above raw materials are directly mixed in water, and there is no need to dissolve polyvinyl pyrrolidone separately, which reduces agglomeration. At the same time, ultrasonic technology is used for dissolution.

[0010] In addition, the polyvinyl alcohol eye drops currently on the market (including the reference preparation of Allergan Company in the UK) ) During long-term storage, there are stability problems such as pH value decrease and osmotic pressure increase. This quality change is more obvious under high temperature conditions. This further shows that temperature is an important factor affecting the stability of polyvinyl alcohol eye drops, and it needs to be strictly controlled during production and storage.

[0011] In summary, the existing polyvinyl alcohol eye drops preparation methods generally have technical problems such as requiring high temperature or special equipment, low production efficiency, poor product stability, etc. Therefore, it is urgent to develop a new formula of polyvinyl alcohol eye drops that does not require high temperature or ultrasonic conditions, has a simple preparation process, and has good product stability, and a preparation method thereof. Summary of the invention

[0012] In order to solve the above technical problems, the purpose of the present invention is to provide a formula of polyvinyl alcohol eye drops that does not require high temperature conditions, has a simple preparation process, and has good product stability, and a preparation method thereof, which can effectively prevent polyvinyl alcohol from dissolving in hot water above 60°C, and at the same time, the dissolution time of polyvinyl alcohol is less than 60 minutes. The production efficiency is high, the cost is low, the process is simple, and it is conducive to large-scale industrial production.

[0013] The solution of the present invention to solve the above technical problems is as follows:

[0014] A method for preparing eye drops containing polyvinyl alcohol, comprising the following components in percentage by mass: 1.2-1.6% polyvinyl alcohol, 0.3-0.8% thickener, 0.3-0.8% surfactant, 0.1-0.6% dispersant, 1.0-5.0% cosolvent, and the remainder is water for injection;

[0015] The preparation method comprises the following steps:

[0016] Step (1) premixing polyvinyl alcohol and a cosolvent to form a mixture 1;

[0017] Step (2) mixing and dissolving the dispersant with 40-60% of the total volume of the injection water, and then adding a surfactant to form a mixed solution 2;

[0018] Step (3) mixing and dissolving the thickener with 20-30% of the total volume of the injection water to form a mixed solution 3;

[0019] Step (4) slowly adding the mixture 1 of step (1) into the mixed solution 2 of step 2 while stirring, and continuing to stir until completely dissolved to obtain a mixed solution 4;

[0020] Step (5) adding the mixed solution 3 of step (3) to the mixed solution 4 of step (4);

[0021] Step (6) after adding an isotonic agent to adjust the pH and osmotic pressure, adding the remaining amount of water for injection to prepare the total volume, to obtain an eye drop intermediate containing polyvinyl alcohol;

[0022] Step (7) performing multi-stage sterilization filtration on the polyvinyl alcohol-containing eye drops intermediate in step (6) to obtain eye drops containing polyvinyl alcohol drops;

[0023] The preparation temperature of steps (1) to (6) is 30-59° C., and the time from steps (1) to (6) to obtain a completely dissolved eye drop intermediate containing polyvinyl alcohol is less than 60 minutes.

[0024] Furthermore, the polyvinyl alcohol-containing eye drops include the following components in percentage by mass: polyvinyl alcohol 1.3-1.5%, thickener 0.4-0.6%, surfactant 0.4-0.6%, dispersant 0.2-0.4%, cosolvent 2.0-4.0%, and the balance is water for injection. The preferred formula of the polyvinyl alcohol-containing eye drops is further defined.

[0025] Furthermore, the average molecular weight of the polyvinyl alcohol is 50,000 to 140,000 Da, and the alcoholysis degree is 87 to 92%.

[0026] Furthermore, the co-solvent is a mixture of glycerol and propylene glycol in any proportion.

[0027] In the above scheme, the average molecular weight of the polyvinyl alcohol is 50,000-140,000Da, and the degree of alcoholysis is 87-92%. The molecular weight and degree of alcoholysis of polyvinyl alcohol have a significant effect on the solubility, viscosity, film-forming property and biocompatibility in eye drops. Polyvinyl alcohol with a lower molecular weight is insufficient in film-forming property and stability, while polyvinyl alcohol with a higher molecular weight has poor solubility and is difficult to prepare into uniform eye drops. Polyvinyl alcohol with an alcoholysis degree of less than 50% is insoluble in water, while fully alcoholyzed polyvinyl alcohol has poor water solubility, and the viscosity of the solution gradually increases over time, and eventually becomes a gel, which may cause changes in the product properties and is not suitable for the preparation of eye drops. The average molecular weight and degree of alcoholysis within the above range can ensure that polyvinyl alcohol has good solubility, is easy to prepare into eye drops, and can form a uniform and stable lubricating film in ocular applications, thereby protecting the eyes and improving eye comfort.

[0028] In the above scheme, the cosolvent is a mixture of glycerol and propylene glycol in any proportion. The polyol compound molecules contain multiple hydroxyl groups, which can break the original hydrogen bonds between polyvinyl alcohol molecules, reduce the interaction between polyvinyl alcohol molecules, and re-form hydrogen bonds with the hydroxyl groups in the polyvinyl alcohol molecules. In addition, the polyol molecules can also form strong hydrogen bonds with free water molecules, breaking the hydrogen bonds between water molecules, which helps to improve the solubility of polyvinyl alcohol in aqueous solution.

[0029] Furthermore, the dispersant is any one or more of polyvinyl pyrrolidone, sodium alginate and xanthan gum in any proportion.

[0030] In the above scheme, the dispersant is any one or more of polyvinyl pyrrolidone, sodium alginate, and xanthan gum in any proportion. The function of the dispersant is similar to that of a surfactant, which can help polyvinyl alcohol to be better dispersed and dissolved in water.

[0031] Furthermore, the surfactant is any one or more of polyoxyethylene sorbitan fatty acid ester, poloxamer and polyethylene glycol mixed in any proportion.

[0032] In the above scheme, the surfactant is any one or more of polyoxyethylene sorbitan fatty acid ester, poloxamer, and polyethylene glycol in any proportion. Adding an appropriate amount of surfactant during the dissolution process can reduce the surface tension of polyvinyl alcohol, prevent it from forming lumps or gels, and thus improve solubility.

[0033] Furthermore, the thickener is any one or more of sodium hyaluronate, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose and carbomer mixed in any proportion.

[0034] In the above scheme, the thickener is any one or more of sodium hyaluronate, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, and carbomer in any proportion. The thickener can increase the viscosity of the liquid medicine, increase the residence time of the liquid medicine in the eye, prolong the action time of the liquid medicine, and improve eye irritation and dryness symptoms.

[0035] Furthermore, the isotonic agent is any one or more of sodium chloride, potassium chloride, borax, boric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide and hydrochloric acid mixed in any proportion.

[0036] Furthermore, the pH value of the eye drops containing polyvinyl alcohol is 5.0-6.0, and the osmotic pressure molar concentration ratio is 0.9-1.1.

[0037] The amount of isotonic agent used in the preparation is not fixed, but is affected by many factors, including but not limited to the type of isotonic agent and its strength, the formulation composition and physicochemical properties, etc. It should be understood by those skilled in the art that the specific amount of isotonic agent used needs to be flexibly adjusted according to the target osmotic pressure and pH value expected to be achieved. For example, the target osmotic pressure and pH value are set first, and after all the ingredients except the water for injection in the prescription are mixed, before the preparation is finally fixed to volume (i.e., reaching a predetermined weight or volume), the osmotic pressure and pH value of the preparation are accurately adjusted by adding an appropriate amount of isotonic agent. This method allows technicians to easily determine the optimal amount of osmotic pressure regulator in the preparation, thereby ensuring that the osmotic pressure and pH value of the eye drops meet the standard requirements of ophthalmic preparations.

[0038] Furthermore, the multi-stage sterilization filtration is a process in which the eye drop intermediate containing polyvinyl alcohol is filtered through three-stage series microporous filter elements, the material of the microporous filter element is polyethersulfone, the pore size of the first-stage microporous filter element is 0.45 μm, the pore size of the second-stage microporous filter element is 0.2 μm, and the pore size of the third-stage microporous filter element is 0.2 μm.

[0039] The second aspect of the present invention obtains an eye drop containing polyvinyl alcohol prepared by the above preparation method, wherein the eye drop comprises the following components in percentage by mass: polyvinyl alcohol 1.2-1.6%, thickener 0.3-0.8%, surfactant 0.3-0.8%, dispersant 0.1-0.6%, cosolvent 1.0-5.0%, and the balance is water for injection;

[0040] Furthermore, the eye drops containing polyvinyl alcohol include the following components in percentage by mass: 1.3-1.5% polyvinyl alcohol, 0.4-0.6% thickener, 0.4-0.6% surfactant, 0.2-0.4% dispersant, 2.0-4.0% cosolvent, and the remainder is water for injection.

[0041] Furthermore, the eye drops containing polyvinyl alcohol are single-dose eye drops, are preservative-free, have precise dosages, are easy to use, and avoid cross infection.

[0042] The design ideas and inventive points of the present invention are as follows:

[0043] In step (1) of the present design, polyvinyl alcohol is first premixed with cosolvents (glycerol and propylene glycol) to form a mixture. Generally, the dissolution process of PVA is divided into two stages: water molecules penetrate into the gaps between PVA molecular chains to cause them to swell, and then the molecular chains dissociate and disperse into water. The present invention unexpectedly discovered that the premixing step can significantly improve the solubility of PVA. This improvement stems from the synergistic effect of glycerol and propylene glycol: glycerol produces a plasticizing effect by penetrating into the molecular chains and forms hydrogen bonds through hydroxyl groups, which not only reduces the forces between molecular chains but also promotes solvation; propylene glycol promotes dissolution by reducing surface tension and solvation effects, and its molecular structure characteristics make water molecules more permeable while interfering with intermolecular interactions. The combination of the two can act on the crystalline and non-crystalline regions of PVA at the same time, accelerate the swelling process, increase the dissolution rate, and reduce the dissolution temperature.

[0044] The effect of this method is affected by factors such as the concentration of the cosolvent, the degree of polymerization and alcoholysis of PVA, and the pH value. In practical applications, the conditions such as the amount of cosolvent, the average molecular weight of polyvinyl alcohol of 50,000 to 140,000 Da, the alcoholysis degree of 87 to 92%, the pH value of the polyvinyl alcohol eye drops of 5.0 to 6.0, and the osmotic pressure molar concentration ratio of 0.9 to 1.1 need to be considered and optimized.

[0045] In step (2) of the present design, the dispersant is mixed and dissolved with 40-60% of the total volume of the injection water, and then a surfactant is added to form a mixed solution 2; in step (3), the thickener is mixed and dissolved with 20-30% of the total volume of the injection water to form a mixed solution 3; in step (4), the mixture 1 of step (1) is slowly added to the mixed solution 2 of step 2 while stirring, and the stirring is continued until it is completely dissolved to obtain a mixed solution 4; in step (5), the mixed solution 3 of step (3) is added to the mixed solution 4 of step (4); from the above preparation steps, the present design does not directly mix polyvinyl alcohol, cosolvent, dispersant, surfactant, thickener and water to prepare the eye drops containing polyvinyl alcohol. The inventor also tried not to add each component in steps, but to add each component together. However, when PVA is directly in contact with water, it is easy to form a hydration layer on the surface, which hinders the penetration of the cosolvent, resulting in a slow and uneven dissolution process, and may form agglomerates that are difficult to dissolve. However, the mixed system of the present design allows the cosolvent to fully penetrate into the PVA molecular chain, and the plasticization and solvation effects are achieved in advance. When the pretreated PVA is added to the aqueous phase system, since the molecular chains have been fully stretched and activated by the cosolvent, it can be more easily dispersed and dissolved. The addition of the dispersant can ensure that the dispersion system of step (1) has better long-term dispersibility. The addition of the surfactant can form a stable dispersion medium environment. Finally, the thickener is added to avoid mutual interference between the thickener and other components, and the viscosity of the system can be more accurately controlled to prevent unevenness caused by excessive local viscosity.

[0046] Compared with the prior art, the present invention has the following beneficial technical effects:

[0047] 1. The problem that PVA eye drops in the prior art need to be prepared at high temperature (80-95°C) is solved. The low-temperature preparation of 30-59°C is achieved through the innovative pre-mixing process of co-solvents, and the dissolution time is shortened to less than 60 minutes.

[0048] 2. By preparing the premixed system of polyvinyl alcohol and cosolvent, the mixed system of dispersant and surfactant, and the mixed system of thickener in steps, and finally mixing the three systems, the problem of PVA directly contacting water to form a hydration layer is avoided, the uniformity and stability of the product system are ensured, and the agglomeration phenomenon that may be caused by one-time mixing is overcome.

[0049] 3. The product can meet the requirements of low temperature and short time dissolution during the production process, and the content, osmotic pressure and pH value of the product system are stable, with good effects and no irritation, which greatly reduces the industrial production cost and facilitates industrial production. DETAILED DESCRIPTION

[0050] The average molecular weight of the polyvinyl alcohol involved in the preparation methods of Examples 1 to 12 is 50,000 to 140,000 Da, and the alcoholysis degree is 87 to 92%.

[0051] Embodiment 1:

[0052] A method for preparing an eye drop containing polyvinyl alcohol, comprising the following components in percentage by mass: 14g (1.4%) polyvinyl alcohol, 5g (0.5%) thickener (sodium carboxymethyl cellulose), 5g (0.5%) surfactant (polyoxyethylene sorbitan fatty acid ester), 3g (0.3%) dispersant (sodium alginate), 30g (3.0%) cosolvent (glycerol and propylene glycol, mass ratio of 1:1), isotonic agents are sodium chloride and sodium hydroxide, the addition amount is determined according to pH and osmotic pressure, the remainder is water for injection, and the total liquid volume is 1000ml;

[0053] The preparation method comprises the following steps:

[0054] Step (1) premixing polyvinyl alcohol and a cosolvent to form a mixture 1;

[0055] Step (2) dissolving the dispersant in 400 ml of water for injection, and then adding a surfactant to form a mixed solution 2;

[0056] Step (3) mixing and dissolving the thickener with 300 ml of water for injection to form a mixed solution 3;

[0057] Step (4) slowly adding the mixture 1 of step (1) into the mixed solution 2 of step 2 while stirring, and continuing to stir until completely dissolved to obtain a mixed solution 4;

[0058] Step (5) adding the mixed solution 3 of step (3) to the mixed solution 4 of step (4);

[0059] Step (6) After adding an isotonic agent to adjust the pH and osmotic pressure, the remaining amount of water for injection is added and the volume is fixed to 1000 ml with water to obtain an eye drop intermediate containing polyvinyl alcohol;

[0060] Step (7) The polyvinyl alcohol-containing eye drop intermediate in step (6) is subjected to three-stage sterilization filtration using 0.45, 0.2, and 0.2 μm polyethersulfone filter elements to obtain eye drops containing polyvinyl alcohol; and the eye drops are filled into a single-dose low-density polyethylene medicinal eye drop bottle under sterile conditions to obtain eye drops containing polyvinyl alcohol.

[0061] The preparation temperature of step (1) to step (6) is 45° C., the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drops intermediate from step (1) to step (6) is 50 minutes, and the operation temperature of step (7) is room temperature. The pH value of the polyvinyl alcohol-containing eye drops is 6.0, and the osmotic pressure molar concentration ratio is 1.0.

[0062] Embodiment 2:

[0063] The difference between Example 2 and Example 1 is that the polyvinyl alcohol eye drops include the following components: polyvinyl alcohol 12g (1.2%), thickener (sodium carboxymethyl cellulose) 3g (0.3%), surfactant (polyoxyethylene sorbitan fatty acid ester) 3g (0.3%), dispersant (sodium alginate) 1g (0.1%), cosolvent (glycerol and propylene glycol, mass ratio of 1:1) 10g (1.0%), isotonic agents are sodium chloride and sodium hydroxide, the amount added is determined according to pH and osmotic pressure, and the remainder is water for injection, added to a total solution volume of 1000ml.

[0064] The difference between its preparation method and Example 1 is:

[0065] Step (2) dissolving the dispersant in 500 ml of water for injection, and then adding a surfactant to form a mixed solution 2;

[0066] Step (3) mixing and dissolving the thickener with 200 ml of water for injection to form a mixed solution 3;

[0067] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0068] Example 3

[0069] The difference between Example 3 and Example 1 is that the polyvinyl alcohol eye drops include the following components: polyvinyl alcohol 13g (1.3%), thickener (sodium carboxymethyl cellulose) 4g (0.4%), surfactant (polyoxyethylene sorbitan fatty acid ester) 4g (0.4%), dispersant (sodium alginate) 2g (0.2%), cosolvent (glycerol and propylene glycol, mass ratio of 1:1) 20g (2.0%), isotonic agents are sodium chloride and sodium hydroxide, the amount added is determined according to pH and osmotic pressure, and the balance is water for injection, added to a total solution volume of 1000ml.

[0070] The difference between its preparation method and Example 1 is:

[0071] Step (2) dissolving the dispersant in 600 ml of water for injection, and then adding a surfactant to form a mixed solution 2;

[0072] Step (3) mixing and dissolving the thickener with 200 ml of water for injection to form a mixed solution 3;

[0073] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0074] Example 4

[0075] The difference between Example 4 and Example 1 is that the polyvinyl alcohol eye drops include the following components: 15g (1.5%) of polyvinyl alcohol, 6g (0.6%) of thickener (sodium carboxymethyl cellulose), 6g (0.6%) of surfactant (polyoxyethylene sorbitan fatty acid ester), 4g (0.4%) of dispersant (sodium alginate), 40g (4.0%) of cosolvent (glycerol and propylene glycol, mass ratio of 1:1), and an appropriate amount of isotonic agent, which is sodium chloride and sodium hydroxide, and the amount added is determined according to pH and osmotic pressure. The remainder is water for injection, which is added to a total solution volume of 1000ml.

[0076] The difference between its preparation method and Example 1 is:

[0077] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0078] Example 5

[0079] The difference between Example 5 and Example 1 is that the polyvinyl alcohol eye drops include the following components: polyvinyl alcohol 16g (1.6%), thickener (sodium carboxymethyl cellulose) 8g (0.8%), surfactant (polyoxyethylene sorbitan fatty acid ester) 8g (0.8%), dispersant (sodium alginate) 6g (0.6%), cosolvent (glycerol and propylene glycol, mass ratio of 1:1) 50g (5.0%), isotonic agents are sodium chloride and sodium hydroxide, the amount added is determined according to pH and osmotic pressure, and the balance is water for injection, added to a total solution volume of 1000ml.

[0080] The difference between its preparation method and Example 1 is:

[0081] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0082] Example 6

[0083] The difference between Example 6 and Example 1 is that the thickener in the polyvinyl alcohol eye drops is 5 g (0.5%) of sodium hyaluronate.

[0084] The difference between its preparation method and Example 1 is:

[0085] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0086] Example 7

[0087] The difference between Example 7 and Example 1 is that the thickener in the polyvinyl alcohol eye drops is 5 g (0.5%) of hypromellose.

[0088] The difference between its preparation method and Example 1 is:

[0089] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0090] Example 8

[0091] The difference between Example 8 and Example 1 is that the thickener in the polyvinyl alcohol eye drops is 5 g (0.5%) of carbomer.

[0092] The difference between its preparation method and Example 1 is:

[0093] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0094] Example 9

[0095] The difference between Example 9 and Example 1 is that the surfactants in the polyvinyl alcohol eye drops are poloxamer and polyethylene glycol (the mass ratio of poloxamer to polyethylene glycol is 2:1), and the usage amount is 6 g (0.6%).

[0096] Example 10

[0097] The difference between Example 10 and Example 1 is that the dispersant in the polyvinyl alcohol eye drops is 3 g (0.3%) of xanthan gum.

[0098] Embodiment 11

[0099] The difference between Example 11 and Example 1 is that the isotonic agent in the polyvinyl alcohol eye drops is sodium chloride, boric acid and borax, and the amount added is determined according to pH and osmotic pressure.

[0100] The difference between its preparation method and Example 1 is:

[0101] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0102] Example 12

[0103] The difference between Example 12 and Example 1 is that the isotonic agent in the polyvinyl alcohol eye drops is sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate, and the amount added is determined according to pH and osmotic pressure.

[0104] The difference between its preparation method and Example 1 is:

[0105] The preparation temperature of step (1) to step (6), and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drop intermediate from step (1) to step (6) are shown in Table 1. The pH value and osmotic pressure molar concentration ratio of the polyvinyl alcohol-containing eye drop are shown in Table 2.

[0106] Comparative Example 1

[0107] Comparative Example 1 was prepared with reference to a polyvinyl alcohol eye drop and a preparation method thereof disclosed in Chinese patent CN118453507A.

[0108] A polyvinyl alcohol eye drop, each 1000 mL of the eye drop comprises: 14 g of polyvinyl alcohol, 7.6 g of an isotonic agent (sodium chloride) and 6 g of a thickener (povidone K30);

[0109] The preparation method of polyvinyl alcohol eye drops comprises the following steps:

[0110] Step a, add the prescribed amount of sodium chloride and povidone K30 to 90% of the total volume of 1000 ml of water for injection, stir and dissolve, add the prescribed amount of polyvinyl alcohol at 95°C, stir and dissolve, and obtain polyvinyl alcohol liquid; step b, add the remaining water for injection to the polyvinyl alcohol liquid, adjust the pH and osmotic pressure with sodium hydroxide, see Table 2, the operating temperature, and the time to obtain the completely dissolved polyvinyl alcohol-containing eye drops, see Table 1. Then filter through polyvinylidene fluoride filter elements with pore sizes of 0.45 μm, 0.2 μm and 0.2 μm in turn, and fill to obtain the polyvinyl alcohol eye drops.

[0111] Comparative Example 2

[0112] Comparative Example 2 was prepared with reference to a single-dose eye drop containing polyvinyl alcohol and a preparation method thereof disclosed in Chinese patent CN106692048A.

[0113] A single-dose eye drop containing polyvinyl alcohol comprises the following components: each 1000 mL of eye drop contains 14.0 g of polyvinyl alcohol, 6.0 g of a thickener (povidone K30), an isotonic agent (7.5 g of sodium chloride, 1.0 g of potassium chloride), and an appropriate amount of water for injection, and the pH is adjusted to 6.0-7.0 with sodium hydroxide.

[0114] The preparation method is as follows: (1) 800 mL of water for injection is heated to 80-90° C., 14.0 g of polyvinyl alcohol, 6.0 g of povidone K30, 7.5 g of sodium chloride, and 1.0 g of potassium chloride are added in sequence, and stirred until completely dissolved, and an appropriate amount of sodium hydroxide is added to adjust the pH to 6.0-7.0. The pH value and osmotic pressure are shown in Table 2.

[0115] (2) The drug solution was filtered through a 1.2 μm microporous filter, water for injection was added to 1000 mL and stirred to obtain a drug solution intermediate. The operating temperature and the time for obtaining a completely dissolved polyvinyl alcohol-containing eye drop are shown in Table 1.

[0116] (3) The liquid intermediate is sterilized and filtered through two sets of 0.2 μm microporous filter cartridges connected in series, and is directly filled into a 0.8 mL low-density polyethylene plastic bottle using a blow-fill-seal integrated device. The filling volume is 0.45 mL to obtain the finished product.

[0117] Comparative Example 3

[0118] Comparative Example 3 was prepared with reference to a polyvinyl alcohol eye drop and its production process disclosed in Chinese patent CN118490631A.

[0119] Weigh 13.8 g of polyvinyl alcohol, 4.6 g of sodium chloride, 0.16 g of potassium chloride, and 6.2 g of glycerol, wherein the content of polyvinyl alcohol of 12-15 Kda in the polyvinyl alcohol is 50%, and the content of polyvinyl alcohol of 2.5-3.5 Kda is 50%.

[0120] Preparation method:

[0121] (1) Weigh about 593 mL of 60-80°C water for injection, slowly add the polyvinyl alcohol API under stirring, and stir until completely dissolved to obtain raw material 1. (2) Slowly add the prescribed amount of sodium chloride, potassium chloride, and glycerol to about 198 mL of 45-50°C water for injection, and stir until clear to obtain a concentrated solution of the excipient, and obtain excipient 2.

[0122] (3) Slowly mix raw material 1 and auxiliary material 2, adjust the pH value and osmotic pressure with anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride, and add water for injection to a total volume of 1000 mL. The operating temperature for dissolving the raw materials and the time for obtaining the completely dissolved polyvinyl alcohol-containing eye drops are shown in Table 1, and the pH value and osmotic pressure are shown in Table 2.

[0123] Comparative Example 4

[0124] Comparative Example 4 was prepared with reference to a polyvinyl alcohol composition and a preparation method thereof disclosed in Chinese patent CN104983786A.

[0125] The polyvinyl alcohol composition is prepared into eye drops, and the specific steps are as follows:

[0126] (1) Add 8 g of polyvinyl alcohol, 0.1 g of polyvinyl pyrrolidone, 0.5 g of xanthan gum and 0.5 g of fatty alcohol ester to 150 ml of water for injection respectively, mix well, and obtain a first mixed solution;

[0127] (2) Then, sodium chloride and sodium dihydrogen phosphate were added to adjust the osmotic pressure and pH value of the solution to obtain the target mixed solution; the pH value and osmotic pressure are shown in Table 2.

[0128] (3) The target mixed solution was subjected to ultrasonic treatment for 30 minutes at a power of 5 W. The time required to obtain completely dissolved polyvinyl alcohol-containing eye drops is shown in Table 1. The mixture was then sterilized by filtration.

[0129] Reference preparation

[0130] Buy directly from Allergan UK As a reference preparation.

[0131] Polyvinyl alcohol dissolution temperature and time:

[0132] The polyvinyl alcohol eye drops and the preparation methods thereof provided in Examples 1 to 12 and Comparative Examples 1 to 4 were prepared, and during the preparation process, the preparation temperature of the polyvinyl alcohol and the time required for complete dissolution and uniform preparation were recorded. The dissolution results are shown in Table 1.

[0133] Table 1 Dissolution results

[0134]

[0135]

[0136] From the results in Table 1, it can be seen that the polyvinyl alcohol in Examples 1 to 12 is completely dissolved evenly, and the time to prepare the intermediate is about 40 to 60 minutes; the dissolution temperature of the polyvinyl alcohol in the comparative example is above 60°C, and the dissolution and preparation time is above 60 minutes, and the lower the dissolution temperature, the longer the dissolution time, and the ultrasonic treatment has a certain effect of promoting dispersion and dissolution. In general, compared with the comparative example, the preparation temperature of the embodiment is lower and the dissolution time is shorter, indicating that the polyvinyl alcohol eye drops and preparation method provided by the present invention have a significant promoting effect on the dissolution of polyvinyl alcohol, can reduce the dissolution temperature and dissolution time, and significantly improve the dissolution and preparation efficiency.

[0137] Quality Inspection:

[0138] The polyvinyl alcohol eye drops and polyvinyl alcohol eye drops reference preparations ( The content, osmotic pressure and pH value of the samples were tested by Allergan Company, UK, and the influencing factors were tested at 60°C for 0, 5 and 10 days in accordance with the Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations). The test results are shown in Table 2.

[0139] Table 2 Test results of influencing factors

[0140]

[0141]

[0142] It can be seen from the results in Table 2 that the polyvinyl alcohol eye drops prepared in Examples 1 to 12 had no significant changes in content, osmotic pressure, and pH value within 10 days at 60°C, while the pH values ​​of the comparative examples and reference preparations showed a significant downward trend, and the stability was poor. The polyvinyl alcohol eye drops prepared by the present invention have good solubility and stability. The surfactants, dispersants, and cosolvents used in the embodiments of the present invention can promote the dissolution and dispersion of polyvinyl alcohol in the eye drops, and can serve as stabilizers to form a stable system for the eye drops, which plays a role in reducing degradation and stabilizing pH. There is no need to prepare the solution at high temperature, which avoids the effect of high temperature on the quality during the preparation process.

[0143] Eye irritation test:

[0144] With reference to the Technical Guidelines for Drug Irritation, Allergy and Hemolysis Research, the eye irritation of Examples 1 to 12 of the present invention was investigated by using the left and right side self-comparison method. The investigation results are shown in Table 3.

[0145] Table 3 Eye irritation test results

[0146] Group Total score of eye irritation reaction Eye irritation evaluation Example 1 0 Non-irritating Example 2 0 Non-irritating Example 3 0 Non-irritating Example 4 0 Non-irritating Example 5 0 Non-irritating Example 6 0 Non-irritating Example 7 0 Non-irritating Example 8 0 Non-irritating Example 9 0 Non-irritating Example 10 0 Non-irritating Embodiment 11 0 Non-irritating Example 12 0 Non-irritating

[0147] It can be seen from Table 3 that the polyvinyl alcohol eye drops prepared in Examples 1 to 12 had no effect on the cornea, conjunctiva, and iris of rabbits, and no edema or secretions occurred, indicating that the polyvinyl alcohol eye drops prepared according to the technical solution of the present invention have no eye irritation and are highly safe for use.

[0148] The above is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited to the above content. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing eye drops containing polyvinyl alcohol, characterized in that: The invention comprises the following components in percentage by weight: 1.2-1.6% polyvinyl alcohol, 0.3-0.8% thickener, 0.3-0.8% surfactant, 0.1-0.6% dispersant, 1.0-5.0% cosolvent, and the balance is water for injection. The preparation method comprises the following steps: Step (1) premixing polyvinyl alcohol and a cosolvent to form a mixture 1; Step (2) mixing and dissolving the dispersant with 40-60% of the total volume of water for injection, and then adding a surfactant to form a mixed solution 2; Step (3) mixing and dissolving the thickener with 20-30% of the total volume of the injection water to form a mixed solution 3; Step (4) slowly adding the mixture 1 of step (1) into the mixed solution 2 of step 2 while stirring, and continuing to stir until completely dissolved to obtain a mixed solution 4; Step (5) adding the mixed solution 3 of step (3) to the mixed solution 4 of step (4); Step (6) after adding an isotonic agent to adjust the pH and osmotic pressure, adding the remaining amount of water for injection to prepare the total volume, to obtain an eye drop intermediate containing polyvinyl alcohol; Step (7) performing multi-stage sterilization filtration on the polyvinyl alcohol-containing eye drops intermediate in step (6) to obtain eye drops containing polyvinyl alcohol drops; The preparation temperature of steps (1) to (6) is 30-59° C., and the time from steps (1) to (6) to obtain a completely dissolved eye drop intermediate containing polyvinyl alcohol is less than 60 minutes.

2. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The invention comprises the following components in percentage by mass: 1.3-1.5% of polyvinyl alcohol, 0.4-0.6% of thickener, 0.4-0.6% of surfactant, 0.2-0.4% of dispersant, 2.0-4.0% of cosolvent, and the balance is water for injection.

3. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The average molecular weight of the polyvinyl alcohol is 50,000-140,000 Da, and the alcoholysis degree is 87-92%.

4. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The cosolvent is a mixture of glycerol and propylene glycol in any proportion.

5. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The dispersant is any one or more of polyvinyl pyrrolidone, sodium alginate and xanthan gum in any proportion.

6. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The surfactant is any one or more of polyoxyethylene sorbitan fatty acid ester, poloxamer and polyethylene glycol mixed in any proportion.

7. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The thickener is any one or more of sodium hyaluronate, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose and carbomer mixed in any proportion.

8. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The isotonic agent is any one or more of sodium chloride, potassium chloride, borax, boric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide and hydrochloric acid mixed in any proportion.

9. The method for preparing an eye drop containing polyvinyl alcohol according to claim 1, characterized in that: The pH value of the eye drops containing polyvinyl alcohol is 5.0-6.0, and the osmotic pressure molar concentration ratio is 0.9-1.

1.

10. The method for preparing eye drops containing polyvinyl alcohol according to claim 1, characterized in that: The multi-stage sterilization filtration is to filter the eye drop intermediate containing polyvinyl alcohol through three-stage series microporous filter elements, the material of the microporous filter element is polyethersulfone, the pore size of the first stage microporous filter element is 0.45μm, the pore size of the second stage microporous filter element is 0.2μm, and the pore size of the third stage microporous filter element is 0.2μm.

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