A tafluprost eye drop aqueous pharmaceutical containing the same and a preparation method thereof

Abstract

The application relates to a tafluprost eye drop and a preparation method thereof, and belongs to the technical field of medicine preparation. In the preparation process, the active component tafluprost is dispersed in Tween 80 and stirred and dissolved, and the remaining auxiliary solution is prepared synchronously; in addition, through optimization and control of the preparation parameters, the preparation process is greatly simplified while the product quality attributes are ensured; finally, the tafluprost eye drop and the preparation method thereof meet the needs of commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing an aqueous eye drop containing tafluprost. Technical Background

[0002] Tafluprost is a novel PGF2α derivative jointly developed by Santen Pharmaceutical, Asahi Glass, and Merck (licensed). It was first approved for marketing in Germany in 2008 for the purpose of lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

[0003] Tafluprost is a colorless or pale yellow viscous liquid, almost insoluble in water, sensitive to heat, and requires cryopreservation. Molecular formula: C 25 H 34 F2O5, molecular weight: 452.53, its structural formula is as follows:

[0004]

[0005] Tafluprost is a novel PGF2α derivative that enhances corneal and scleral permeability. After enzymatic hydrolysis, it is converted into an active carboxylic acid form that enters the aqueous humor. Through interaction with prostaglandin FR receptors, it promotes the outflow of aqueous humor between the choroid and sclera, thereby lowering intraocular pressure. Existing literature and experimental data indicate that tafluprost raw material is poorly soluble in water, easily oxidized, and readily adsorbs onto the inner packaging material of eye drops, potentially reducing the actual dosage.

[0006] In response to the aforementioned adsorption problem of tafluprost eye drops, the reference formulation manufacturer, Santen Pharmaceutical Co., Ltd. of Japan, added the nonionic surfactant polysorbate 80 when developing the eye drops in its patent CN102083413B, but did not mention the preparation method of tafluprost eye drops.

[0007] Currently, tafluprost is marketed as an aqueous eye drop. However, because tafluprost is a viscous liquid and almost insoluble in water, the inclusion technology used in CN102083413A, while improving its solubility, has a complex formulation process that is difficult to implement and widely applicable. Therefore, there is a need to find an effective, convenient, and time-saving preparation method to improve the solubility of tafluprost in aqueous media, while ensuring that the prepared product meets relevant quality standards. Summary of the Invention

[0008] Given the poor water solubility and stability of tafluprost, the purpose of this invention is to provide a stable tafluprost-containing eye drop and its preparation method by screening ideal process parameters. This solves the problem of low solubility of tafluprost during preparation and improves its stability in aqueous solution, reducing the formation of related substances, thereby achieving the goal of safe and effective treatment of glaucoma. Furthermore, process validation in three batches has shown that it can easily produce tafluprost eye drops with high content, low impurities, stable and uniform solution, and high quality standards.

[0009] The objective of this invention can be achieved through the following measures, which include the following steps:

[0010] A method for preparing an aqueous eye drop containing tafluprost, characterized by comprising the following steps:

[0011] (1) Solution preparation: Prepare a solution containing polysorbate 80 and tafluprost, and add water for injection and stir until completely dissolved;

[0012] (2) Adding materials: Add the excipients to the solution obtained in the above solution preparation process, make up to the full volume, and stir evenly;

[0013] (3) Sterilization filtration: The solution after volume adjustment is sterilized and filtered to obtain the finished product;

[0014] The excipients include antioxidants, pH adjusters, buffers and binders. The sterilization filtration step uses a microporous membrane for filtration. The microporous membrane is made of one of PES, PVDF or PTFE.

[0015] In a preferred embodiment, the filter membrane used in the filtration process is made of PVDF.

[0016] In a preferred embodiment, the eye drops use water for injection as a solvent, and the concentration (w / v) of the water for injection is 0% to 40%, preferably 0% to 15%, and more preferably 0% to 10%.

[0017] In a preferred embodiment, the antioxidant is disodium edetate, the buffer is sodium dihydrogen phosphate, and the wetting agent is glycerin.

[0018] In a preferred embodiment, the solution preparation process is carried out in a solution preparation tank, and the optimal solution temperature in the tank is ≤25℃.

[0019] In a preferred embodiment, a method for preparing an aqueous eye drop containing tafluprost includes the following steps:

[0020] (1) Weigh the amount of active ingredient and nonionic surfactant required by the formula to prepare a mixture of active ingredient and solubilizer;

[0021] (2) Weigh out the amount of buffer, antioxidant and binder specified in the formula and add them to the above mixture;

[0022] (3) Prepare a pH adjuster and use the prepared pH adjuster to adjust the pH value of the above mixture;

[0023] (4) Add water for injection to the above mixture until the volume is reached;

[0024] (5) The solution after volume adjustment is sterilized by filtration;

[0025] (6) Package the sterilized and filtered medicine to complete the production.

[0026] In a preferred embodiment, in step 1, during the preparation of the mixture of active ingredient and solubilizer, tafluprost and polysorbate 80 are placed in a container, a stir bar is added, water for injection is added, and the mixture is stirred until completely dissolved.

[0027] In a preferred embodiment, in step 2, the excipients in the prescribed amount are added to the preparation tank in a specific order. The preferred order of addition is: sodium dihydrogen phosphate, glycerin, and disodium edetate. The beaker used to weigh the excipients is cleaned with water for injection, and the cleaning solution is transferred to the preparation tank. After the excipients are added, stirring continues under vacuum, and the solution temperature is maintained at 20–60°C. Preferably, in the preparation of tafluprost eye drops as described above, the excipients are added in the following order: disodium edetate, sodium dihydrogen phosphate, and glycerin. Throughout the preparation process, the solution temperature should be maintained at 20–30°C.

[0028] In a preferred embodiment, in step 3, the pH adjuster is prepared by adding solid sodium hydroxide to water for injection, with a concentration of 1 mol / L.

[0029] In a preferred embodiment, in step 4, water for injection is added to the preparation tank to bring it to full volume, and the sample is sent to QC for intermediate testing.

[0030] In a preferred embodiment, in step 5, intermittent filtration is used to filter the drug solution. After discarding an appropriate amount of the drug solution that has passed through the sterilization filter to the front end of the buffer tank, the filtered drug solution is then transported to the buffer tank.

[0031] In a preferred embodiment, a stir bar made of polytetrafluoroethylene is placed in a 100ml tall beaker containing tafluprost and polysorbate 80, and 0% to 30% (w / v) of water for injection is added and stirred until completely dissolved.

[0032] Preferably, in the preparation of tafluprost eye drops as described above, 0% to 10% (w / v) of water for injection is added to the solubilizing mixture, and the mixture is stirred until completely dissolved. More preferably, in the preparation of tafluprost eye drops as described above, as the batch size is scaled up, 0% water for injection is added to the solubilizing mixture, and the mixture is stirred until completely dissolved.

[0033] In a preferred embodiment, under negative pressure weighing hood and yellow light conditions, magnetic stirring is turned on to mix tafluoroprostol and polysorbate 80(II). During stirring, it should be ensured that the mixture exhibits obvious vortex and that the liquid does not splash. The stirring time is 0.5h to 2.0h, the stirring speed is 500 to 700rpm, and the mixture should be a uniform colorless to pale yellow viscous liquid.

[0034] Preferably, in the preparation of tafluprost eye drops as described above, the solution is stirred for 1.0 h at a stirring speed of 500–700 rpm, and the mixture should be a uniform, colorless to pale yellow viscous liquid.

[0035] In a preferred embodiment, in step 3, 1 mol / L sodium hydroxide solution is added to adjust the pH of the solution to 6.0 ± 0.2. If it is lower than 5.8, 1 mol / L sodium hydroxide solution is added until the pH meets the requirements. In step 4, water for injection is added to the preparation tank to the full volume, and the sample is sent to QC for intermediate testing. In step 5, intermittent filtration is used to filter the solution. After discarding an appropriate amount of the solution that has passed through the sterilization filter to the front end of the buffer tank, the filtered solution is then transported to the buffer tank.

[0036] In a preferred embodiment, the filtration area of ​​the microporous membrane in the filtration process is 800 cm². 2 ~2000cm 2 Further optimization resulted in a filtration area of ​​500 cm². 2 ~1500cm 2 .

[0037] The beneficial effects of this invention are:

[0038] 1. Compared with the prior art, the tafluprost eye drops of the present invention have a reasonable preparation process that is easy to operate. The developed process parameters can significantly reduce the impurities generated and increase the stability, which not only helps to improve product quality but also improves efficacy. Under the premise of ensuring product quality attributes, by optimizing the formulation process parameters of different processes, the final result is a simplified process, convenient operation, and good reproducibility.

[0039] 2. This invention addresses the challenges of existing tafluprost eye drop formulations, such as API degradation, poor water solubility, easy adsorption to packaging materials, inaccurate dosage, complex formulation composition, and inability to achieve high-temperature sterilization. By combining the nonionic surfactant polysorbate 80 with tafluprost eye drops, the solubility of tafluprost in aqueous media is effectively improved, and the quality properties of the prepared product meet relevant standards.

[0040] 3. This invention improves the stability of tafluprost in aqueous solution and reduces the formation of related substances, thereby achieving the goal of safe and effective treatment of glaucoma. Furthermore, process verification of three batches shows that it can easily produce tafluprost eye drops with high content, few impurities, stable and uniform solution, and high quality standards, demonstrating high industrial applicability. Detailed Implementation

[0041] The following examples provide a more detailed description of the formulation and preparation process of the tafluprost eye drops involved in this invention. However, this should not be construed as limiting the scope of the above-mentioned subject matter of this invention to the following examples. All technologies implemented based on the above content of this invention fall within the scope of this invention.

[0042] Example 1: Comparison of stirring time for different initial dissolved water volumes and increased solution volumes

[0043] formula:

[0044]

[0045] Preparation process:

[0046] Weigh the raw materials and excipients according to the formula. First, prepare the solution of API and polysorbate 80, and add 20% water for injection. Stir for 0.5h, 1.0h, 1.5h and 2.0h respectively. After stirring, add the remaining excipients, adjust the pH of the solution to 6.0±0.2, and make up to the total volume. Continue stirring for 10min. Take samples to detect the content, pH and osmolality. The test data are shown in Table 1.

[0047] Based on the detection data in Table 1, the stirring time for the API and polysorbate 80 solution was selected as 1.0 h. Further investigation was conducted by adding 0%, 15%, 30%, and 40% water for injection and stirring for 1.0 h in each case. After stirring, the remaining excipients were added, the pH of the solution was adjusted to 6.0 ± 0.2, and the volume was brought to a final volume. Stirring was continued for 10 min, and samples were taken to detect the content, pH, and osmolality. The detection data are shown in Table 2.

[0048] Table 1. Detection data of solution with different stirring times.

[0049]

[0050] Table 2. Detection data of different amounts of water for injection added to the solution.

[0051]

[0052] Conclusion: The above data show that different amounts of water for injection have a certain impact on the dissolution of the active pharmaceutical ingredient. The amount of water for injection within the range of 0-40% meets the production requirements. In addition, the stirring time significantly affects the content, and stirring for 1 hour can meet the production requirements.

[0053] Example 2: Comparison of the order of addition of different raw and auxiliary materials

[0054] formula:

[0055]

[0056] Preparation process:

[0057] Weigh the raw materials and excipients according to the formula. First, prepare the solution of API and polysorbate 80, and add 20% water for injection. Stir for 1.0 h, then add the excipients in the order of addition. Adjust the pH of the solution to 6.0±0.2, bring the volume to the total volume, and continue stirring for 10 min. Take samples to test the properties, content, pH, and osmolality. The test data are shown in Table 3.

[0058] Table 3. Detection data for different raw and auxiliary material addition sequences.

[0059]

[0060] Conclusion: The above data show that the order of adding raw materials and excipients significantly affects the dissolution of excipients in each step. The method of adding solution → sodium dihydrogen phosphate → glycerol → disodium edetate significantly shortens the dissolution time.

[0061] Example 3: Comparison of different solution preparation temperatures

[0062] formula:

[0063]

[0064] Preparation process:

[0065] Weigh the raw materials and excipients according to the formula. First, prepare a solution of API and polysorbate 80, and add 20% water for injection. Stir for 1.0 h, then control the solution temperature at 10℃, 20℃, 30℃, 60℃, and 80℃, and add excipients such as disodium edetate, sodium dihydrogen phosphate, and glycerol in sequence. After stirring until completely dissolved, adjust the pH of the solution to 6.0±0.2, bring the volume to the total volume, and continue stirring for 10 min. Take samples at 0 h, 12 h, and 24 h to detect the content, pH, and related substances. The test data are shown in Table 4.

[0066] Table 4. Data on the temperature of different solution preparations

[0067]

[0068]

[0069] Conclusion: The above data shows that the stability of the sample is greatly guaranteed when the solution preparation temperature is 10℃, 20℃, and 30℃. However, the temperature is too low, which not only affects the dissolution time of the excipients, but also increases the production cost. Based on the comprehensive data and actual production conditions, the optimal solution preparation temperature is 20-30℃.

[0070] Example 4: Comparison of different filter membrane models and retention areas

[0071] formula:

[0072]

[0073] Preparation process:

[0074] Weigh the raw materials and excipients according to the formula. First, prepare a solution of API and polysorbate 80, add 20% water for injection, and stir for 1.0 h. Then, add the excipients such as disodium edetate, sodium dihydrogen phosphate, and glycerol in sequence. After stirring until completely dissolved, adjust the pH of the solution to 6.0±0.2, bring the volume to the total volume, and continue stirring for 10 min. Statically immerse 0.22 μm microporous filter membranes made of PES, PVDF, and PTFE, respectively. Take samples at 0 h, 12 h, and 24 h to detect the content and related substances. The test data are shown in Tables 5 and 6.

[0075] Furthermore, based on the results in Tables 5 and 6, a PVDF 0.22μm microporous membrane was ultimately used, and the filter element retention area of ​​500cm² was investigated. 2 1000cm 2 1500cm 2 2900cm 2 Different volumes of drug solution were filtered, and the solution content was measured separately. The test data are shown in Tables 7-10.

[0076] Finally, based on the process parameters determined in Examples 1 to 4, process verification samples were prepared and stability was investigated. The test data are shown in Table 11.

[0077] Table 5 Adsorption test data for different filter membrane types

[0078]

[0079] Conclusion: The above data shows that PTFE, PES and PVDF filter membranes all adsorb the content of this product, but PVDF filter membranes have the lowest adsorption capacity.

[0080] Table 6 Compatibility test data for different filter membrane models

[0081]

[0082] Conclusion: The above data shows that PTFE, PES and PVDF filter membranes all affect the stability of this product, but PVDF filter membranes have the least impact on the stability of this product. Based on the data in Table 5, PVDF filter membranes are ultimately the preferred choice.

[0083] Table 7. Filter membrane retention area 500 cm² 2 Test data

[0084] Discarded liquid volume API content (%) EDTA content (%) pH Unfiltered 100.1 100.7 6.02 Primary filtrate 74.2 97.7 6.01 400ml 92.9 100.2 6.04 800ml 95.3 100.1 6.02 1500ml 99.2 99.6 6.03 3000ml 98.6 100.4 6.00 4000ml 100.4 100.1 6.03 5000ml 99.7 100.6 6.01 Mixture 98.2 99.8 6.03

[0085] Table 8. Filter membrane retention area (1000 cm²) 2 Test data

[0086]

[0087]

[0088] Table 9. Filter membrane retention area 1500 cm² 2 Test data

[0089] Discarded liquid volume API content (%) EDTA content (%) pH Unfiltered 101.3 100.6 6.00 Primary filtrate 62.0 94.7 6.03 400ml 85.7 100.1 6.02 800ml 88.3 100.6 6.02 1500ml 94.2 100.0 6.03 3000ml 96.0 100.1 6.00 4000ml 98.7 100.4 6.03 5000ml 101.1 100.4 6.03 Mixture 95.4 99.8 6.00

[0090] Table 10 Filter membrane retention area 2900 cm² 2 Test data

[0091] Discarded liquid volume API content (%) EDTA content (%) pH Unfiltered 101.0 99.1 6.02 Primary filtrate 47.0 94.0 6.03 400ml 65.7 100.0 6.02 800ml 78.1 99.8 6.02 1500ml 84.2 100.1 6.03 3000ml 95.3 100.2 6.00 4000ml 98.0 100.1 6.02 5000ml 98.4 100.4 6.03 Mixture 94.1 99.5 6.00

[0092] Conclusion: Due to the adsorption of the active pharmaceutical ingredient by the filter membrane, the retention area of ​​different filter membranes was investigated. The above data shows that a retention area of ​​500 cm⁻¹ is optimal. 2 1000cm 2 1500cm 2 The filter cartridge reached saturation when the discarded liquid volumes were 1.5L, 3.0L, and 5.0L, respectively. Since the single-vial dosage of this product is 0.3ml, excessive discarded liquid would result in an excessively large finished product. Additionally, although the retention area is 500cm²... 2 While it minimizes waste liquid, it can easily clog the filter cartridge when filtering to a certain volume for large-scale commercial production. Therefore, the optimal filter membrane retention area is 1000 cm². 2 ~1500cm 2 .

[0093] Table 11 Process Validation Stability Test Data

[0094]

[0095] Conclusion: The above data show that the process validation samples prepared according to the established process parameters of this product meet the quality standards for all test items when accelerated to 6M. This indicates that by preparing according to the process parameters of this product, it is easy to formulate tafluprost eye drops with high content, few impurities, stable and uniform solution, and high quality standards.

Claims

1. A method for preparing an aqueous eye drop containing tafluprost, characterized in that, Includes the following steps: (1) During the preparation of the mixture, tafluprost and polysorbate 80 are put into the mixing tank, a stir bar is added, water for injection is added, and the mixture is stirred until completely dissolved. (2) Weigh out the amount of buffer sodium dihydrogen phosphate, antioxidant disodium edetate and binder glycerin according to the formula, and add them to the above mixture in the order of sodium dihydrogen phosphate, glycerin and disodium edetate; after the addition is completed, continue stirring under vacuum negative pressure, and maintain the temperature of the mixture at 20~30℃. (3) Prepare a pH adjuster and adjust the pH value of the mixture with the prepared pH adjuster; the pH adjuster is prepared by adding solid sodium hydroxide to water for injection, with a concentration of 1 mol / L, and adjusts the pH value of the solution to 6.0±0.2; (4) Add water for injection to the mixture until the volume is reached; (5) The solution after volume adjustment is sterilized and filtered; the filtration is carried out in an intermittent manner, discarding an appropriate amount of drug solution that has passed through the sterilization filter to the front end of the buffer tank, and then continuing to filter the drug solution and transport it to the buffer tank; the sterilization and filtration step is carried out using a microporous filter membrane, and the material of the microporous filter membrane is PVDF; (6) Package the sterilized and filtered medicine to complete the production.

2. The method for preparing the aqueous eye drops containing tafluprost according to claim 1, characterized in that, In step (1), under the condition of negative pressure weighing hood and yellow light, magnetic stirring is turned on to mix tafluoroprostol and polysorbate 80. The stirring time is 0.5h~2.0h and the stirring speed is 500~700rpm. The stir bar is made of polytetrafluoroethylene.

3. The method for preparing an aqueous eye drop containing tafluprost according to claim 1, characterized in that, The filtration area of ​​the filter membrane in the filtration process is 500cm² to 2900cm².

4. The method for preparing a water-based eye drop containing tafluprost according to claim 1, characterized in that, The filtration area of ​​the filter membrane in the filtration process is 1000cm²~1500cm².

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