A polyvinyl alcohol hydrogel punctal plug and a method of making the same

Abstract

The application discloses a polyvinyl alcohol hydrogel punctal plug and a preparation method thereof. The punctal plug is provided with a cap structure and an anchor structure at two ends respectively, and a conical shaft structure provided with a circular rib in the middle, and a central blind hole is not arranged. Since the volume of the punctal plug is small, the punctal plug is prepared by combining an injection molding method, a double-crosslinking method of physical crosslinking first and then chemical crosslinking, and a gradient soaking and shaping process of an excipient, and the obtained punctal plug is uniform in crosslinking, stable in form, can be rapidly expanded after implantation, and the risk of falling out and bacterial infection is reduced.

Description

Technical Field

[0001] This invention belongs to the field of medical devices, specifically relating to a polyvinyl alcohol hydrogel tear spot plug and its preparation method. Background Technology

[0002] Dry eye syndrome, also known as keratoconjunctivitis sicca or xerophthalmia, is a general term for a series of eye diseases caused by pathological changes in the tear film, resulting in insufficient lubrication of the cornea and conjunctiva. The etiology and pathophysiology of dry eye syndrome are very complex, and clinically it is mainly controlled through drug therapy, physical therapy, punctal plugging, and surgery. Among these, punctal plugging involves blocking the tear ducts by plugging the punctum or lacrimal ducts, thereby increasing tear volume, improving the ocular symptoms and signs of dry eye patients, and reducing the level of inflammatory factors on the ocular surface.

[0003] Lacrimal duct plugs are typically cylindrical, placed entirely within the lacrimal duct, directly at the opening of the lacrimal punctum, and partially extended into the vertical portion of the lacrimal duct. They are held in place by the tension within the lacrimal duct. Due to their shallow placement, punctal plugs are relatively easy to install and remove. Based on their duration of action, lacrimal duct plugs can be categorized as degradable or non-degradable. Degradable plugs generally last 2–6 months, requiring frequent implantation. Degradable and hydrogel-based plugs are typically implanted into the lacrimal canaliculi in a dry state. Due to their hard surface, they can easily damage the lacrimal duct mucosa during implantation, leading to adverse reactions such as chronic inflammation and scarring. Non-degradable plugs are commonly made of materials such as silicone, hydroxyethyl methacrylate, polyethylene, and hydrophilic acrylics. Representative products include Herrick Lacrimal Plug and Smart Plug. These products are not visible under a slit lamp when placed within the lacrimal canaliculus, and are difficult to retrieve if they shift, sometimes requiring surgical removal.

[0004] Most punctal plugs on the market are made of medical-grade silicone, which is elastic. The mainstream shape is a top-cap type, consisting of a cap (sometimes called a collar) and a stem (or anchor), with a central blind hole for easy implantation. However, because punctal plugs are close to the ocular surface, they can easily cause ocular irritation or dislodgement due to accidental movement by the patient. This is often related to factors such as the size, structure, hardness, surface quality, and placement position of the plug. Furthermore, to accommodate different punctal sizes, punctal plugs are available in multiple sizes. However, in practical applications, silicone plugs do not always fit the punctum perfectly. Plugs that are too large can lead to implantation difficulties and lacrimal muscle relaxation, while plugs that are too small cannot be properly secured and are prone to dislodgement.

[0005] Chinese patent CN115651131A discloses a method for preparing a secondary-expansion punctal plug. It involves polymerizing cationic monomers such as methacryloylpropyltrimethylammonium chloride and dimethylaminoethyl methacrylate, followed by polymerization with anionic monomers such as polymethacrylic acid and polystyrene sulfonic acid to prepare a hydrogel punctal plug. Before and during implantation, the plug absorbs water and swells, becoming soft. After implantation, it expands again to provide fixation. However, this patent uses ammonium persulfate as a photoinitiator in the hydrogel polymerization process. Ammonium persulfate is irritating and corrosive to the skin and mucous membranes; prolonged skin contact may cause allergic dermatitis. Furthermore, the punctal plug in this patent is cylindrical. After implantation into the lacrimal canaliculus, because its head is lower than the lacrimal punctum, it creates a dead space at the tip, easily leading to bacterial accumulation and complications such as dacryocystitis, and there is also a risk of displacement. In addition, tear spot plugs are small in size and require high precision. Their overall size should not exceed that of a sesame seed. If chemical crosslinking agents such as polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, and cellulose are directly used for preparation, the crosslinking agent will have poor dispersion in the matrix, resulting in uneven crosslinking and local "scorching". The prepared tear spot plugs will have poor precision and uncontrollable appearance, size and swelling rate. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a polyvinyl alcohol hydrogel punctal plug, prepared using a double cross-linking and shaping technology (DCS technology). The resulting polyvinyl alcohol hydrogel punctal plug is dimensionally precise and has stable performance. It offers advantages such as reducing skin irritation and minimizing post-implantation complications like dacryocystitis. Furthermore, it can expand rapidly, preventing displacement and detachment after implantation and improving the safety of punctal plug use.

[0007] The technical solution of this invention is implemented as follows:

[0008] In a first aspect, the present invention provides a polyvinyl alcohol hydrogel tear punctum plug, which is prepared by a dual cross-linking and shaping process of physical cross-linking followed by chemical cross-linking.

[0009] Furthermore, the teardrop plug has a cap structure and an anchor structure at both ends, and a tapered shaft structure in the middle, without a central blind hole.

[0010] Furthermore, the length of the punctum plug is 1.1 to 2.2 mm, for example: 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.77 mm, 1.9 mm, 2.05 mm, 2.1 mm, 2.2 mm.

[0011] Furthermore, the diameter of the cap structure is 1.0 to 1.4 mm, for example: 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm.

[0012] Furthermore, the thickness of the cap structure is 0.1 to 0.2 mm, for example: 0.1 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.2 mm.

[0013] Furthermore, the minimum surface diameter of the tapered shaft structure is 0.4 to 0.8 mm, for example: 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm.

[0014] Furthermore, the height of the conical structure is 0.4 to 0.8 mm, for example: 0.4 mm, 0.45 mm, 0.5 mm, 0.55 mm, 0.6 mm, 0.65 mm, 0.7 mm, 0.75 mm, 0.8 mm.

[0015] Furthermore, the diameter of the largest surface of the anchor structure is 0.8 to 1.5 mm, for example: 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm.

[0016] Furthermore, the height of the anchor structure is 0.6 to 1.4 mm, for example: 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.15 mm, 1.2 mm, 1.3 mm, 1.4 mm.

[0017] Furthermore, the bottom taper of the anchor structure is 35° to 50°, for example: 35°, 38°, 40°, 42°, 45°, 47°, 49.53°, 50°.

[0018] Furthermore, the tapered shaft structure is provided with at least three circular ribs.

[0019] Furthermore, the circular ribs are connected by a circular arc transition.

[0020] This invention employs an injection molding process to perform a dual cross-linking reaction of polyvinyl alcohol (PVA) in a mold, involving both physical and chemical cross-linking, to obtain a polyvinyl alcohol hydrogel punctal plug. After implantation, this punctal plug absorbs tears, expands rapidly, and is fixed to the punctum at the designed size, preventing it from falling out.

[0021] Secondly, the present invention provides a method for preparing polyvinyl alcohol hydrogel tear spot plugs, the preparation method comprising the following steps:

[0022] (1) Degassing polyvinyl alcohol aqueous solution, injecting it into a mold, and freezing and melting it to obtain physically cross-linked polyvinyl alcohol hydrogel tear spot plugs;

[0023] (2) Take the tear spot plug obtained in step (1) out of the mold and soak it in the crosslinking agent solution to crosslink it, so as to obtain the polyvinyl alcohol hydrogel tear spot plug.

[0024] Further, the mass concentration of the polyvinyl alcohol aqueous solution in step (1) is 20% to 50%, for example: 20%, 25%, 30%, 35%, 40%, 45%, 50%.

[0025] Furthermore, the degree of alcoholysis of the polyvinyl alcohol is 90% to 99.9%.

[0026] In step (1), the preparation process of the polyvinyl alcohol aqueous solution is as follows: weigh polyvinyl alcohol, add it to water, and stir until the polyvinyl alcohol is completely dissolved.

[0027] Furthermore, the dissolution temperature of the polyvinyl alcohol is 90-100℃, for example: 90℃, 91℃, 92℃, 93℃, 94℃, 95℃, 96℃, 97℃, 98℃, 99℃, 100℃.

[0028] Furthermore, in step (1), the degassing of the polyvinyl alcohol aqueous solution is performed by centrifugal degassing or vacuum degassing, and centrifugal degassing is preferred.

[0029] Further, in step (1), the freeze-thaw process is as follows: the mold is frozen at -70 to -5°C for 4 to 24 hours, then removed and thawed at 20 to 50°C for 20 to 240 minutes. The freeze-thaw process is repeated 3 to 10 times.

[0030] Furthermore, the freezing temperature is selected from any one of -70℃, -60℃, -50℃, -40℃, -30℃, -20℃, -18℃, -15℃, -10℃, or -5℃.

[0031] Furthermore, the freezing time is selected from any one of 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h or 24h.

[0032] Furthermore, the thawing temperature is selected from any one of 20℃, 25℃, 27℃, 30℃, 35℃, 37℃, 40℃, 45℃, 47℃ or 50℃.

[0033] Furthermore, the thawing time is selected from any one of 20 min, 30 min, 40 min, 60 min, 90 min, 120 min, 150 min, 180 min, 210 min, or 240 min.

[0034] Furthermore, the number of repetitions of the freeze-thaw process is selected from any one of 3, 4, 5, 6, 7, 8, 9, or 10 times.

[0035] Furthermore, the crosslinking agent solution in step (2) is prepared by adding the crosslinking agent to the catalyst solution.

[0036] Furthermore, the mass-volume concentration of the crosslinking agent in the crosslinking agent solution is 3% to 6% (W / V, unit g / mL), for example: 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%.

[0037] Furthermore, the crosslinking agent is an epoxide, such as ethylene oxide, propylene oxide, 1,2-epoxybutane, 1,4-epoxybutane, 1,4-butanediol diglycidyl ether, 1,2,3,4-diepoxybutane, triglyceride (1,2-epoxy)propyl ether, etc.

[0038] Further, the mass concentration of the catalyst solution is 10%–40%, for example: 10%, 15%, 20%, 25%, 30%, 35%, 40%.

[0039] Furthermore, the catalyst is an alkali metal hydroxide or an alkali metal carbonate.

[0040] Furthermore, the catalyst is any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, sodium carbonate, potassium carbonate, zinc carbonate, calcium carbonate, magnesium carbonate, iron carbonate, or copper carbonate.

[0041] Furthermore, in step (2), the soaking time is 0.5 to 3 hours, for example: 0.5 hours, 1 hour, 2 hours, or 3 hours.

[0042] Furthermore, the soaking temperature is 2 to 10°C, for example: 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C.

[0043] By controlling the soaking conditions of the polyvinyl alcohol hydrogel teardrop plug in the crosslinking agent solution, and soaking it at a low temperature, the crosslinking agent can be made to slowly penetrate into the interior of the polyvinyl alcohol hydrogel, preventing the crosslinking reaction from occurring too quickly, thereby improving the uniformity of subsequent crosslinking.

[0044] Furthermore, the cross-linking reaction time is 0.5 to 3 hours, for example: 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours.

[0045] Furthermore, the temperature of the crosslinking reaction is 60-80°C, for example: 60°C, 65°C, 70°C, 75°C, 80°C.

[0046] This invention uses a physical cross-linking process involving freeze-thaw to obtain a pre-formed punctal plug from a polyvinyl alcohol solution. Then, chemical cross-linking is performed in a cross-linking agent and catalyst solution system. By controlling the degree of cross-linking within a suitable range, the prepared punctal plug can achieve structural stability and a suitable swelling rate. This effectively solves the problems of low cross-linking in polyvinyl alcohol hydrogel punctal plugs, resulting in low initial dry size and excessive softness after swelling, leading to deformation and loss during clinical use; and high cross-linking in hydrogels, resulting in high initial dry size and greater hardness, which can easily scratch the lacrimal duct mucosa during implantation, and also has a low swelling rate, hindering rapid punctal closure. This invention is more suitable for clinical application.

[0047] Furthermore, after the crosslinking reaction, the process also includes cleaning and shaping.

[0048] Furthermore, the cleaning process involves washing away the cross-linking agent solution in the punctum plug with an acidic solution, followed by rinsing with water for injection at least once to remove the acidic solution.

[0049] Furthermore, the acidic solution includes, but is not limited to, hydrochloric acid solution, acetic acid solution, citric acid solution, acidic phosphate buffer, and acidic citrate buffer.

[0050] Furthermore, the shaping treatment involves soaking the cleaned tear spot plug in a shaping agent solution.

[0051] Furthermore, the excipient is selected from one or more of ethanol, isopropanol, acetone, n-butanol, or tert-butanol.

[0052] Furthermore, the excipient solution immersion is carried out using a gradient immersion method in which the volume concentration of the excipient gradually increases.

[0053] Furthermore, the total soaking time of the excipient is 4 to 24 hours, for example: 4 hours, 6 hours, 7 hours, 8 hours, 12 hours, 16 hours, 20 hours, 21 hours, and 24 hours.

[0054] Furthermore, the soaking time for each gradient is 1 to 6 hours, for example: 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours.

[0055] Furthermore, the concentrations of the gradient soaking are 15-30%, 50-60%, 70-85%, and 100%.

[0056] Furthermore, the gradient concentration of the excipient solution is 30%→60%→80%→100%, 15%→50%→85%→100%, or 25%→50%→75%→100%.

[0057] Furthermore, the solvent for the excipient solution is water.

[0058] In existing technologies, hydrogel punctal plugs are typically dried directly after obtaining them. This can easily damage the porous structure of the hydrogel, making it compact and resulting in low expansion efficiency. In contrast, this invention treats the punctal plugs with an excipient solution before drying, which better fixes the porous structure of the polyvinyl alcohol hydrogel. Specifically, by using an excipient solution with a gradient concentration from low to high for soaking treatment, the water in the gel can be slowly replaced, which helps to steadily solidify the porous structure in the gel and maintain its shape better during the drying process. This allows it to expand to the predetermined size in a shorter time after implantation, achieving a rapid expansion effect and reducing the risk of dislodgement due to unsuitable punctal plug size.

[0059] Furthermore, the shaping process also includes a drying process.

[0060] Furthermore, the drying process is vacuum drying.

[0061] Furthermore, the drying temperature is 30 to 70°C, for example: 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C.

[0062] Furthermore, the drying time is 4 to 24 hours, for example: 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 20 hours, 24 hours.

[0063] Thirdly, the present invention provides the application of polyvinyl alcohol hydrogel punctal plugs in the preparation of medical devices for treating eye diseases.

[0064] Furthermore, the punctal plug of the present invention can be quickly soaked and rinsed before use. The soaking and rinsing solution can be water for injection or physiological saline, or a solution containing one or more ophthalmic therapeutic drugs.

[0065] Furthermore, the ophthalmic treatment drugs include, but are not limited to, dexamethasone, cyclosporine, tetracycline hydrochloride, hydrocortisone acetate, polymyxin B, glutathione, atropine sulfate, streptomycin sulfate, gentamicin sulfate, zinc sulfate, and moxifloxacin.

[0066] The beneficial effects of this invention are:

[0067] 1. This invention employs a dual cross-linking and shaping process. First, a preliminary tear punctum plug is obtained through physical cross-linking via freeze-thaw. Then, the degree of cross-linking of the hydrogel is controlled by low-temperature immersion followed by high-temperature chemical cross-linking. The low-temperature immersion allows the cross-linking agent to slowly penetrate into the polyvinyl alcohol hydrogel, preventing the cross-linking reaction from occurring too quickly. This improves the uniformity of the subsequent high-temperature cross-linking, resulting in a stable tear punctum plug structure with a suitable swelling rate. This maintains the uniformity of the overall cross-linking degree and the stability of the hydrogel, making it less prone to deformation and more suitable for clinical application.

[0068] 2. This invention obtains physically cross-linked punctal plugs by freezing and melting them in a mold. The subsequent chemical cross-linking process does not need to be carried out in the mold. On the one hand, it avoids the corrosion of metal molds by strong alkaline catalysts, avoids the risk of introducing heavy metals into the product during the processing and manufacturing process, and increases the reusability of the mold. On the other hand, it enables the punctal plugs to achieve long-term effective clinical results after implantation and reduces the foreign body sensation caused by traditional silicone punctal plugs.

[0069] 3. The present invention uses a gradient soaking treatment of excipients to treat the cross-linked punctal plugs, which helps to solidify the porous structure in the gel and maintain a better shape during the drying process of the punctal plugs. This allows them to expand to the predetermined size in a shorter time after implantation, achieving the technical effect of rapid expansion and reducing the risk of dislodgement due to unsuitable punctal plug size.

[0070] 4. The present invention eliminates the central blind hole in the structural design of the punctum plug, which can avoid the formation of dead space fluid accumulation in the punctum plug, thereby reducing the risk of bacterial infection. Attached Figure Description

[0071] Figure 1 The diagram shown is a schematic of the polyvinyl alcohol hydrogel tear spot plug of the present invention.

[0072] Figure 2 The tear duct plug of Example 4;

[0073] Figure 3 For comparison example 5, the tear duct plug.

[0074] The components in the diagram are labeled as follows: 1-cap structure, 2-conical shaft structure, 3-round rib, 4-anchor structure. Detailed Implementation

[0075] The technical solution of the present invention will be further described below with reference to embodiments and accompanying drawings. The advantages and features of the present invention will become clearer as the description unfolds. However, it should be understood that the embodiments are merely exemplary and do not constitute a limitation on the scope of the present invention.

[0076] It should be noted that, unless otherwise specified, the experimental methods used in the following embodiments are conventional methods in the art. Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0077] Example 1: Preparation of tear spot plug sample 1

[0078] The teardrop plug is 1.1 mm long, the cap structure 1 has a diameter of 1.0 mm and a thickness of 0.1 mm. The tapered shaft structure 2 has a minimum face diameter of 0.4 mm and a height of 0.4 mm, and the tapered shaft surface contains 3 circular ribs 4. The anchor structure 3 has a maximum face diameter of 0.8 mm, a height of 0.6 mm, and a bottom taper of 35°. A stainless steel mold is prepared according to the shape of the teardrop plug.

[0079] Weigh 20g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 22-30 mPa·s) and add purified water to a total mass of 100g. Stir at 90℃ until the polyvinyl alcohol is completely dissolved. After centrifugation to remove bubbles, pour the solution into a stainless steel mold for teardrop plugs. Freeze the mold at -70℃ for 4 hours, remove it, and thaw at 20℃ for 6 hours. Repeat the above freeze-thaw operation 3 times. Remove the frozen and thawed teardrop plugs from the mold and immerse them in a 3% (w / v) 1,4-butanediol diglycidyl ether crosslinking agent solution (prepared by weighing 0.6g of 1,4-butanediol diglycidyl ether and adding it to 20mL of 10wt% sodium hydroxide solution). Soak at 2℃ for 3 hours and crosslink at 60℃ for 3 hours. After removal, the punctum plugs were soaked and washed with phosphate buffer (pH 6.5) for 24 hours, and then rinsed three times with water for injection. The punctum plugs were then soaked sequentially in 30%, 60%, 80%, and 100% n-butanol, for 6 hours at each concentration gradient. After soaking, they were removed and dried in a vacuum oven at 70°C for 4 hours. After trimming and cutting, the punctum plugs were obtained. A schematic diagram of their structure is shown below. Figure 1 As shown.

[0080] Example 2: Preparation of tear spot plug sample 2

[0081] The teardrop plug is 2.2 mm long, the cap structure 1 has a diameter of 1.4 mm and a thickness of 0.2 mm. The tapered shaft structure 2 has a minimum face diameter of 0.8 mm and a height of 0.8 mm, and the tapered shaft surface contains 4 circular ribs 4. The anchor structure 3 has a maximum face diameter of 1.5 mm, a height of 1.4 mm, and a bottom taper of 50°. A stainless steel mold is prepared according to the shape of the teardrop plug.

[0082] Weigh 50g of polyvinyl alcohol (degree of hydrolysis 98-99%; viscosity 5.2-6.0 mPa·s) and add purified water to a total mass of 100g. Stir at 100℃ until the polyvinyl alcohol is completely dissolved. After centrifugation to remove bubbles, pour the solution into a stainless steel mold for teardrop plugs. Freeze the mold at -5℃ for 24 hours, then remove it and thaw at 50℃ for 20 minutes. Repeat the above freeze-thaw operation 10 times. Remove the frozen and thawed teardrop plugs from the mold and immerse them in a 3% (w / v) propylene oxide solution (prepared by adding 0.6g of propylene oxide to 20mL of 40wt% sodium hydroxide solution), soak at 10℃ for 30 minutes, and then crosslink at 60℃ for 3 hours. After removal, the punctum plugs were soaked and cleaned with 5mM hydrochloric acid solution for 8 hours, and then cleaned with water for injection 4 times. The punctum plugs were then soaked in 15%, 50%, 85%, and 100% acetone solutions in sequence, for 1 hour at each concentration gradient. After soaking, the plugs were removed and placed in a vacuum oven to dry at 60°C for 8 hours. After trimming and cutting, the punctum plugs were obtained.

[0083] Example 3: Preparation of tear spot plug sample 3

[0084] The teardrop plug is 1.77 mm long, the cap structure 1 has a diameter of 1.2 mm and a thickness of 0.12 mm. The tapered shaft structure 2 has a minimum face diameter of 0.4 mm and a height of 0.65 mm, and the tapered shaft surface contains 3 circular ribs 4. The anchor structure 3 has a maximum face diameter of 1.0 mm, a height of 1.0 mm, and a bottom taper of 49.53°. A stainless steel mold is prepared according to the shape of the teardrop plug.

[0085] Weigh 20g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 78-88 mPa·s) and add purified water to a total mass of 100g. Stir at 95℃ until the polyvinyl alcohol is completely dissolved. After centrifugation to remove bubbles, pour the solution into a stainless steel mold for teardrop plugs. Freeze the mold at -20℃ for 8 hours, remove it, and thaw at 37℃ for 1 hour. Repeat the above freeze-thaw operation 6 times. Remove the frozen and thawed teardrop plugs from the mold and immerse them in 6% (w / v) 1,4-butanediol diglycidyl ether (prepared by weighing 1.2g of 1,4-butanediol diglycidyl ether and adding it to 20mL of 30wt% sodium hydroxide solution). Soak at 5℃ for 3 hours and crosslink at 60℃ for 3 hours. After removal, the punctum plugs were soaked and cleaned with 0.01% citric acid solution for 6 hours, and then cleaned three times with water for injection. The punctum plugs were then soaked in 25%, 50%, 75%, and 100% isopropanol solutions, with each concentration gradient lasting 2 hours. After soaking, the plugs were removed and placed in a vacuum oven to dry at 30°C for 24 hours. After trimming and cutting, the punctum plugs were obtained.

[0086] Example 4: Preparation of tear spot plug sample 4

[0087] The teardrop plug is 2.05 mm long, the cap structure 1 has a diameter of 1.4 mm and a thickness of 0.15 mm. The tapered shaft structure 2 has a minimum face diameter of 0.6 mm and a height of 0.75 mm, and the tapered shaft surface contains 4 circular ribs 4. The anchor structure 3 has a maximum face diameter of 1.4 mm, a height of 1.15 mm, and a bottom taper of 50°. A stainless steel mold is prepared according to the shape of the teardrop plug.

[0088] Weigh 30g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 78-88 mPa·s) and add purified water to a total mass of 100g. Stir at 98℃ until the polyvinyl alcohol is completely dissolved. After centrifugation to remove bubbles, pour the solution into a stainless steel mold for teardrop plugs. Freeze the mold at -18℃ for 16 hours, remove it, and thaw at 25℃ for 2 hours. Repeat the above freeze-thaw operation 5 times. Remove the frozen and thawed teardrop plugs from the mold and immerse them in a 5% (w / v) solution of 1,2,3,4-diepoxybutane (prepared by adding 1.0g of 1,2,3,4-diepoxybutane to 20mL of 15wt% sodium hydroxide solution). Soak at 8℃ for 2 hours and crosslink at 80℃ for 0.5 hours. After removal, the punctum plugs were soaked and cleaned in 5mM acetic acid solution for 8 hours, and then cleaned 4 times with water for injection. The punctum plugs were then soaked in 25%, 50%, 75%, and 100% ethanol for 1.5 hours at each concentration gradient. After soaking, the plugs were removed and placed in a vacuum oven to dry at 40°C for 15 hours. After trimming and cutting, the punctum plugs were obtained.

[0089] Preparation of Comparative Example 1: Tear Drop Plugs (Comparative Sample 1)

[0090] The tear punctum plug mold is the same as the mold used in Example 4. Weigh 30g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 78-88 mPa·s) and add purified water to a total mass of 100g. Stir at 98°C until the polyvinyl alcohol is completely dissolved. After centrifugation to remove bubbles, pour it into the stainless steel mold for the tear punctum plug. Place the mold in a -18°C environment to freeze for 16h, take it out and thaw at 25°C for 2h. Repeat the above freeze-thaw operation 5 times. After the last thawing, soak the tear punctum plug in 25%, 50%, 75%, and 100% ethanol for 1.5h for each gradient concentration. After soaking, take it out and place it in a vacuum oven to dry at 40°C for 15h. After trimming and cutting, the tear punctum plug is obtained.

[0091] Preparation of tear spot plugs (Comparative Example 2)

[0092] The tear punctum plug mold is the same as the mold used in Example 4. The tear punctum plug material is common medical silicone rubber. After mixing A glue and B glue (silicone rubber brand Nusil, Inc. MED 4870) in a 1:1 mass ratio, the mixture is injected into the mold and cured at 150°C for 2 hours. The tear punctum plug is then trimmed and cut to obtain the tear punctum plug.

[0093] Preparation of Comparative Example 3: Tear Drop Plugs (Comparative Sample 3)

[0094] The tear spot plug has the same appearance as in Example 4, except that the cap structure 1 and the shaft structure 2 have a central blind hole with a diameter of 200 μm and a depth of 800 μm. The preparation process of the tear spot plug is the same as in Example 4.

[0095] Preparation of Comparative Example 4: Tear Drop Plugs as Comparative Sample 4

[0096] The tear punctum plug mold is the same as that used in Example 4. 30g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 78-88 mPa·s) was weighed and purified water was added to a total mass of 100g. The mixture was stirred at 98°C until the polyvinyl alcohol was completely dissolved. 1.0g of 1,2,3,4-diepoxybutane and 20mL of 15wt% sodium hydroxide solution were weighed and mixed, then added to the polyvinyl alcohol solution. The mixture was stirred until homogeneous, centrifuged to remove bubbles, and then injected into the stainless steel mold for the tear punctum plug. The mold was placed at 80°C for 0.5h for crosslinking. After removal, the plug was soaked and cleaned with 5mM acetic acid solution for 8h, and then cleaned four times with water for injection. The tear punctum plugs were then soaked in 25%, 50%, 75%, and 100% ethanol, with each concentration gradient requiring 1.5h of soaking. After soaking, the plugs were removed and placed in a vacuum oven to dry at 40°C for 15h. After trimming and cutting, the tear punctum plugs were obtained.

[0097] Preparation of Comparative Example 5: Tear Drop Plugs (Comparative Sample 5)

[0098] The tear duct plug mold is the same as the mold used in Example 4. Weigh 30g of polyvinyl alcohol (degree of hydrolysis 99-100%; viscosity 78-88 mPa·s) and add purified water to a total mass of 100g. Stir at 98°C until the polyvinyl alcohol is completely dissolved. Weigh 1.0g of 1,2,3,4-diepoxybutane and 2mL of 15wt% sodium hydroxide solution and mix them. Add the mixture to the polyvinyl alcohol solution, mix well, centrifuge to remove bubbles, and inject it into the stainless steel mold of the tear duct plug. Place the mold at 80°C for crosslinking for 0.5h. The punctum plugs were frozen at -18°C for 16 hours, then removed and thawed at 25°C for 2 hours. This freezing and thawing process was repeated 5 times. After the last thawing, the plugs were removed and soaked in 5mM acetic acid solution for 8 hours, and then rinsed with water for injection 4 times. The punctum plugs were then soaked in 25%, 50%, 75%, and 100% ethanol for 1.5 hours at each concentration. After soaking, the plugs were removed and placed in a vacuum oven to dry at 40°C for 15 hours. After trimming and cutting, the punctum plugs were obtained.

[0099] Preparation of tear spot plugs (Comparative Example 6)

[0100] The tear duct plug mold was identical to that used in Example 4. 30g of polyvinyl alcohol (degree of hydrolysis 99–100%; viscosity 78–88 mPa·s) was weighed and purified water was added to a total mass of 100g. The mixture was stirred at 98°C until the polyvinyl alcohol was completely dissolved. After centrifugation to remove bubbles, the solution was poured into the stainless steel mold for the tear duct plug. The mold was placed at -18°C and frozen for 16 hours. It was then removed and thawed at 25°C for 2 hours. This freeze-thaw cycle was repeated 5 times. The frozen and thawed tear duct plugs were removed from the mold and immersed in a 5% (w / v) solution of 1,2,3,4-diepoxybutane (prepared by adding 1.0g of 1,2,3,4-diepoxybutane to 20mL of 15wt% sodium hydroxide solution). The solution was soaked at 8°C for 2 hours and then crosslinked at 80°C for 0.5 hours. After removal, the plugs were rinsed with a 5mM acetic acid solution for 8 hours and then rinsed four times with water for injection. Remove and place in a vacuum oven, dry at 40°C for 15 hours, then trim and cut to obtain the tear spot plug.

[0101] Preparation of tear spot plugs (Comparative Example 7)

[0102] The tear duct plug mold was identical to that used in Example 4. 30g of polyvinyl alcohol (degree of hydrolysis 99–100%; viscosity 78–88 mPa·s) was weighed and purified water was added to a total mass of 100g. The mixture was stirred at 98°C until the polyvinyl alcohol was completely dissolved. After centrifugation to remove bubbles, the mixture was poured into the stainless steel mold for the tear duct plug. The mold was placed in a -18°C environment and frozen for 16 hours. It was then removed and thawed at 25°C for 2 hours. This freeze-thaw cycle was repeated 5 times. The frozen and thawed tear duct plugs were removed from the mold and immersed in a 10% (w / v) solution of 1,2,3,4-diepoxybutane (prepared by adding 2.0g of 1,2,3,4-diepoxybutane to 20mL of 15wt% sodium hydroxide solution). The solution was soaked at 8°C for 2 hours and then crosslinked at 80°C for 0.5 hours. After removal, the punctum plugs were soaked and cleaned in 5mM acetic acid solution for 8 hours, and then rinsed four times with water for injection. The plugs were then soaked in 25%, 50%, 75%, and 100% ethanol solutions for 1.5 hours at each concentration. After soaking, they were removed and placed in a vacuum oven at 40°C for 15 hours. After trimming and cutting, the punctum plugs were obtained.

[0103] Performance testing

[0104] Material hardness testing

[0105] Hardness test specimens for Examples 1-4 and Comparative Examples 1-2 and 4-7 were prepared according to the specimen requirements for hardness testing. After repeated swelling for 2 days, testing began. The testing followed GB / T2411-2008. The height of the Shore hardness tester (Type A) on the stand was adjusted, and calibration began. When the lower platen of the Shore hardness tester was in complete contact with the glass plate, the pointer on the reading dial should indicate "100". When the pointer was completely removed from the glass plate, it should indicate "0". The maximum allowable deviation is ±1 Shore hardness value. Two thin specimens were stacked on the test platform, with the indenter tip at least 12 mm from the edge of the specimen. The Shore hardness tester was pressed smoothly and without impact onto the specimen under the specified weight. The reading was taken immediately 15 seconds after the lower platen was in complete contact with the specimen. The hardness was measured three times at different points on the specimen, spaced at least 6 mm apart, and the arithmetic mean was taken. The test results are shown in Table 1.

[0106] Table 1 Hardness of samples of different tear duct plug materials

[0107]

[0108] As shown in Table 1, the hardness of the polyvinyl alcohol hydrogel material after swelling (Examples 1-4 and Comparative Examples 1, 4-7) is lower than that of medical silicone rubber (Comparative Example 2). Therefore, the punctal plugs prepared using polyvinyl alcohol hydrogel can provide better comfort. Furthermore, in Examples 1-4, under constant immersion crosslinking temperature and time, the hardness of the polyvinyl alcohol hydrogel material increased with increasing PVA concentration and degree of crosslinking.

[0109] Comparative Example 1 underwent only physical crosslinking via freeze-thaw, and its material hardness was significantly lower than that of the double-crosslinked material of Example 4, which underwent physical crosslinking followed by chemical crosslinking. This is because the entanglement of molecular chain segments in physical crosslinking is not as tight as that in double crosslinking, resulting in lower hardness and a greater risk of deformation and detachment during use. Comparative Examples 4 and 5 underwent only chemical crosslinking and chemical crosslinking followed by physical crosslinking, respectively. Although their hardness was similar to the average hardness of the material in Example 4, the chemical crosslinking method was a blend crosslinking, which is significantly different from the low-temperature immersion followed by high-temperature crosslinking method of this application. As the blend crosslinking reaction proceeded, the viscosity of the system further increased, making it increasingly difficult to disperse the small amount of crosslinking agent solution. Consequently, the prepared material exhibited uneven crosslinking, leading to significant differences in hardness at different locations. This is also reflected in the large differences in hardness among the three sets of parallel data in Table 1 for Comparative Examples 4-5.

[0110] Furthermore, the appearance of the prepared tear punctum plugs can also reflect the uniformity of crosslinking. Figure 2As can be seen from the above, the tear duct plug prepared in Example 4 has a complete morphology and stable dimensions, indicating that physical cross-linking through freeze-thaw followed by chemical cross-linking can improve the hardness and stability of the tear duct plug; while the tear duct plug prepared in Comparative Example 5 (see...) Figure 3 The appearance of the teardrop plug has been deformed to a certain extent. This is mainly because the cross-linking environment is carried out in the mold. Due to the small volume of the mold, the cross-linking agent solution is poorly dispersed in the high viscosity polyvinyl alcohol solution, which easily leads to uneven cross-linking of the teardrop plug and eventually shrinkage and deformation.

[0111] Material elongation at break test

[0112] Elongation at break can be used to measure the toughness of a material. Materials with high elongation at break are soft and elastic, and have good toughness. Elongation at break test specimens for Examples 1-4 and Comparative Examples 1-2 and 4-7 were prepared according to the requirements for elongation at break testing. The tests were conducted according to GB / T528-2009. A type 2 cutter was used to prepare the specimens into dumbbell-shaped strips, with the narrow section having a width of 4.0 mm ± 0.1 mm. The dumbbell-shaped strips were mounted on the fixture of an electronic universal testing machine. The test scheme was "Tensile Strength - Large Deformation 1", the test speed was 500 mm / min, and the extensometer gauge length was 20 mm. The test results are shown in Table 2.

[0113] Table 2. Elongation at break of samples from different tear duct plug materials

[0114] Example 1 309 Example 2 398 Example 3 354 Example 4 387 Comparative Example 1 292 Comparative Example 2 415 Comparative Example 4 360 Comparative Example 5 375

[0115] As shown in Table 2, compared to the physically cross-linked polyvinyl alcohol hydrogel in Comparative Example 1, the polyvinyl alcohol hydrogel in Example 4, which underwent physical-to-chemical cross-linking, exhibited a higher elongation at break. Furthermore, compared to the chemically cross-linked polyvinyl alcohol hydrogel in Comparative Example 4 and the chemically-to-physical cross-linked polyvinyl alcohol hydrogel in Comparative Example 5, the elongation at break of the physically-to-chemically cross-linked polyvinyl alcohol hydrogel in Example 4 was slightly higher, indicating that the polyvinyl alcohol hydrogel with both physical and chemical cross-linking exhibited better toughness. Although the elongation at break of the polyvinyl alcohol hydrogels in Examples 1-4 was lower than that of the silicone rubber material in Comparative Example 2, the hardness test results in Table 1 show that the use of polyvinyl alcohol material combines softness and toughness. Moreover, the elongation at break of medical silicone rubber products is typically >250%, a value that polyvinyl alcohol hydrogel material can also meet.

[0116] Teardrop plug extraction test

[0117] The tear spot plug samples prepared in Examples 3-4 and Comparative Examples 1, 4-5 were dried to constant weight in a vacuum oven at 60℃±5℃. Before weighing, the samples were cooled to room temperature in a vacuum or in a sealed container containing an active desiccant, and the weighing accuracy was ±0.1 mg (m1). The samples were placed in an extraction sleeve, and purified water was added to the flask at approximately 70% of its volume. If necessary, boiling stones could be added to the flask. The round-bottom flask was placed on a heating mantle, the extraction sleeve was inserted into a Soxhlet extractor, and then the extractor was connected to the flask, with a condenser inserted at the top. The water supply was turned on and heating was started. The extraction should be carried out for at least 4 hours. After the solvent cooled to room temperature, the samples were removed from the extraction sleeve. The samples were dried as described above, and the weighing accuracy was ±0.1 mg (m2). The amount of water lost in the purified water was calculated according to Equation (1) (expressed as a percentage), and the final stability of the sample was represented by the amount of water lost.

[0118]

[0119] In the formula:

[0120] m1—Sample mass before extraction, in milligrams (mg);

[0121] m2 — Mass of the sample after extraction, in milligrams (mg);

[0122] Table 3 Loss of different tear duct plug samples

[0123] Loss 28％ 21％ 99％ 45％ 40％

[0124] As shown in Table 3, the tear duct plugs of Examples 3-4 had losses of 28% and 21%, respectively, indicating that they partially dissolved. However, due to the uniform cross-linking and high degree of cross-linking, their losses were relatively low. The loss of Comparative Example 1 was 99%, indicating that the tear duct plug sample of Comparative Example 1 was almost completely dissolved. This is because Comparative Example 1 only underwent physical cross-linking through freeze-thaw, which is difficult to maintain stability in a high-temperature water bath and therefore was completely dissolved. The losses of the tear duct plug samples of Comparative Examples 4 and 5 were over 40%, indicating that chemical cross-linking alone, or chemical cross-linking followed by physical cross-linking, is also difficult to effectively achieve uniform cross-linking of the tear duct plug. Therefore, the methods of chemical cross-linking alone or chemical cross-linking followed by physical cross-linking are not suitable for the preparation of tear duct plugs with small size and high dimensional accuracy requirements. The aforementioned methods will result in uneven mixing of the cross-linking agent, leading to low degree of cross-linking and low stability of the tear duct plug.

[0125] Tear plug swelling test

[0126] The minimum diameter at the conical axis of the tear punctum plug was used as the observation object to test its swelling equilibrium time and dimensional changes before and after swelling. The minimum diameter at the conical axis 2 of the dry tear punctum plugs from Examples 1-2, Example 4, and Comparative Examples 1-2 and 4-7 was measured using a reading microscope. The samples were then immersed in physiological saline at 37°C. The swelling size of the samples was observed under a microscope at time intervals. When the size of the tear punctum plug no longer changed, it indicated that the tear punctum plug had reached swelling equilibrium. The time required for swelling equilibrium was recorded, and the results are shown in Table 4.

[0127] Table 4. Swelling properties of different tear spot plug samples

[0128] Example 1 268 405 5 Example 2 547 761 15 Example 4 379 588 10 Comparative Example 1 330 609 10 Comparative Example 2 599 599 - Comparative Example 4 397 580 20 Comparative Example 5 406 576 20 Comparative Example 6 361 590 15 Comparative Example 7 428 560 30

[0129] The swelling rate of polyvinyl alcohol (PVA) punctal plugs is mainly related to factors such as the size of the hydrogel, the content of PVA, the crosslinking density of the hydrogel, and the ionic strength of the swelling solution. Table 4 shows that the swelling equilibrium time for Example 1 was 5 minutes, while for Example 2 it was 10 minutes. This indicates that, with the same swelling system, the lower the PVA content and the smaller the size, the faster the swelling rate. Examples 1, 2, and 4 all achieved swelling equilibrium within 15 minutes, demonstrating that the punctal plugs prepared using the double crosslinking shaping process of this invention can expand rapidly, meeting clinical requirements. The initial size (330 μm) of Comparative Example 1 after drying is smaller than the initial size (379 μm) of Example 4, posing a risk of detachment from the punctum before swelling equilibrium. Furthermore, although Comparative Example 1 also reached swelling equilibrium within 10 minutes, its low crosslinking density, soft material, and poor stability, due to only physical crosslinking, are unsuitable for clinical application. The punctal plug of Comparative Example 2, being made of silicone, does not swell, so its size remains essentially unchanged. The initial size of the punctal plugs in Comparative Examples 4-5 after drying is significantly larger than that of Example 4, making them difficult to implant into the punctum and prone to irritating the lacrimal duct mucosa and causing complications such as inflammation. Furthermore, they require 20 minutes to reach swelling equilibrium, making it difficult to quickly and effectively seal the punctum. The only difference between Example 4 and Comparative Example 6 is that Comparative Example 6 did not use an excipient for shaping, while the dry size of Comparative Example 6 is slightly smaller than that of Example 4, and its swelling time is slightly longer than that of Example 4. This indicates that the swelling rate of Example 4 is faster, suggesting that using an excipient is more conducive to the formation of the pore structure of the punctal plug, thus enabling rapid sealing of the punctum during implantation. However, Comparative Example 7 has a high degree of chemical cross-linking, resulting in a large dry size (468 μm) and the disadvantage of being difficult to implant into the tear duct. At the same time, its swelling rate is slow, requiring about 30 minutes to reach swelling equilibrium. This is mainly because as the degree of cross-linking increases, the distance between the intermolecular entanglement points decreases, and the number of hydroxyl groups that bind to water decreases, which is not conducive to rapid swelling.

[0130] Detection of microbial attachment and growth in tear duct plugs

[0131] Fresh cultures of Staphylococcus aureus (ATCC 6538) and Escherichia coli (8099) were prepared with dilution buffer (0.03 mol / L PBS (pH = 7.4) containing 1% peptone) to a bacterial count of 5 × 10⁻⁶. 5 ~10×10 6 CFU / mL bacterial suspension. The tear punctum plugs from Examples 4, 2, and 3 were placed in centrifuge tubes, each with 5 mL of bacterial suspension added. They were incubated at 37°C in a shaking incubator at 120 rpm for 6 hours. After incubation, the plugs were rinsed with sterile PBS to remove any unadhered bacteria. The surface of the tear punctum plugs was disinfected with 75% medical alcohol and then wiped clean with cotton balls. Simultaneously, the samples were placed in 5 mL nutrient broth tubes and incubated for 7 days. The test samples were visually observed to check for microbial growth on the surface of the tear punctum plugs. The results are shown in Table 5.

[0132] Table 5. Results of microbial adhesion and growth detection in different tear punctum plug samples.

[0133] Growth status - - +

[0134] Note: "+" indicates the presence of microbial growth, and "-" indicates the absence of microbial growth.

[0135] As shown in Table 5, microbial growth occurred in Comparative Example 3, which had a central pore. This was mainly due to the presence of the central pore (200 μm in diameter and 800 μm in depth), which allowed bacteria to survive and multiply in the fluid accumulation within the central pore. In contrast, the tear duct plugs in Example 4 and Comparative Example 2 eliminated the central pore design, thus avoiding fluid accumulation. Therefore, no bacterial growth was observed during the experiment, which is more beneficial for future clinical applications.

[0136] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A polyvinyl alcohol hydrogel tear duct plug, characterized in that: The tear punctum plugs are prepared by a dual cross-linking and shaping process involving physical cross-linking followed by chemical cross-linking. The method for preparing the tear punctum plug includes the following steps: (1) Degassing polyvinyl alcohol aqueous solution, injecting it into a mold, and freezing and thawing it to obtain physically cross-linked polyvinyl alcohol hydrogel tear spot plugs; (2) Take the teardrop plug obtained in step (1) out of the mold and soak it in the crosslinking agent solution to crosslink it, so as to obtain the polyvinyl alcohol hydrogel teardrop plug; The soaking time in step (2) is 0.5~3 h, the soaking temperature is 2~10℃, the cross-linking time is 0.5~3 h, and the cross-linking temperature is 60~80℃.

2. The method for preparing the polyvinyl alcohol hydrogel tear spot plug according to claim 1, characterized in that: The preparation method includes the following steps: (1) Degassing polyvinyl alcohol aqueous solution, injecting it into a mold, and freezing and thawing it to obtain physically cross-linked polyvinyl alcohol hydrogel tear spot plugs; (2) Take the teardrop plug obtained in step (1) out of the mold and soak it in the crosslinking agent solution to crosslink it, so as to obtain the polyvinyl alcohol hydrogel teardrop plug; The soaking time in step (2) is 0.5~3 h, the soaking temperature is 2~10℃, the cross-linking time is 0.5~3 h, and the cross-linking temperature is 60~80℃.

3. The preparation method according to claim 2, characterized in that: The mass concentration of the polyvinyl alcohol aqueous solution in step (1) is 20-50%.

4. The preparation method according to claim 2, characterized in that, The freeze-thaw process in step (1) is as follows: the mold is frozen at -70~-5℃ for 4~24 h, and then thawed at 20~50℃ for 20 min~240 min.

5. The preparation method according to claim 4, characterized in that, The freeze-thaw process is repeated 3 to 10 times in step (1).

6. The preparation method according to claim 2, characterized in that: In step (2), the crosslinking agent solution is prepared by adding the crosslinking agent to the catalyst solution.

7. The preparation method according to claim 2, characterized in that: The mass-volume concentration of the crosslinking agent in the crosslinking agent solution is 3%-6%.

8. The preparation method according to claim 6, characterized in that: The crosslinking agent is an epoxide, and the catalyst is an alkali metal hydroxide or an alkali metal carbonate.

9. The preparation method according to any one of claims 2-8, characterized in that: In step (2), after the soaking and crosslinking, the steps of cleaning and excipient soaking are also included; the excipient is selected from one or more of ethanol, isopropanol, acetone, n-butanol or tert-butanol; the total soaking time of the excipient is 4~24 h.

10. The preparation method according to claim 9, characterized in that: After the excipient is soaked, a drying process is also included.

11. The preparation method according to claim 10, characterized in that: The drying process is vacuum drying, with a drying temperature of 30~70℃ and a drying time of 4~24 h.

12. The preparation method according to claim 9, characterized in that: The excipient immersion is a gradient immersion.

13. The preparation method according to claim 12, characterized in that: The concentrations for the gradient soaking are 15-30%, 50-60%, 70-85%, and 100%.

14. The preparation method according to claim 13, characterized in that: The soaking time for each gradient is 1 to 6 hours.

15. The use of the punctal plug of claim 1 or the punctal plug prepared by the method of any one of claims 2-14 in the preparation of a medical device for treating eye diseases.

Images