A method for preparing cyclopentolate hydrochloride eye drops

Abstract

The application discloses a preparation method of cyclopentolate hydrochloride eye drops, and belongs to the technical field of ophthalmic preparation. In view of the defects of the existing cyclopentolate hydrochloride eye drops, such as easy hydrolysis of the main drug, substandard storage particles and poor temperature stability, the preparation method is optimized. The eye drops are prepared by using a fine chemical process of water deoxygenation pretreatment, step-by-step dissolution of auxiliary materials, metal ion passivation, controllable swelling of HPMC, accurate pH adjustment, fractional filtration and sterile filling, so as to construct a composite buffer system, chelate metal ions in sufficient amount, and colloid-coat the main drug, and the ester bond hydrolysis of the main drug is effectively inhibited. Tests show that the product has excellent temperature change stability, stable drug efficacy and low irritation, the process is suitable for large-scale sterile production, and has good clinical and industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of ophthalmic preparation technology, specifically relating to a method for preparing cyclopentolate hydrochloride eye drops. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Cyclopentolate hydrochloride is a commonly used short-acting anticholinergic ophthalmic drug that competitively blocks M-cholinergic receptors in the eye, effectively relaxing the ciliary muscle, paralyzing the eye's accommodative function, and dilating the pupil. It has the advantages of rapid onset of mydriasis, good ciliary muscle paralysis effect, and short postoperative recovery period. It is widely used in the refraction of refractive errors in adolescents, screening and diagnosis of fundus diseases, and as an adjunct clinical treatment for iridocyclitis. It is an indispensable core mydriatic drug in ophthalmic diagnosis and treatment, and there is a large demand for its clinical application.

[0004] Cyclopentolate hydrochloride contains easily hydrolyzed ester bonds in its molecular structure, making its chemical stability highly sensitive to the pH environment, metal ions, dissolved oxygen, and storage temperature. During long-term storage, it is prone to hydrolytic degradation, leading to a decrease in the active pharmaceutical ingredient content and pH shift in the solution. Furthermore, degradation products can cause turbidity and the precipitation of particulate matter, severely restricting the storage stability and shelf-life quality of cyclopentolate hydrochloride eye drops. Therefore, a rational formulation system and refined dispensing processes are crucial for ensuring the stable quality and safe use of this type of eye drop.

[0005] Currently available commercially available and literature-reported formulations of cyclopentolate hydrochloride eye drops generally suffer from numerous technical defects. For example, conventional formulations often use boric acid alone as a pH adjuster without combining it with borax to construct a complete buffer system. This results in extremely low buffering capacity, which cannot offset the pH fluctuations caused by the slow hydrolysis of the active ingredient. Long-term storage, especially under high temperatures, leads to significant pH shifts, further accelerating the hydrolysis and degradation of the active ingredient's ester bonds, resulting in a decrease in the effective drug content. Simultaneously, the traditional formulations use extremely low amounts of disodium edetate, limiting their chelation and passivation effects on trace heavy metal ions in water. These heavy metal ions continue to catalyze the hydrolysis of the active ingredient, exacerbating the deterioration of the solution.

[0006] In addition, most traditional cyclopentolate hydrochloride eye drops formulations do not contain viscosity-regulating excipients such as hydroxypropyl methylcellulose (HPMC). On the one hand, the low viscosity of the solution results in a short retention time of the drug on the ocular surface, poor bioavailability, and poor duration of clinical efficacy. On the other hand, the lack of the protective coating effect of high molecular weight colloids means that the active pharmaceutical ingredient is directly exposed to the aqueous environment, making it highly sensitive to temperature and impurities, more prone to degradation and deterioration, and more likely to generate fine impurities and insoluble particles during storage, reducing the clarity and safety of the eye drops.

[0007] At the manufacturing process level, traditional solution preparation technology is crude and has obvious shortcomings: the water used for solution preparation is not deoxygenated, and dissolved oxygen in the water can induce oxidation and deterioration of the active pharmaceutical ingredient; all raw materials and excipients are mixed and added at once without refined processes such as stepwise dissolution, metal ion passivation, and controlled swelling of polymers, which easily leads to problems such as HPMC agglomeration, insufficient dissolution of excipients, and incomplete passivation of metal ions; at the same time, there is a lack of refined treatment through graded filtration, relying only on single terminal filtration, which cannot completely remove trace flocculent matter and fine insoluble particles. Ultimately, this leads to problems such as opalescence, turbidity, and excessive particulate matter in the finished eye drops after long-term storage. The product has poor temperature stability, and its quality deteriorates significantly under high and low temperature storage conditions, which seriously affects the safety and effectiveness of medication within the product's shelf life.

[0008] In summary, existing cyclopentolate hydrochloride eye drops suffer from multiple problems, including a lack of buffer system, unreasonable stabilizer ratios, absence of colloidal protective structure, and crude preparation processes. They generally exhibit poor pH stability, rapid degradation of the active ingredient, excessive levels of insoluble microparticles, weak temperature resistance, and unstable quality over shelf life, making it difficult to meet the demands for high-quality, highly stable ophthalmic preparations for production and clinical use. Therefore, this invention proposes a novel method for preparing cyclopentolate hydrochloride eye drops. By optimizing the formulation ratios and refining the step-by-step preparation process, it addresses many of the technical bottlenecks of existing technologies. Summary of the Invention

[0009] To address the problems existing in the prior art, the present invention provides the following solution: In a first aspect, a method for preparing cyclopentolate hydrochloride eye drops is provided, wherein the components of the eye drops are as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.10~0.14mg, boric acid 7~9mg, borax 0.20~0.24mg, potassium chloride 1.8~2.0mg, HPMC 0.7~0.9mg, diluted to 1mL with water for injection, and the pH adjusted to 3.8±0.2 with hydrochloric acid; The method for preparing the solution is characterized by first adding boric acid, borax, and potassium chloride to water for injection to construct a buffer base, then adding disodium edetate to passivate metal ions in the water, adding hydroxypropyl methylcellulose (HPMC) to form a thickening base, and then adding cyclopentolate hydrochloride, dissolving, and adjusting the pH value after volume adjustment.

[0010] To address the poor stability and pH sensitivity of cyclopentolate hydrochloride, this invention proposes a boric acid buffer system to suppress pH drift. Furthermore, traditional solution preparation processes, which involve a one-time mixing and addition of raw materials and excipients, are prone to defects such as insufficient dissolution of excipients, poor system stability, precipitation of insoluble particles during storage, and weak temperature stability. To resolve these issues, this invention optimizes the eye drop formulation by incorporating a boric acid-borax composite buffer system, appropriately increasing the amount of disodium edetate, and adding HPMC as a functional excipient. Simultaneously, the solution preparation process is optimized through a step-by-step, precise preparation process: pre-preparation of the buffer substrate, pre-passivation of metal ions, initial addition of a colloidal thickening substrate, and final addition of the active pharmaceutical ingredient. This allows for precise pH control of the solution.

[0011] Experimental verification shows that the optimized solution preparation process of this invention can effectively inhibit the hydrolytic degradation of the active pharmaceutical ingredient, significantly reduce the pH drift of the solution, and reduce the precipitation of insoluble particles. This allows the eye drops to maintain a good appearance and stable active pharmaceutical ingredient content under both high and low temperature storage conditions. At the same time, the thickening effect of HPMC also helps to prolong the drug's residence time on the ocular surface and reduce ocular irritation, significantly improving the overall quality stability and clinical safety of the product.

[0012] Furthermore, the above solution preparation process steps are as follows: (1) Preparation of buffer substrate: Boil 60-80% of the prescription amount of water for injection to deoxygenate, add boric acid, borax and potassium chloride and stir at room temperature until dissolved to obtain the substrate solution; (2) Metal ion passivation: Add disodium edetate to the substrate solution, stir in the dark until dissolved, and obtain solution passivation; (3) Preparation of thickening base: HPMC is added to allow it to swell fully and form a thickening base; (4) Dissolving the main drug: Add cyclopentolate hydrochloride in the dark and stir until completely dissolved; (5) Volume adjustment and homogenization: Add the remaining water for injection to the prescribed amount and continue stirring for a period of time to ensure that the drug solution is fully homogenized; (6) pH adjustment: While maintaining stirring, add hydrochloric acid to adjust the pH to 3.8±0.05; (7) Graded filtration sterilization: The drug solution obtained in step (6) is filtered sequentially through 0.45μm and 0.22μm filter membranes; (8) Aseptic filling: The filtered liquid from step (7) is immediately aseptically filled.

[0013] The operating temperature for the above-mentioned solution preparation process is room temperature, or more specifically, 20~22℃.

[0014] The stirring speed of the above-mentioned liquid preparation process is 80~120r / min, and the speed can be adjusted according to the properties of the added materials; further, in the above step (3), after adding HPMC, the first step is to use a fast stirring method to disperse it, and then to use a slow stirring method to make it fully swollen; in a further embodiment, the speed of the fast stirring is 100~120r / min for 4~6min, and the speed of the slow stirring is 80~90r / min for 15~25min.

[0015] The above-mentioned solution preparation process is carried out under light-protected conditions, and in a more preferred embodiment, it is carried out in an inert gas atmosphere.

[0016] In step (7) above, the appropriate flow rate for the graded filtration is 15~19 mL / min.

[0017] In step (8) above, the cleanliness of the filling environment should reach level D or above, and the relative humidity should be 40-60%.

[0018] In the embodiment of the present invention that has been verified to have good results, the specific steps of the solution preparation process are as follows: (1) Preparation of buffer base: Take 70% of the prescribed amount of water for injection, boil for 3-5 minutes for deoxygenation treatment, and cool naturally to a constant temperature of 20-22℃ in a sealed environment; add the prescribed amount of boric acid, borax and potassium chloride in sequence, and stir at a speed of 100-120 r / min for 12-15 minutes in a sealed environment at room temperature until the excipients are completely clear and dissolved to form a base solution; (2) Metal ion passivation: Add disodium edetate to the substrate solution obtained in step (1), maintain the temperature at 20-22℃ and under sealed and light-proof conditions, stir at 90-110r / min for 8-10min to allow disodium edetate to fully dissociate, and complete the solution passivation pretreatment; (3) Preparation of thickening base: Keep the system at a constant temperature of 20-22℃ and in a closed, light-proof, low-oxygen environment. Sprinkle in 0.8 mg of the prescribed amount of HPMC. First, disperse and stir rapidly at 110-120 r / min for 5 min to avoid clumping and agglomeration. Then, reduce the speed to 80-90 r / min and continue to swell at a low speed for 20 min to allow HPMC to fully hydrate and swell to form a thickening base. (4) Dissolving the main drug: Maintain a constant temperature of 20-22℃, in a dark and low-oxygen environment, add cyclopentolate hydrochloride, and stir continuously at 80-100 r / min for 25-30 min until the drug solution is completely clear and there are no visible particles; (5) Volume adjustment and homogenization: Add sterile water for injection at a remaining temperature of 20-22℃ to adjust the volume to the full prescription volume. Close the system and stir at a low speed of 70-90r / min for 10-12min to complete the homogenization and mixing of the drug solution. (6) pH adjustment: Maintain a constant temperature of 20-22℃ and a low-speed uniform stirring state of 70-90r / min; accurately deliver hydrochloric acid solution through an automated metering pump, with a single drop volume controlled at 0.5-1.0μL. After the drop is added, the equipment automatically delays stirring for 2-3 minutes. After the system values ​​stabilize, collect pH data online and repeatedly correct until the pH of the solution is stably locked at 3.8±0.05. (7) Graded filtration and sterilization: In a Class D clean area environment and at a temperature of 20-22℃, the homogenized drug solution is first pre-filtered through a 0.45μm aqueous microporous membrane to remove trace amounts of HPMC flocculents and insoluble particles of raw materials and excipients, and then terminally sterilized through a 0.22μm Millipore aqueous microporous membrane. The filtration flow rate is controlled at 15-20mL / min. (8) Aseptic filling: The filtered medicine solution is immediately aseptically filled. The 1mL / vial specification is filled and capped within 3 seconds. The cleanliness of the filling environment is Class D. The ambient temperature is controlled at 18-22℃ and the relative humidity is 40%-60%. Finally, it is sealed and stored in a sterile LDPE eye drop bottle.

[0019] Compared with the prior art, the beneficial effects of the present invention are: This invention addresses the shortcomings of existing cyclopentolate hydrochloride eye drops formulations, such as imperfections, crude preparation processes, and poor product stability. It optimizes the design of a proprietary buffer formulation, functional excipient system, and refined step-by-step preparation process. Compared to existing technologies, it possesses several significant technical advantages and beneficial effects: First, this invention constructs a boric acid-borax composite buffer system, replacing the traditional single boric acid adjustment mode, and significantly improving the buffer capacity of the drug solution. This buffer system can form a stable buffer equilibrium within the pH range of 3.8±0.05, where cyclopentolate hydrochloride is most stable. It can effectively counteract the acidic substances generated by the trace hydrolysis of the active ingredient, greatly suppress pH drift during long-term storage and under fluctuating temperature conditions, and avoid accelerating the hydrolysis of the ester bonds of the active ingredient due to acid-base imbalance. It stabilizes the drug solution system from the source of the formulation, effectively reduces the degradation rate of the active ingredient, ensures the stability of the content of active ingredients within the product's shelf life, and improves the consistency of drug quality.

[0020] Secondly, this invention optimizes the dosage ratio of disodium edetate. Compared with the traditional low-dose addition scheme, it can fully chelate trace heavy metal ions in the water used for preparing the solution, thoroughly complete the passivation pretreatment of water metal ions, eliminate the catalytic effect of heavy metal ions on the hydrolysis of cyclopentolate hydrochloride ester bonds, reduce the oxidation and hydrolysis of the main drug, further improve the chemical stability of the drug solution, reduce the amount of impurities generated, and reduce the occurrence of quality problems such as turbidity and discoloration of the drug solution.

[0021] Third, this invention innovatively adds hydroxypropyl methylcellulose (HPMC) as a functional excipient, which has the dual functions of enhancing efficacy and stabilizing the formulation. On the one hand, HPMC can moderately increase the viscosity of the drug solution, effectively prolonging the retention time of the drug on the ocular surface and cornea, preventing rapid drug loss, significantly improving drug bioavailability, and optimizing the clinical therapeutic effects of mydriasis and cycloplegia. On the other hand, HPMC polymer colloid can form a protective coating on the cyclopentolate hydrochloride active ingredient, isolating it from interference from the water environment, temperature changes, and trace impurities, further inhibiting the degradation of the active ingredient. At the same time, it can effectively improve the homogeneity of the drug solution system, reduce the precipitation of insoluble particles during storage, and improve the clarity and safety of the eye drops. In addition, HPMC has good ocular surface lubrication, which can effectively reduce the foreign body sensation and irritation in the eye after administration of the eye drops, improving the comfort of use.

[0022] Fourth, this invention employs a refined solution preparation process that includes deoxygenation pretreatment, stepwise dissolution of excipients, pre-passivation of metal ions, controllable swelling of HPMC, precise pH control, and staged filtration for sterilization, completely abandoning the traditional crude process of one-time mixing. Deoxygenation of the solution using water removes dissolved oxygen, preventing oxidation and deterioration of the active pharmaceutical ingredient. Stepwise feeding and gradient stirring processes eliminate problems such as HPMC agglomeration, insufficient dissolution of excipients, and incomplete passivation of metal ions, ensuring that each excipient system functions fully. Precise addition of hydrochloric acid to control pH ensures the solution pH is precisely locked within the optimal stable range. A 0.45μm pre-filtration combined with a 0.22μm terminal staged filtration mode thoroughly removes trace amounts of flocculent matter and insoluble particles, significantly improving the cleanliness of the solution.

[0023] Fifth, the overall formulation and process of this invention synergistically enhance the temperature resistance and long-term storage stability of cyclopentolate hydrochloride eye drops. After long-term storage verification at high and low temperatures, the eye drops prepared by this invention showed no abnormal appearance such as turbidity, precipitation, or discoloration, minimal pH drift, high retention rate of the active ingredient, and a significantly lower number of insoluble microparticles compared to traditional formulations. This effectively addresses the industry pain points of existing products, such as susceptibility to high-temperature deterioration, excessive microparticles, and unstable shelf-life quality. It significantly improves the safety and efficacy of the medication within its shelf life, meets the needs of large-scale aseptic production, and possesses extremely high industrialization and promotion value. Attached Figure Description

[0024] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0025] Figure 1 This is a schematic diagram of the intelligent liquid preparation system described in Example 4; Among them, 1 is the solution preparation unit, 2 is the water for injection unit, 3 is the pH adjustment unit, 4 is the material storage unit, 5 is the filtration unit, and 6 is the filling unit. 101 is the thermal jacket, 102 is the stirrer, 103 is the power assembly, 104 is the gravity sensor, 105 is the temperature sensor, 106 is the sterilization device, 201 is the water for injection storage tank, 202 is the temperature control device, 301 is the micro-volume hydrochloric acid titration pump, 302 is the pH detection electrode, 401 is the first hopper, 402 is the second hopper, 403 is the hopper, 404 is the main hopper, 501 is the primary filter membrane, and 502 is the secondary filter membrane. Detailed Implementation

[0026] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0028] In the context of this invention, the word "comprising" is considered to mean "particularly including". It should not be interpreted as "consisting of only".

[0029] In the description of this invention, it should be understood that the term "and / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, and B existing alone. The symbol " / " in this document indicates that the related objects are in an "or" relationship; for example, A / B means A or B.

[0030] In the description of embodiments of the present invention, the words "exemplary" or "for example" are used to indicate that they are examples, illustrations, or descriptions. Any embodiment or design that is described as "exemplary" or "for example" in the embodiments of the present invention should not be construed as being more preferred or advantageous than other embodiments or design. Specifically, the use of the words "exemplary" or "for example" is intended to present the relevant concepts in a specific manner.

[0031] In the description of the embodiments of this invention, unless otherwise stated, "a plurality of" means two or more. To enable those skilled in the art to more clearly understand the technical solutions of this invention, the technical solutions of this invention will be described in detail below with reference to specific embodiments and comparative examples.

[0032] Example 1 This embodiment provides a method for preparing cyclopentolate hydrochloride eye drops, the components of which are as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.12mg, boric acid 8mg, borax 0.22mg, potassium chloride 1.9mg, HPMC 0.8mg, diluted to 1mL with water for injection, and the pH was adjusted to 3.8 with 0.05mol / L hydrochloric acid.

[0033] The preparation method for the above eye drops is as follows: (1) Preparation of buffer base: Take 70% of the prescription amount of water for injection, boil for 4 minutes for deoxygenation treatment, and cool naturally to a constant temperature of 21°C in a sealed environment; add the prescription amount of boric acid, borax and potassium chloride in sequence, and stir at a speed of 110 r / min for 13 minutes in a sealed environment at room temperature until the excipients are completely clear and dissolved to form a base solution. (2) Metal ion passivation: Add disodium edetate to the substrate solution obtained in step (1), maintain the temperature at 21°C and under sealed and light-proof conditions, stir at 100 r / min for 9 min to allow disodium edetate to fully dissociate and complete the solution passivation pretreatment; (3) Preparation of thickening base: Keep the system at a constant temperature of 21°C and in a closed, light-proof, low-oxygen environment. Add the prescribed amount of HPMC. First, disperse and stir rapidly at 115r / min for 5min to avoid clumping and agglomeration. Then, reduce the speed to 85r / min and continue to swell at a low speed for 20min to allow HPMC to fully hydrate and swell to form a thickening base. (4) Dissolving the main drug: Maintain a constant temperature of 21°C, a light-proof and low-oxygen environment, add cyclopentolate hydrochloride, and stir continuously at 90 r / min for 27 min until the drug solution is completely clear and there are no visible particles. (5) Volume adjustment and homogenization: Add sterile water for injection at the remaining temperature of 21°C to adjust the volume to the full prescription volume. Close the system and stir at a low speed of 80r / min for 12min to complete the homogenization and mixing of the drug solution. (6) pH adjustment: Maintain a constant temperature of 21℃ and a low-speed uniform stirring state of 80r / min; accurately deliver hydrochloric acid solution through an automated metering pump, with a single drop volume controlled at 0.7μL. After the drop is added, the equipment automatically delays stirring for 2.5min. After the system values ​​stabilize, collect pH data online and repeatedly correct until the pH of the solution is stably locked at 3.8±0.05. (7) Graded filtration and sterilization: In a Class D clean area environment and at a temperature of 21°C, the homogenized drug solution is first pre-filtered through a 0.45μm aqueous microporous membrane to remove trace amounts of HPMC flocculents and insoluble particles of raw materials and excipients, and then terminally sterilized through a 0.22μm Millipore aqueous microporous membrane. The filtration flow rate is controlled at 17mL / min. (8) Aseptic filling: The filtered medicine solution is immediately aseptically filled. The 1mL / vial specification is filled and capped within 3 seconds. The cleanliness of the filling environment is Class D, the ambient temperature is controlled at 20℃ and the relative humidity is 50%. Finally, it is sealed and stored in a sterile LDPE eye drop bottle.

[0034] Example 2 This embodiment provides a method for preparing cyclopentolate hydrochloride eye drops, the components of which are as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.10mg, boric acid 7mg, borax 0.20mg, potassium chloride 1.8mg, HPMC 0.7mg, diluted to 1mL with water for injection, and the pH was adjusted to 3.8 with 0.05mol / L hydrochloric acid.

[0035] The preparation method for the above eye drops is as follows: (1) Preparation of buffer base: Take 70% of the prescription amount of water for injection, boil for 3 minutes for deoxygenation treatment, and cool naturally to a constant temperature of 20°C in a sealed environment; add the prescription amount of boric acid, borax and potassium chloride in sequence, and stir at a speed of 100 r / min for 15 minutes in a sealed environment at room temperature until the excipients are completely clear and dissolved to form a base solution. (2) Metal ion passivation: Add disodium edetate to the substrate solution obtained in step (1), maintain the temperature at 20°C and the conditions of sealing and avoiding light, stir at 90 r / min for 10 min to allow disodium edetate to fully dissociate, and complete the solution passivation pretreatment. (3) Preparation of thickening base: Keep the system at a constant temperature of 20℃ and in a closed, light-proof, low-oxygen environment. Sprinkle in 0.8 mg of the prescribed amount of HPMC. First, disperse and stir rapidly at 120 r / min for 5 min to avoid clumping and agglomeration. Then, reduce the speed to 90 r / min and continue to swell at a low speed for 20 min to allow HPMC to fully hydrate and swell to form a thickening base. (4) Dissolving the main drug: Maintain a constant temperature of 20°C, a light-proof and low-oxygen environment, add cyclopentolate hydrochloride, and stir continuously at 80 r / min for 30 min until the drug solution is completely clear and there are no visible particles. (5) Volume adjustment and homogenization: Add sterile water for injection at the remaining temperature of 20°C to adjust the volume to the full prescription volume, close the system, and stir at a low speed of 70r / min for 12min to complete the homogenization and mixing of the drug solution. (6) pH adjustment: Maintain a constant temperature of 20℃ and a low-speed uniform stirring state of 70r / min; accurately deliver hydrochloric acid solution through an automated metering pump, with a single drop volume controlled at 0.5μL. After the drop is added, the equipment automatically delays stirring for 2 minutes. After the system values ​​stabilize, collect pH data online and repeatedly correct until the pH of the solution is stably locked at 3.8±0.05. (7) Graded filtration and sterilization: In a Class D clean area environment and at a temperature of 20℃, the homogenized drug solution is first pre-filtered through a 0.45μm aqueous microporous membrane to remove trace amounts of HPMC flocculents and insoluble particles of raw materials and excipients, and then terminally sterilized through a 0.22μm Millipore aqueous microporous membrane. The filtration flow rate is controlled at 15mL / min. (8) Aseptic filling: The filtered medicine solution is immediately aseptically filled. The 1mL / vial specification is filled and capped within 3 seconds. The cleanliness of the filling environment is Class D, the ambient temperature is controlled at 18℃ and the relative humidity is 40%. Finally, it is sealed and stored in a sterile LDPE eye drop bottle.

[0036] Example 3 This embodiment provides a method for preparing cyclopentolate hydrochloride eye drops, the components of which are as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.14mg, boric acid 9mg, borax 0.24mg, potassium chloride 2.0mg, HPMC 0.9mg, diluted to 1mL with water for injection, and the pH was adjusted to 3.8 with 0.05mol / L hydrochloric acid.

[0037] The preparation method for the above eye drops is as follows: (1) Preparation of buffer base: Take 80% of the prescription amount of water for injection, boil for 5 minutes for deoxygenation treatment, seal and isolate from air and cool naturally to a constant temperature of 22°C; add the prescription amount of boric acid, borax and potassium chloride in sequence, and stir at a speed of 120 r / min for 15 minutes in a sealed room temperature environment until the excipients are completely clear and dissolved to form a base solution. (2) Metal ion passivation: Add disodium edetate to the substrate solution obtained in step (1), maintain the temperature at 22℃ and the conditions of sealing and avoiding light, stir at 110r / min for 8min to allow disodium edetate to fully dissociate, and complete the solution passivation pretreatment. (3) Preparation of thickening base: Keep the system at a constant temperature of 22℃ and in a closed, light-proof, low-oxygen environment. Sprinkle in 0.8 mg of the prescribed amount of HPMC. First, disperse and stir rapidly at 120 r / min for 5 min to avoid clumping and agglomeration. Then, reduce the speed to 90 r / min and continue to swell at a low speed for 20 min to allow HPMC to fully hydrate and swell to form a thickening base. (4) Dissolving the main drug: Maintain a constant temperature of 22°C, a light-proof and low-oxygen environment, add cyclopentolate hydrochloride, and stir continuously at 100 r / min for 25 min until the drug solution is completely clear and there are no visible particles. (5) Volume adjustment and homogenization: Add sterile water for injection at the remaining temperature of 22°C to adjust the volume to the full prescription volume, close the system, and stir at a low speed of 90r / min for 10min to complete the homogenization and mixing of the drug solution. (6) pH adjustment: Maintain a constant temperature of 22℃ and a low-speed uniform stirring state of 90r / min; accurately deliver hydrochloric acid solution through an automated metering pump, with a single drop volume controlled at 1.0μL. After the drop is added, the equipment automatically delays stirring for 3 minutes. After the system values ​​stabilize, collect pH data online and repeatedly correct until the pH of the solution is stably locked at 3.8±0.05. (7) Graded filtration and sterilization: In a Class D clean area environment and at a temperature of 22℃, the homogenized drug solution is first pre-filtered through a 0.45μm aqueous microporous membrane to remove trace amounts of HPMC flocculents and insoluble particles of raw materials and excipients, and then terminally sterilized through a 0.22μm Millipore aqueous microporous membrane. The filtration flow rate is controlled at 20mL / min. (8) Aseptic filling: The filtered medicine solution is immediately aseptically filled. The 1mL / vial specification is filled and capped within 3 seconds. The cleanliness of the filling environment is Class D, the ambient temperature is controlled at 22℃ and the relative humidity is 60%. Finally, it is sealed and stored in a sterile LDPE eye drop bottle.

[0038] Example 4 In this embodiment, an intelligent solution preparation system for the cyclopentolate hydrochloride eye drops described in Examples 1-3 is provided. The structure of the intelligent solution preparation system is as follows: Figure 1 As shown, it includes a solution preparation unit 1, a water for injection unit 2, a pH adjustment unit 3, a storage unit 4, a filtration unit 5, and a filling unit 6.

[0039] The liquid preparation unit 1 is a vessel for mixing various raw materials. The vessel contains a thermal jacket 101, a stirrer 102, a power assembly 103, a gravity sensor 104, a temperature sensor 105, and a sterilization device 106. The thermal jacket 101 is attached to the inner wall of the vessel and is used to regulate the temperature of the materials inside. The stirrer 102 extends into the vessel from the top and, driven by the power assembly 103, agitates the liquid within the vessel. The gravity sensor is located at the bottom of the vessel and measures the weight of the liquid to control the feed rate and the volumetric dosage of water for injection. The sterilization device 106 is located at the top of the vessel and is used to disinfect and sterilize the interior of the vessel.

[0040] The water for injection unit 2 is used to complete the boiling and deoxygenation and closed cooling of water for injection, providing a low-oxygen and sterile purified water source for the solution preparation process. The water for injection unit 2 includes a water for injection storage tank 201 and a temperature control device 202. The water for injection storage tank 201 has a heat jacket, which can achieve the boiling, sterilization and heat preservation of water for injection under the regulation of the temperature control device 202.

[0041] The pH adjustment unit 3 is located at the bottom of the vessel of the liquid preparation unit 1, and includes a micro-hydrochloric acid titration pump 301 and a pH detection electrode 302. The pH detection electrode 302 is located at the bottom of the vessel, and the micro-hydrochloric acid titration pump 301 is located outside the vessel.

[0042] The storage unit 4 includes a first silo 401, a second silo 402, a third silo 403, and a main silo 404; wherein, the first silo 401 is used to hold boric acid, borax, and potassium chloride mixed in proportion, the second silo is used to hold disodium edetate, the third silo is used to hold HPMC, and the main silo is used to hold cyclopentolate hydrochloride. Each of the above silos has an automatic feeding structure.

[0043] The filtration unit 5 includes a primary filter membrane 501 and a secondary filter membrane 502, which are connected in series on the pipeline from the bottom of the liquid preparation unit 1 to the filling unit 6. It can remove trace amounts of flocculent matter and insoluble particles step by step and complete aseptic sterilization; finally, the medicine is rapidly and tightly filled and capped by the aseptic filling mechanism 8.

[0044] The filling unit 6 is located in a Class D clean area, where the ambient humidity is controlled at 40-60%.

[0045] The intelligent liquid preparation system also has core intelligent control components, which are electrically connected to the liquid preparation unit 1, the water for injection unit 2, the pH adjustment unit 3, the storage unit 4, the filtration unit 5, and the filling unit 6, respectively. It adopts a PLC programmable controller as the core and integrates a temperature control module, a speed control module, a pH acquisition and control module, a quantitative feeding module, a timing control module, and an environmental monitoring module to achieve full-process programmed and closed-loop intelligent management and control.

[0046] Comparative Example 1 In this comparative example, another method for preparing cyclopentolate hydrochloride eye drops is provided. The difference from Example 1 is that the raw material components of the eye drops do not contain borax, and the dosage of the other components is the same as in Example 1, supplemented by water for injection.

[0047] The remaining settings are the same as in Example 1.

[0048] Comparative Example 2 In this comparative example, another method for preparing cyclopentolate hydrochloride eye drops is provided. The difference from Example 1 is that the raw material components of the eye drops do not contain HPMC, and the dosage of the other components is the same as in Example 1, supplemented by water for injection.

[0049] The remaining settings are the same as in Example 1.

[0050] Comparative Example 3 This comparative example provides a method for preparing a conventional cyclopentolate hydrochloride eye drop solution, the composition of which is as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.05mg, boric acid 8mg, potassium chloride 1.9mg, pH adjusted to 3.8 with 0.05mol / L hydrochloric acid solution, and water for injection added to 1ml.

[0051] The preparation steps for the above eye drops are as follows: (1) Dissolving: Take 60% of the prescribed amount of water for injection, add cyclopentolate hydrochloride and stir until visually dissolved, then add potassium chloride and stir until visually dissolved, then add disodium edetate and boric acid and stir until visually dissolved.

[0052] (2) pH adjustment: The pH of the above solution was adjusted to 3.8 with 0.05 mol / L hydrochloric acid solution.

[0053] (3) Volume adjustment: Add water for injection to adjust the volume to the prescribed amount.

[0054] (4) Filtration and sterilization: The above solution is filtered and sterilized through a 0.22μm microporous membrane (Millipore, water system).

[0055] (5) Filling: Fill the LDPE eye drop bottle with a filling volume of 1ml / vial.

[0056] Performance testing To verify the physicochemical stability of the eye drops prepared in the above embodiments and comparative examples at different storage temperatures, the temperature resistance of the above eye drop products was investigated: Temperature resistance performance: The encapsulated samples of Example 1 and Comparative Examples 1-3 were placed under low temperature conditions (5℃±2℃), normal temperature conditions (25℃±2℃), and high temperature conditions (45℃±2℃), respectively. The humidity was uniformly controlled at 60%±5%, and the samples were stored in a sealed and light-proof environment throughout the process. Samples were taken, photographed, and measured at 0d and 60d.

[0057] 1. Appearance condition measurement Visually observe the state of each group of sample solutions under natural light, and record whether there are any abnormalities such as turbidity, discoloration, white spots, flocculent precipitates, or precipitated particles. Compare the differences in appearance stability of each group of samples. The results are shown in Table 1 below.

[0058] Table 1. Results of appearance measurement for Examples 1-3 and Comparative Examples 1-3 The samples in Examples 1-3 showed basic stability at different temperatures, demonstrating that the boric acid-borax buffer system and HPMC colloidal protection effectively inhibited the hydrolysis of the active pharmaceutical ingredient's ester bonds and the precipitation of impurities. In the comparative examples, Comparative Example 3, lacking multiple excipients and without deoxygenation pretreatment, exhibited the greatest degree of active pharmaceutical ingredient hydrolysis and the most severe deterioration in appearance. Comparative Example 2 showed more pronounced precipitation compared to Comparative Example 1, proving that HPMC can effectively encapsulate the drug and resist drug precipitation caused by temperature changes.

[0059] 2. pH value detection Using a calibrated precision laboratory pH meter, the pH values ​​of each group of samples were measured under a constant temperature of 20℃. Each group was measured in triplicate, and the average value was calculated. The pH shift was recorded, and the pH drift amplitude of each group was compared. The results are shown in Table 2 below. Table 2. pH drift measurement results of Examples 1-3 and Comparative Examples 1-3 This invention inhibits pH drift of drugs during storage by constructing a boric acid-borax buffer pair. According to the results in Table 2, the buffer system in the examples was complete, with pH fluctuations ≤ ±0.04 across the entire temperature range; Comparative Example 1 lacked borax and only contained boric acid, resulting in insufficient buffer capacity; as the active pharmaceutical ingredient hydrolyzed, organic acids were generated, leading to a significant pH decrease; Comparative Example 2 had a complete buffer system but lacked HPMC, resulting in insufficient molecular stabilization and a higher pH drift than the examples; Comparative Example 3 had no buffer system and insufficient EDTA, accelerating hydrolysis and generating a large amount of organic acids, resulting in the largest pH shift.

[0060] 3. Detection of cyclopentolate hydrochloride content Chromatographic conditions and system suitability tests were performed using cyano-bonded silica gel as the stationary phase; acetonitrile-phosphate buffer (pH 7.0) (50:50) as the mobile phase; and a detection wavelength of 220 nm. The detection results are shown in Table 3 below. Table 3. Results of active ingredient content determination in Examples 1-3 and Comparative Examples 1-3 According to the results in Table 3, the examples relied on a four-pronged synergistic effect: buffering to stabilize pH, EDTA passivation of metal ions to inhibit catalytic hydrolysis, HPMC coating of the active pharmaceutical ingredient to isolate it from the aquatic environment, and solution preparation for oxygen removal and anti-oxidation. This resulted in the slowest degradation of the active pharmaceutical ingredient, with a maximum reduction of <3.5% after 60 days. Comparative Examples 1 and 2, lacking only a single component, showed a slight increase in degradation rate, with contents exceeding 90% of the acceptable limit across all temperature ranges. Comparative Example 3, lacking all multiple protective elements, experienced significant hydrolysis of the active pharmaceutical ingredient's ester bonds under high-temperature conditions, resulting in a content very close to the 90% pharmacopoeia limit after 60 days of high-temperature storage.

[0061] 4. Detection of insoluble particulate matter The number of particles ≥10μm and ≥25μm per milliliter of drug solution was detected using an insoluble particulate detector. The effects of staged filtration and HPMC dispersion processes on improving the cleanliness of the drug solution were evaluated. The results are shown in Table 4 below: Table 4. Results of insoluble particulate matter content determination in Examples 1-3 and Comparative Examples 1-3 According to Table 4, the examples showed the best performance in terms of degradation impurities and particulate matter during storage. Comparative Example 1 had no buffer system, and Comparative Example 2 had no HPMC. During storage, hydrolytic impurities continued to precipitate, and the particulate matter increased step by step. Comparative Example 3 had no stabilizing excipients, no deoxygenation and refined solution preparation process. As a result, a large amount of impurities precipitated, and the particulate matter seriously exceeded the standard, which did not meet the pharmacopoeia requirements for eye drops.

[0062] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing cyclopentolate hydrochloride eye drops, characterized in that, The ingredients of the eye drops are as follows: Cyclopentolate hydrochloride 10mg, disodium edetate 0.10~0.14mg, boric acid 7~9mg, borax 0.20~0.24mg, potassium chloride 1.8~2.0mg, HPMC 0.7~0.9mg, diluted to 1mL with water for injection, and the pH adjusted to 3.8±0.2 with hydrochloric acid; The solution preparation method is characterized by first adding boric acid, borax, and potassium chloride to water for injection to construct a buffer substrate, then adding disodium edetate to passivate metal ions in the water, adding HPMC to form a thickening substrate, and then adding cyclopentolate hydrochloride, dissolving, and adjusting the pH value.

2. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 1, characterized in that, The solution preparation process steps are as follows: (1) Preparation of buffer substrate: Boil 60-80% of the prescription amount of water for injection to deoxygenate, add boric acid, borax and potassium chloride and stir at room temperature until dissolved to obtain the substrate solution; (2) Metal ion passivation: Add disodium edetate to the substrate solution, stir in the dark until dissolved, and obtain solution passivation; (3) Preparation of thickened base: HPMC is added to allow it to swell fully and form a thickened base; (4) Dissolving the main drug: Add cyclopentolate hydrochloride in the dark and stir until completely dissolved; (5) Volume adjustment and homogenization: Add the remaining water for injection to the prescribed amount and continue stirring for a period of time to ensure that the drug solution is fully homogenized; (6) pH adjustment: While maintaining stirring, add hydrochloric acid to adjust the pH to 3.8±0.05; (7) Graded filtration sterilization: The drug solution obtained in step (6) is filtered sequentially through 0.45μm and 0.22μm filter membranes; (8) Aseptic filling: The filtered liquid from step (7) is immediately aseptically filled.

3. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 2, characterized in that, The operating temperature of the solution preparation process is room temperature, and more specifically, 20~22℃.

4. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 2, characterized in that, The stirring speed involved in the liquid preparation process is 80~120 r / min.

5. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 4, characterized in that, In step (3), after adding HPMC, first use a fast stirring method to disperse it, and then use a slow stirring method to make it fully swell; the speed of the fast stirring is 100~120r / min for 4~6min, and the speed of the slow stirring is 80~90r / min for 15~25min.

6. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 2, characterized in that, The solution preparation process is carried out under light-protected conditions, and more preferably, it is carried out in an inert gas atmosphere.

7. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 2, characterized in that, In step (7), the appropriate flow rate for the graded filtration is 15~19 mL / min.

8. The method for preparing cyclopentolate hydrochloride eye drops as described in claim 2, characterized in that, In step (8), the cleanliness of the filling environment should reach level D or above, and the relative humidity should be 40-60%.

9. The method for preparing cyclopentolate hydrochloride eye drops according to any one of claims 1-8, characterized in that, The specific steps of the solution preparation process are as follows: (1) Preparation of buffer base: Take 70% of the prescribed amount of water for injection, boil for 3-5 minutes for deoxygenation treatment, and cool naturally to a constant temperature of 20-22℃ in a sealed environment; add the prescribed amount of boric acid, borax and potassium chloride in sequence, and stir at a speed of 100-120 r / min for 12-15 minutes in a sealed environment at room temperature until the excipients are completely clear and dissolved to form a base solution; (2) Metal ion passivation: Add disodium edetate to the substrate solution obtained in step (1), maintain the temperature at 20-22℃ and under sealed and light-proof conditions, stir at 90-110r / min for 8-10min to allow disodium edetate to fully dissociate, and complete the solution passivation pretreatment; (3) Preparation of thickening base: Keep the system at a constant temperature of 20-22℃ and in a closed, light-proof, low-oxygen environment. Sprinkle in 0.8 mg of the prescribed amount of HPMC. First, disperse and stir rapidly at 110-120 r / min for 5 min to avoid clumping and agglomeration. Then, reduce the speed to 80-90 r / min and continue to swell at a low speed for 20 min to allow HPMC to fully hydrate and swell to form a thickening base. (4) Dissolving the main drug: Maintain a constant temperature of 20-22℃, in a dark and low-oxygen environment, add cyclopentolate hydrochloride, and stir continuously at 80-100 r / min for 25-30 min until the drug solution is completely clear and there are no visible particles; (5) Volume adjustment and homogenization: Add sterile water for injection at a remaining temperature of 20-22℃ to adjust the volume to the full prescription volume. Close the system and stir at a low speed of 70-90r / min for 10-12min to complete the homogenization and mixing of the drug solution. (6) pH adjustment: Maintain a constant temperature of 20-22℃ and a low-speed uniform stirring state of 70-90r / min; accurately deliver hydrochloric acid solution through an automated metering pump, with a single drop volume controlled at 0.5-1.0μL. After the drop is added, the equipment automatically delays stirring for 2-3 minutes. After the system values ​​stabilize, collect pH data online and repeatedly correct until the pH of the solution is stably locked at 3.8±0.

05. (7) Graded filtration and sterilization: In a Class D clean area environment with a temperature of 20-22℃, the homogenized drug solution is first pre-filtered through a 0.45μm aqueous microporous membrane to remove trace amounts of HPMC flocculents and insoluble particles of raw materials and excipients, and then terminally sterilized through a 0.22μm Millipore aqueous microporous membrane. The filtration flow rate is controlled at 15-20mL / min. (8) Aseptic filling: The filtered medicine solution is immediately aseptically filled. The 1mL / vial specification is filled and capped within 3 seconds. The cleanliness of the filling environment is Class D. The ambient temperature is controlled at 18-22℃ and the relative humidity is 40%-60%. Finally, it is sealed and stored in a sterile LDPE eye drop bottle.

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