Method for testing leakage of eye drop container

Abstract

The invention provides a method for testing leakage of an eye drop container, and the method comprises the following steps: providing the eye drop container which contains liquid; the eye drop container is placed in an environment with the temperature not higher than 0 DEG C for 3-10 h, and / or the eye drop container is placed in an environment with the temperature ranging from 40 DEG C to 60 DEG C for 3-10 h; and / or placing the eye drop container in an environment of 5 Hz to 25 Hz for 3 h to 10 h, and / or placing the eye drop container in an environment of 80 Hz to 100 Hz for 3 h to 10 h; the eye drop container is placed in a vacuum test box, the vacuum test box is vacuumized, so that the eye drop container generates internal and external pressure difference, and the leakage detection result of the eye drop container is obtained through the change of the internal and external pressure difference. According to the test method, the test difficulty of tiny leakage of the eye drop container can be reduced, the test sensitivity and accuracy are improved, and the quality of leakage test of the eye drop container is improved.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical analysis technology, and more specifically, to a test method for leaks in eye drop containers. Background Technology

[0002] The seal integrity of ophthalmic preparation containers refers to the ability of the container to maintain its safety and quality requirements, preventing loss of contents, microbial intrusion, and the entry of gases (oxygen, air, and water vapor, etc.) or other substances. The most commonly used container for ophthalmic preparations is the three-piece eye drop container, which typically refers to a sterile eye drop packaging system consisting of three independent but working components. Leakage testing of the three-piece container is usually required before the product is officially marketed.

[0003] Currently, the main method for determining leakage in eye drop containers is the vacuum test. This involves observing whether water leaks out under a certain vacuum pressure to determine if a leak exists. While this method is simple and efficient, it still has several limitations. For example, existing vacuum tests cannot quantitatively detect leaks. The results can be affected by various factors (the eye drop container itself, the testing environment, etc.), especially for minute leaks, particularly those tiny pores or cracks insufficient to form visible water droplets. Furthermore, existing vacuum tests can only detect the seal of the eye drop container in its current state and cannot guarantee that the container will maintain the same seal after being placed in certain environments for a period of time.

[0004] Therefore, providing a method for accurately testing leaks in eye drop containers is one of the urgent problems that needs to be solved. Summary of the Invention

[0005] This application provides a test method for leak detection of eye drop containers, which improves upon existing vacuum testing methods. It can detect minute leaks in eye drop containers while simulating eye drop containers in a specific environment, thereby improving the sensitivity and accuracy of leak detection and enhancing the product quality of the liquid inside the eye drop container.

[0006] This application provides a test method for leak testing of eye drop containers, comprising the following steps:

[0007] Provide an eye drop container, wherein the eye drop container contains liquid;

[0008] The eye drop container is pretreated, the pretreatment including: placing the eye drop container in an environment not exceeding 0°C for 3 to 10 hours, and / or placing the eye drop container in an environment of 40°C to 60°C for 3 to 10 hours; and / or

[0009] Place the eye drop container in an environment of 5Hz to 25Hz for 3h to 10h, and / or place the eye drop container in an environment of 30Hz to 100Hz for 3h to 10h.

[0010] The eye drop container is placed in a vacuum test chamber, and a vacuum is drawn into the chamber to create a pressure difference between the inside and outside of the eye drop container. The leakage detection result of the eye drop container is obtained by observing the change in the pressure difference.

[0011] In some embodiments, the pretreatment includes: first placing the eye drop container in an environment not higher than -16°C for 3 to 10 hours, then thawing it and placing the eye drop container in an environment of 40°C to 60°C for 3 to 10 hours.

[0012] In some embodiments, the pretreatment includes: first placing the eye drop container in an environment of 10Hz to 18Hz for 3h to 10h, and then placing the eye drop container in an environment of 80Hz to 100Hz for 3h to 10h.

[0013] In some embodiments, the vacuum pressure inside the vacuum test chamber is determined by the following method:

[0014] Take a batch of eye drop containers containing liquid, seal them, and obtain the negative control;

[0015] Take a batch of eye drop containers, puncture the eye drop containers with micropores to prepare a positive control, and inject liquid into the positive control, the volume of the injected liquid being the same as the volume of liquid in the negative control;

[0016] Multiple negative control samples and multiple positive control samples were mixed and placed in vacuum environments with different pressures to determine whether the eye drop container leaked, and the vacuum pressure corresponding to different leakage rates of the eye drop container was statistically analyzed.

[0017] In some implementations, the vacuum pressure corresponding to a leakage detection rate of 70% or higher for the eye drop container is statistically analyzed.

[0018] In some embodiments, the eye drop container includes a bottle body, a cap, and a stopper that cooperate with each other. The eye drop container has assembly points, including a first assembly point, a second assembly point, and a third assembly point. The first assembly point is the contact position between the top of the cap and the stopper. The second assembly point is the contact position between the inner part of the stopper and the outer part of the bottle body. The third assembly point is the contact position between the outer wall of the stopper and the inner wall of the bottle body.

[0019] In some embodiments, the bottle body and stopper, and the cap and stopper are sealed in the eye drop container of the negative control;

[0020] The positive control includes positive control 1, positive control 2 and positive control 3;

[0021] The positive control 1 is obtained by the following method: take a batch of eye drop containers and puncture the plane where the first assembly point of the eye drop containers is located to obtain the positive control 1 with the first micropore;

[0022] The positive control 2 is obtained by the following method: take a batch of eye drop containers and puncture the plane where the second assembly point of the eye drop containers is located to obtain the positive control 2 with the second micropore;

[0023] The positive control 3 is obtained by the following method: a batch of eye drop containers are taken and punctured on the plane where the third assembly point of the eye drop container is located to obtain the positive control 3 with a third micropore.

[0024] In some embodiments, the first micropore, the second micropore, and the third micropore all include pores with a diameter of 1 μm to 10 μm, and the diameters of the first micropore, the second micropore, and the third micropore are all different.

[0025] In some embodiments, a first hollow tube is inserted into the first micropore, a second hollow tube is inserted into the second micropore, and a third hollow tube is inserted into the third micropore, wherein the first hollow tube, the second hollow tube, and the third hollow tube are all inclined.

[0026] In some embodiments, the vacuum pressure inside the vacuum test chamber is less than or equal to -85 kPa.

[0027] The technical solution of this application has at least the following beneficial effects:

[0028] The testing method provided in this application pre-treats the eye drop container, causing it to undergo changes under a set environment, such as deformation, cracking, and sealing fatigue. This amplifies even minor leaks in the eye drop container and can simulate changes in real-world environments such as transportation and storage. Specifically, treating the eye drop container in an environment not exceeding 0°C for 3-10 hours and / or in an environment of 40°C-60°C for 3-10 hours causes the container to experience low-temperature creep and / or thermal stress concentration. Exposing the eye drop container to an environment of 5Hz-25Hz for 3-10 hours and / or in an environment of 30Hz-100Hz for 3-10 hours causes sealing fatigue, such as hard contact and resonance, to occur in the bottle body. The treated eye drop container is then placed in a vacuum test chamber, and a vacuum is created inside the chamber, resulting in a pressure difference between the inside and outside of the container. The leakage detection result is obtained by analyzing the change in this pressure difference. Compared to existing vacuum testing methods, the testing method of this application can reduce the difficulty of testing for leakage in eye drop containers, improve testing sensitivity and accuracy, and improve the product quality of the liquid inside the eye drop container. Attached Figure Description

[0029] Figure 1 A flowchart illustrating a test method for leak testing of eye drop containers, provided as an embodiment of this application;

[0030] Figure 2 This is a schematic diagram of the structure of an eye drop container provided in an embodiment of this application;

[0031] Figure 3 for Figure 2 A magnified view of part I. Detailed Implementation

[0032] To better illustrate this application and facilitate understanding of its technical solutions, the following detailed description is provided. However, the following embodiments are merely simplified examples and do not represent or limit the scope of protection of this application. The scope of protection of this application is determined by the claims.

[0033] The leakage test of existing eye drop containers mainly refers to the third item "Sealing" in "YBB00062002-2015 Low-density polyethylene pharmaceutical eye drop bottle". The method is as follows: (1) Take several of these products. Under the condition of torque of 55 N·cm to 80 N·cm, the bottle mouth and bottle cap should fit properly and there should be no slippage. (2) Take several of these products. First, open the eye drop container, and then tighten the bottle cap (use a torque wrench to tighten the bottle and cap, with a torque of 55 N·cm to 80 N·cm). Place it in a container with a vacuum device, add a baffle, immerse it in water, and evacuate it to a vacuum degree of 20 kPa. Maintain for 2 minutes. There should be no water entering or bubbling in the bottle. The commonly used test method in the laboratory is the vacuum test method. Generally, take several eye drop containers, inject water into the containers, assemble them according to the assembly standard of the containers, place the containers in a vacuum chamber, evacuate the vacuum chamber to a vacuum degree of 40 kPa, maintain for 3 minutes, and there should be no water leakage.

[0034] The aforementioned testing methods primarily determine leakage by observing the presence of water seepage. This only qualitatively detects leaks in eye drop containers and cannot provide quantitative detection. In some cases, understanding the specific extent of the leak is crucial for assessing the safety and stability of the medication. For example, knowing the rate or amount of leakage allows for a more accurate assessment of quality changes within the drug's shelf life. Furthermore, this method may fail to detect minute leaks, especially those tiny pores or cracks insufficient to form visible water droplets. In practical applications, even minor leaks can lead to contamination or deterioration of the medication, so this method may miss potential sealing issues. Additionally, the results of vacuum testing can be affected by various factors, such as the container's material, shape, surface roughness, and the testing environment. These factors can lead to inaccurate or inconsistent results. For instance, minute scratches or imperfections on the container surface may affect sealing performance but may not be detected in a vacuum test.

[0035] Therefore, in order to solve the above problems, this application provides a test method for leakage of eye drop containers. Figure 1 A flowchart of the test method of this application is shown, as follows: Figure 1 As shown, it includes the following steps:

[0036] Provides an eye drop container, which holds the liquid;

[0037] Place the eye drop container in an environment not exceeding 0°C for 3 to 10 hours, and / or place the eye drop container in an environment of 40°C to 60°C for 3 to 10 hours; and / or

[0038] Place the eye drop container in an environment of 5 Hz to 25 Hz for 3 h to 10 h, and / or place the eye drop container in an environment of 30 Hz to 100 Hz for 3 h to 10 h.

[0039] The eye drop container is placed inside a vacuum test chamber, and a vacuum is drawn inside the chamber to create a pressure difference between the inside and outside of the eye drop container. The leakage detection result of the eye drop container is obtained by measuring the change in the pressure difference.

[0040] The testing method provided in this application pre-treats the eye drop container, causing it to undergo changes under a set environment, such as deformation, cracking, and sealing fatigue. This amplifies even minor leaks in the eye drop container and can simulate changes in real-world environments such as transportation and storage. Specifically, treating the eye drop container in an environment not exceeding 0°C for 3-10 hours and / or in an environment of 40°C-60°C for 3-10 hours causes the container to experience low-temperature creep and / or thermal stress concentration. Exposing the eye drop container to an environment of 5Hz-25Hz for 3-10 hours and / or in an environment of 30Hz-100Hz for 3-10 hours causes sealing fatigue, such as hard contact and resonance, to occur in the bottle body. The treated eye drop container is then placed in a vacuum test chamber, and a vacuum is created inside the chamber, resulting in a pressure difference between the inside and outside of the container. The leakage detection result is obtained by analyzing the change in this pressure difference. Compared to existing vacuum testing methods, the testing method of this application can reduce the difficulty of testing for leakage in eye drop containers, improve testing sensitivity and accuracy, and improve the product quality of the liquid inside the eye drop container.

[0041] The testing methods of this application are described in detail below through examples.

[0042] S100, Provides an eye drop container, which contains liquid.

[0043] Eye drop containers (three-piece containers) are primarily used to hold ophthalmic preparations and are packaging systems assembled from three independent components: the bottle body, the stopper, and the cap. Their materials include polyethylene terephthalate (PET), polyethylene (high-density polyethylene (HDPE) and low-density polyethylene (LDPE)), and polypropylene (PP).

[0044] In some embodiments, the liquid contained in the eye drop container is mainly used for leak testing. The liquid can be water, eye drops, contact lens solution, etc. For example, the solution can be levofloxacin eye drops and vitamin B12 eye drops, etc. The liquid can also be a solution with a certain color, i.e., colored water (e.g., methylene blue).

[0045] In some implementations, the eye drop containers are visually inspected before being provided to ensure they have an acceptable appearance. Specifically:

[0046] a. Check that the bottle cap, stopper, and bottle body are free from obvious scratches, cracks, protruding demolding points, deformation, or other appearance defects.

[0047] b. Use tools such as vernier calipers to measure and record dimensions. Refer to the mold design drawings to accurately record the dimensions of each stopper, cap, and bottle body to verify the requirements.

[0048] c. Use a combination of endoscope and magnifying glass to confirm the thread surface and ensure that there are no abnormal shapes on the outer surface of the thread.

[0049] It is understood that the eye drop containers provided in S100 of this application are a portion of the batch of eye drop containers sampled for use in detecting leakage of the batch of eye drop containers.

[0050] S200. Pre-treat the eye drop container, the pre-treatment including: placing the eye drop container in an environment not higher than 0°C for 3h to 10h, and / or placing the eye drop container in an environment of 40°C to 60°C for 3h to 10h; and / or placing the eye drop container in an environment of 5Hz to 25Hz for 3h to 10h, and / or placing the eye drop container in an environment of 30Hz to 100Hz for 3h to 10h.

[0051] This application allows for the selective temperature and frequency treatment of eye drop containers. Specifically, this includes the following scenarios:

[0052] In some implementations, the eye drop container is placed in an environment not exceeding 0°C for 3 to 10 hours.

[0053] In some implementations, the eye drop container is placed in an environment of 40°C to 60°C for 3 to 10 hours.

[0054] In some embodiments, the eye drops are placed in an environment not higher than 0°C for 3 to 10 hours, thawed, and then placed in an environment of 40°C to 60°C for 3 to 10 hours.

[0055] In some embodiments, the eye drops are placed in an environment of 40°C to 60°C for 3 to 10 hours, cooled to room temperature, and then placed in an environment not higher than 0°C for 3 to 10 hours.

[0056] In some implementations, the eye drop container is placed in an environment of 5Hz to 25Hz for 3h to 10h.

[0057] In some implementations, the eye drop container is placed in an environment of 30Hz to 100Hz for 3h to 10h.

[0058] In some embodiments, the eye drop container is placed in an environment of 5Hz to 25Hz for 3h to 10h, and then placed in an environment of 30Hz to 100Hz for 3h to 10h.

[0059] In some embodiments, the eye drop container is placed in an environment of 30Hz to 100Hz for 3h to 10h, and then placed in an environment of 5Hz to 25Hz for 3h to 10h.

[0060] The above four temperature processing methods can also be combined with the four specific frequency processing methods in any way, which will not be described in detail here.

[0061] In some embodiments, the eye drop container is placed in an environment not exceeding 0°C for 3 to 10 hours. The environment not exceeding 0°C can specifically be -20°C, -16°C, -13°C, -10°C, -5°C, or 0°C, or other values ​​within the above range, without limitation. The treatment time in the environment not exceeding 0°C can specifically be 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or other values ​​within the above range, without limitation. Under the above parameter constraints, the liquid inside the eye drop container easily expands in volume at low temperatures, causing the eye drop container to bulge and the container material to undergo slight creep. This makes the eye drop container more likely to expose any minor leaks and slight deformations, and can also simulate the changes in the eye drop container during transportation and storage. Preferably, the eye drop container is placed in an environment not exceeding -16°C for 3 to 10 hours.

[0062] In some embodiments, the eye drop container is placed in an environment of 40°C to 60°C for 3 to 10 hours. The specific temperature can be 40°C, 42°C, 45°C, 47°C, 50°C, 53°C, 55°C, 58°C, or 60°C, or other values ​​within the above range, without limitation. The processing time in the 40°C to 60°C environment can be 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or other values ​​within the above range, without limitation. Under the above parameter conditions, the eye drop container is prone to thermal stress concentration, which can easily lead to defects such as deformation and cracking of the container body and mouth. This makes the eye drop container more likely to expose its own minor leaks and slight deformations, and can also simulate the changes of the eye drop container in the transportation and storage environment.

[0063] Preferably, the eye drop container is placed in an environment not higher than -16°C for 6 hours, and after thawing, it is placed in an environment of 50°C for 6 hours.

[0064] In some implementations, the eye drop container can be placed in a refrigerator to achieve an environment temperature not exceeding 0°C.

[0065] In some implementations, the eye drop container can be placed in an oven to achieve an environmental treatment of 40°C to 60°C.

[0066] This application improves the sensitivity of leak testing by treating eye drops at a specific temperature range for a period of time, making it easier for the eye drop container to expose minor leaks and slight deformations.

[0067] In some implementations, the eye drop container is placed in an environment of 5Hz to 25Hz for 3 to 10 hours. The specific frequency range of 5Hz to 25Hz can be 5Hz, 8Hz, 10Hz, 15Hz, 17Hz, 20Hz, 23Hz, or 25Hz, or other values ​​within this range, without limitation. The processing time in the 5Hz to 25Hz environment can be 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or other values ​​within this range, without limitation. Under these parameter constraints, resonance of the entire eye drop container can easily occur, leading to sealing fatigue of the container structure under low-frequency vibration. Simultaneously, the 5Hz to 25Hz environment can simulate the effects of transportation on the eye drop container during transport.

[0068] In some implementations, the eye drop container is placed in an environment of 30Hz to 100Hz for 3 to 10 hours. The 30Hz to 100Hz environment can specifically be 30Hz, 40Hz, 50Hz, 60Hz, 70Hz, 80Hz, 90Hz, or 100Hz, or other values ​​within this range, without limitation. The processing time in an environment of 5Hz to 25Hz can specifically be 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or other values ​​within this range, without limitation. Under the above parameter constraints, vibrations of 30Hz to 100Hz will cause hard contact in the eye drop container, leading to fatigue, such as thread fit fatigue, stress fatigue at the break point of the safety ring, cracks, and breakage. Simultaneously, the 30Hz to 100Hz environment can also simulate the impact of air and sea transport on the eye drop container. Preferably, the eye drop container is placed in an environment of 80Hz to 100Hz for 3 to 10 hours.

[0069] This application improves the sensitivity of leak testing by treating eye drops at a specific vibration frequency for a period of time, making it easier for the eye drop container to expose minute leaks and slight deformations.

[0070] Preferably, the eye drop container is first placed in an environment of 15 Hz for 6 hours, and then placed in an environment of 90 Hz for 6 hours.

[0071] In some implementations, equipment such as mechanical vibration tables, electro-hydraulic servo vibration tables, and electric vibration tables can be used to test the eye drop container at a specific vibration frequency.

[0072] In some embodiments, step S200 further includes: placing the eye drop container in a negative pressure environment for treatment. Since quantitative leakage detection is achieved under a certain pressure, this application first performs negative pressure treatment on the eye drop container before quantitative leakage detection to ensure the accuracy of subsequent leakage detection.

[0073] Preferably, the eye drop container is placed in an environment of -85 kPa for 3 to 10 hours.

[0074] In some implementations, the process further includes placing the eye drop container in a positive pressure environment (0.3 bar) before treating it in a negative pressure environment to remove crystallization blockage from the tiny leak holes in the eye drop container and ensure the accuracy of the negative pressure test.

[0075] In some implementations, positive pressure can be provided by an air compressor. Negative pressure can be provided by a vacuum pump (e.g., a rotary vane vacuum pump, a screw vacuum pump, etc.).

[0076] S300. Place the eye drop container inside a vacuum test chamber and evacuate the chamber to create a pressure difference between the inside and outside of the eye drop container. Obtain the leakage detection result of the eye drop container by observing the change in the pressure difference.

[0077] S301. Confirm the specific pressure required for evacuating the vacuum test chamber.

[0078] (1) Preparation of negative control standards

[0079] like Figure 2 The diagram shown is a structural schematic of the eye drop container of this application. Figure 3 for Figure 2 A magnified view of part I in the middle, as shown below. Figure 2 and Figure 3 As shown, the eye drop container includes a bottle body 1, a bottle cap 2, and a bottle stopper 3. The bottle cap 2 and the bottle body 1 are connected by threads, and the bottle stopper 3 is engaged with the bottle body 1. The top of the bottle stopper 3 contacts and fits against the inner wall of the bottle cap 2.

[0080] Take a batch of eye drop containers containing liquid, and seal the bottle body 1 and stopper 3, and the cap 2 and stopper 3 of the eye drop containers to obtain a negative control.

[0081] In some embodiments, a photosensitive adhesive can be applied between the bottle body 1 and the stopper 3, and between the bottle cap 2 and the stopper 3, followed by ultraviolet light irradiation to achieve a seal. The photosensitive adhesive is a light-curing adhesive that can rapidly cure under light of a specific wavelength. Those skilled in the art can choose a suitable photosensitive adhesive, and this application does not impose any limitations on this choice.

[0082] (2) Preparation of positive control standards

[0083] Three different assembly points are set on the eye drop container, such as Figure 3 As shown, the first assembly point A is the contact point between the top of the bottle cap 2 and the bottle stopper 3; the second assembly point B is the contact point between the inner part of the bottle stopper 3 and the outer part of the bottle body 1; and the third assembly point C is the contact point between the outer wall of the bottle stopper 3 and the inner wall of the bottle body 1. In the specific implementation process, after the eye drop container is assembled, the assembly points of the eye drop container are located by cutting, thereby determining the above-mentioned contact points.

[0084] a. Punctures are made in the planes of the first assembly point A, the second assembly point B, and the third assembly point C of the eye drop container to form several first micropores. A first hollow tube is inserted into the first micropores to obtain positive control 1.

[0085] The first micropore comprises pores with a diameter of 1 μm to 10 μm. Specifically, the pore diameter can be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm, etc. Preferably, the first micropore is a pore with a diameter of 3 μm.

[0086] b. Punctures are made in the planes of the first assembly point A, the second assembly point B, and the third assembly point C to form several second micro-holes. A second hollow tube is inserted into the second micro-holes to obtain positive control 2.

[0087] The second micropore comprises pores with a diameter of 1 μm to 10 μm. Specifically, the pore diameter can be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. Preferably, the second micropore has a diameter of 5 μm.

[0088] c. Punctures are made at the planes of the first assembly point A, the second assembly point B, and the third assembly point C to form several third micro-holes. A third hollow tube is inserted into the third micro-holes to obtain positive control 3.

[0089] The third micropore includes pores with a diameter of 1μm to 10μm. Specifically, the pore diameter can be 1μm, 2μm, 3μm, 4μm, 5μm, 6μm, 7μm, 8μm, 9μm or 10μm, etc. Preferably, the third micropore is a pore with a diameter of 10μm.

[0090] The first, second, and third micropores all have different pore sizes to simulate varying degrees of micro-leakage on the eye drop container. Furthermore, in the positive control 1 of this application, the number of first micropores in different eye drop containers can be the same or different.

[0091] In some embodiments, hollow tubes with corresponding outer diameters are inserted into the first, second, and third micropores, respectively. Specifically, a first hollow tube is inserted into the first micropore, and the outer diameter of the first hollow tube matches the pore diameter of the first micropore tube. Similarly, a second hollow tube is inserted into the second micropore, and the outer diameter of the second hollow tube matches the pore diameter of the second micropore tube. A third hollow tube is inserted into the third micropore, and the outer diameter of the third hollow tube matches the pore diameter of the third micropore tube.

[0092] In some embodiments, the first hollow tube, the second hollow tube, and the third hollow tube are all inserted at an angle into the corresponding micropores.

[0093] In some embodiments, the first hollow tube, the second hollow tube, and the third hollow tube are all capillary tubes with a length of 5 mm.

[0094] (3) Inject liquid into positive control 1, positive control 2 and positive control 3 respectively, ensuring that the volume of liquid injected is the same as the volume of liquid in the negative control.

[0095] In some embodiments, the liquid injected into positive control 1, positive control 2 and positive control 3 may be colored water, levofloxacin eye drops and vitamin B12 eye drops, etc.

[0096] (4) The prepared negative control, positive control 1, positive control 2, and positive control 3 are mixed and placed in vacuum environments with different pressures. Leakage is determined by observing whether the liquid level changes or whether liquid seeps out. The vacuum pressure corresponding to different leakage detection rates of the eye drop containers is statistically analyzed. The vacuum pressure corresponding to a leakage rate of 70% or higher in the eye drop containers is used as the vacuum pressure for evacuating the vacuum test chamber. It can be understood that a leakage rate of 70% or higher means that the leakage rates of positive control 1, positive control 2, and positive control 3 all reach 70% or higher. More preferably, the vacuum pressure corresponding to a leakage rate of 90% or higher in the eye drop containers is used as the vacuum pressure for evacuating the vacuum test chamber. Even more preferably, the vacuum pressure corresponding to a leakage rate of 99% or higher in the eye drop containers is used as the vacuum pressure for evacuating the vacuum test chamber.

[0097] Specifically, the leakage rate test of eye drop containers includes the following steps: In step (4), multiple negative controls, multiple positive controls 1, multiple positive controls 2, and multiple positive controls 3 are mixed to obtain a test sample. Then, the test sample is placed in a vacuum environment with different pressures for measurement, and the leakage rate results of different positive controls are calculated. For example, the test sample is placed under a specific vacuum pressure for testing. After the test, the number of eye drop containers that leaked liquid in the test sample is counted, and the number of leaks of positive control 1 is counted as n (units). The number of positive controls 1 in the test sample is N (units). Then, the leakage rate (%) = n / N*100%. The leakage rate calculation method of positive control 2 and positive control 3 is similar and will not be described in detail here.

[0098] Experimental Group 1:

[0099] Take 30 eye drop containers, coat the space between bottle body 1 and stopper 3, and between bottle cap 2 and stopper 3 with Loctite UV-curable adhesive (Loctite V-3218), and then seal them by irradiation with ultraviolet light to obtain negative control samples.

[0100] Take 100 eye drop containers and puncture the planes of the first assembly point A, the second assembly point B, and the third assembly point C of each eye drop container to obtain a positive control 1 with a first micropore diameter of 3 μm.

[0101] Take 100 eye drop containers and puncture the planes of the first assembly point A, the second assembly point B, and the third assembly point C of each eye drop container to obtain a positive control 2 with a second micropore diameter of 5 μm.

[0102] Take 100 eye drop containers and puncture the planes of the first assembly point A, the second assembly point B, and the third assembly point C of each eye drop container to obtain a positive control 3 with a third micropore. The pore size of the third micropore is 10 μm.

[0103] Insert capillary tubes of the corresponding size into the holes of the above-mentioned eye drop containers at an angle.

[0104] Negative control, positive control 1, positive control 2, and positive control 3 were mixed and placed in a vacuum testing chamber (model: MFY-HS intelligent sealing instrument, manufacturer: Sanquan Zhongshi). The vacuum pressure was -70 kPa, and the time was 10 min. Experimental group 2:

[0105] The difference from experimental group 1 is that the negative control, positive control 1, positive control 2 and positive control 3 were mixed and placed in a vacuum test chamber (model: MFY-HS intelligent sealing instrument manufacturer: Sanquan Zhongshi), the vacuum pressure was -75kPa and the time was 6h.

[0106] Experimental group 3:

[0107] The difference from experimental group 1 is that the negative control, positive control 1, positive control 2 and positive control 3 were mixed and placed in a vacuum test chamber (model: MFY-HS intelligent sealing instrument manufacturer: Sanquan Zhongshi), the vacuum pressure was -85kPa and the time was 6h.

[0108] Experimental group 4:

[0109] The difference from experimental group 1 is that the negative control, positive control 1, positive control 2 and positive control 3 were mixed and placed in a vacuum test chamber (model: MFY-HS intelligent sealing instrument manufacturer: Sanquan Zhongshi), the vacuum pressure was -90kPa and the time was 6h.

[0110] Observe the leakage of each micropore in the eye drop containers in each experimental group and statistically calculate the leakage rate of different micropores. The specific calculation method is as follows: if the liquid level in a certain eye drop container changes or liquid seepage is observed, it is recorded as a leaking container. Observe all eye drop containers with the first micropore in sequence and count the number of leaking eye drop containers with the first micropore. Then, the leakage rate (%) of eye drop containers with the first micropore = number of leaking eye drop containers with the first micropore / 100 * 100%. The testing and calculation methods for the leakage rate of eye drop containers with the second and third micropores are similar, and the calculation results are shown in Table 1.

[0111] Table 1. Leakage rate measurement results of different experimental groups

[0112]

[0113] It is understandable that the above leakage rate test results are rounded to the nearest whole number.

[0114] According to the data in Table 1, the leakage rate of the three different microporous eye drop containers all reached 99% or higher, and the corresponding vacuum pressure was less than or equal to -85 kPa. The above vacuum pressure was used as the vacuum pressure for evacuating the vacuum test chamber in this application.

[0115] S302. Place the batch of eye drop containers processed in S100 and S200 into a vacuum test chamber. Use the vacuum pressure obtained in S301 to evacuate the vacuum test chamber, so that a pressure difference is generated inside and outside the eye drop containers. The leakage rate of the eye drop containers is obtained by the change of the pressure difference.

[0116] In some implementations, the batch of eye drop containers processed in S100 and S200 are placed in a vacuum test chamber and treated at a pressure of -85 kPa for 3 to 10 hours. The pressure change inside the vacuum chamber is observed to determine whether the eye drop containers have leaked, and the leakage rate of the eye drop containers is further manually counted.

[0117] In some implementations, stability testing of the eye drop container is required before or after it is provided to ensure that the eye drop container has adequate stability.

[0118] The stability testing steps are as follows:

[0119] 1) Routine conditions: Take a batch of eye drop containers that have been tested and found to be leak-free by the test method of this application, fill them with liquid (e.g., 100 eye drop containers filled with colored water, 100 eye drop containers filled with levofloxacin eye drops, and 100 eye drop containers filled with vitamin B12 eye drops), and store the filled eye drop containers in an environment of 40°C for 3 months. During the storage period, take a number of eye drop containers at intervals and conduct a leak test according to the test method of this application.

[0120] 2) Accelerated conditions: Take a batch of eye drop containers that have been tested and found to be leak-free by the test method of this application, fill the eye drop containers with liquid (e.g., 100 eye drop containers filled with colored water, 100 eye drop containers filled with levofloxacin eye drops, and 100 eye drop containers filled with vitamin B12 eye drops), and store the filled eye drop containers in an environment of 60°C for 1 month. During the storage period, take a number of eye drop containers at intervals and conduct a leak test according to the test method of this application.

[0121] 3) In some implementations, the eye drop container needs to be destructively tested before or after it is provided to reduce human interference and minimize the effect of the liquid on opening the eye drop container.

[0122] The destructive testing steps are as follows:

[0123] 1) Pinch the shoulder of the eye drop container, use a sharp knife to break it open at the bottom, and use a syringe to remove the liquid from the container.

[0124] 2) Cut open the eye drop container from the bottom after the liquid has been taken out, and clean out the liquid inside the container.

[0125] 3) Place the sample after the liquid has been removed into an oven to dry it. Set the temperature to 40℃ and the time to 4 hours.

[0126] 4) Take out the dried sample and cool it at room temperature.

[0127] 5) Using disposable gloves, with the container upright and the top facing upwards, unscrew the cap while holding the shoulder of the bottle. The tester should then inspect the threads of the bottle and the stopper, checking for any leaking dry powder from the eye drops container inside the cap threads. If no dry powder is found, the destructive test is passed.

[0128] The embodiments of this application will be further described below with reference to several examples. However, the embodiments of this application are not limited to the specific embodiments described below. Appropriate modifications and implementations can be made within the scope of protection.

[0129] Example 1

[0130] (1) Take 100 eye drop containers (Graceheim 5ml three-piece eye drop bottle set) that have undergone visual inspection. The eye drop containers are filled with colored water, and the filling dosage of colored water is the normal dosage.

[0131] (2) Treat the eye drop container in a refrigerator at -20°C for 6 hours.

[0132] (3) Place the eye drop container inside the container and use an air compressor (to send compressed air into the sealed container through a pipe) to inject air so that the pressure inside the container is 0.3 bar. Then place the eye drop container inside the vacuum test container (model: MFY-HS type intelligent sealing instrument manufacturer: Sanquan Zhongshi) and use a vacuum pump to evacuate air so that the pressure inside the container is -85 kPa and maintain it for 6 hours.

[0133] (4) Place the eye drop container in a vacuum test chamber (MFY-HS type intelligent sealing instrument manufacturer: Sanquan Zhongshi), evacuate the vacuum test chamber to make the pressure inside the vacuum test chamber -85kPa, and use the pressure sensor built into the vacuum test chamber to detect the pressure change inside the vacuum test chamber in real time to confirm whether there is leakage in the eye drop container, and observe and count the leakage rate of the eye drop container by eye.

[0134] Example 2

[0135] Unlike Example 1, (2) the eye drop container was treated in an oven at 60°C for 6 hours.

[0136] Example 3

[0137] Unlike Example 1, (2) the eye drop container was placed on a mechanical vibration table (electromagnetic vibration testing machine QB-Z0211 Shanghai Qingbo Instruments), and the vibration frequency of the mechanical vibration table was controlled to be 15Hz for 6 hours.

[0138] Example 4

[0139] Unlike Example 1, (2) the eye drop container was placed on a mechanical vibration table (electromagnetic vibration testing machine QB-Z0211 Shanghai Qingbo Instruments), and the vibration frequency of the mechanical vibration table was controlled to be 90Hz for 6h.

[0140] Example 5

[0141] Unlike Example 1, (2) the eye drop container was treated in a -20°C refrigerator for 6 hours, thawed, and then treated in a 60°C oven for 6 hours; then the eye drop container was placed on a mechanical vibration table (electromagnetic vibration testing machine QB-Z0211 Shanghai Qingbo Instruments), and the vibration frequency of the mechanical vibration table was controlled at 15Hz for 6 hours; finally, the eye drop container was placed on a mechanical vibration table, and the vibration frequency of the mechanical vibration table was controlled at 90Hz for 6 hours.

[0142] Comparative Example 1

[0143] Unlike Example 1, step (5) is: the vacuum pressure in the vacuum test chamber is -70 kPa and the time is 10 min.

[0144] Comparative Example 2

[0145] Unlike Example 1, step (2) is omitted.

[0146] The test results are shown in Table 2. At the same time, the eye drop containers that have completed the test were visually inspected.

[0147] Table 2. Performance measurements of each embodiment and comparative example

[0148]

[0149] As shown in Table 2, the test results, according to Examples 1 to 5, by pre-treating the eye drop container, the minute leaks of the eye drop container are amplified. On the one hand, the location of the leak can be observed with the naked eye; on the other hand, the changes of the eye drop container in real environments such as transportation and storage can be simulated. Compared with existing vacuum testing methods, the testing method of this application can reduce the difficulty of testing for eye drop container leaks, and can also improve the testing sensitivity and accuracy, enabling a direct and effective quantitative test of eye drop container leaks.

[0150] In Comparative Example 1, the vacuum pressure inside the vacuum test chamber was -70 kPa, and the time was 10 minutes. The vacuum pressure was too low to effectively expose the tiny leaks in the eye drop container, which reduced the accuracy of the leak test results.

[0151] In Comparative Example 2, the eye drop containers were not pre-treated, making it impossible to know whether there were any minor leaks or the impact of transportation and storage on the eye drop containers. This could lead to sealing failure during subsequent use of the eye drop containers, resulting in contamination or deterioration of the medicine inside.

[0152] The applicant declares that the above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention fall within the scope of protection and disclosure of the present invention.

Claims

1. A test method for leaking eye drop containers, characterized in that, Includes the following steps: Provide an eye drop container, wherein the eye drop container contains liquid; The eye drop container is pretreated, the pretreatment including: placing the eye drop container in an environment not exceeding 0°C for 3 to 10 hours, and / or placing the eye drop container in an environment of 40°C to 60°C for 3 to 10 hours; and / or Place the eye drop container in an environment of 5Hz to 25Hz for 3h to 10h, and / or place the eye drop container in an environment of 30Hz to 100Hz for 3h to 10h. The eye drop container is placed in a vacuum test chamber, and a vacuum is drawn into the test chamber to create a pressure difference between the inside and outside of the eye drop container. The leakage detection result of the eye drop container is obtained by the change of the pressure difference.

2. The test method according to claim 1, characterized in that, The pretreatment includes: first placing the eye drop container in an environment not higher than -16°C for 3 to 10 hours, then thawing it and placing the eye drop container in an environment of 40°C to 60°C for 3 to 10 hours.

3. The test method according to claim 1 or 2, characterized in that, The pretreatment includes: first placing the eye drop container in an environment of 10Hz to 18Hz for 3h to 10h, and then placing the eye drop container in an environment of 80Hz to 100Hz for 3h to 10h.

4. The test method according to claim 1, characterized in that, The vacuum pressure inside the vacuum test chamber is determined by the following method: Take a batch of eye drop containers containing liquid, seal them, and obtain the negative control; Take a batch of eye drop containers, puncture the eye drop containers with micropores to prepare a positive control, and inject liquid into the positive control, the volume of the injected liquid being the same as the volume of liquid in the negative control; Multiple negative control samples and multiple positive control samples were mixed and placed in vacuum environments with different pressures to determine whether the eye drop container leaked, and the vacuum pressure corresponding to different leakage rates of the eye drop container was statistically analyzed.

5. The test method according to claim 4, characterized in that, The vacuum pressure corresponding to a leakage detection rate of 70% or higher for the aforementioned eye drop containers is statistically analyzed.

6. The test method according to claim 4, characterized in that, The eye drop container includes a bottle body, a bottle cap, and a bottle stopper that cooperate with each other. The eye drop container has assembly points, including a first assembly point, a second assembly point, and a third assembly point. The first assembly point is the contact position between the top of the bottle cap and the bottle stopper. The second assembly point is the contact position between the inner part of the bottle stopper and the outer part of the bottle body. The third assembly point is the contact position between the outer wall of the bottle stopper and the inner wall of the bottle body.

7. The test method according to claim 6, characterized in that, In the eye drop container of the negative control, the bottle body and the stopper, and the cap and the stopper are in a sealed state. The positive control includes positive control 1, positive control 2 and positive control 3; The positive control 1 is obtained by the following method: a batch of eye drop containers are taken and punctured on the planes of the first assembly point, the second assembly point, and the third assembly point of the eye drop containers respectively to obtain the positive control 1 with the first micropore. The positive control 2 is obtained by the following method: a batch of eye drop containers are taken and punctured on the plane where the first assembly point, the second assembly point, and the third assembly point are located, respectively, to obtain the positive control 2 with the second micropore. The positive control 3 is obtained by the following method: a batch of eye drop containers are taken and punctured on the planes of the first assembly point, the second assembly point, and the third assembly point of the eye drop containers respectively to obtain the positive control 3 with a third micropore.

8. The test method according to claim 7, characterized in that, The first micropore, the second micropore, and the third micropore all include pores with a diameter of 1μm to 10μm, and the diameters of the first micropore, the second micropore, and the third micropore are all different.

9. The test method according to claim 6 or 7, characterized in that, A first hollow tube is inserted into the first micropore, a second hollow tube is inserted into the second micropore, and a third hollow tube is inserted into the third micropore. The first hollow tube, the second hollow tube, and the third hollow tube are all inclined.

10. The test method according to claim 1, characterized in that, The vacuum pressure inside the vacuum test chamber is less than or equal to -85 kPa.

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