Polyvinyl alcohol hydrogel punctum plug and preparation method thereof

Abstract

The invention discloses a polyvinyl alcohol hydrogel punctal plug and a preparation method thereof. The two ends of the punctum plug are provided with a cap structure and an anchor structure respectively, the middle of the punctum plug is provided with a conical shaft structure with round ribs, and no central blind hole is formed. As the punctal plug is small in volume, the punctal plug is prepared by a method of combining injection molding, double crosslinking of physical crosslinking and chemical crosslinking, an excipient gradient soaking and shaping process and the like, the obtained punctal plug is uniform in crosslinking and stable in form, and can be quickly expanded after being implanted, and the risks of separation and bacterial infection are reduced.

Description

Technical Field

[0001] The present invention belongs to the field of medical devices, and in particular relates to a polyvinyl alcohol hydrogel punctal plug and a preparation method thereof. Background Art

[0002] Dry eye, also known as keratoconjunctivitis sicca or dry eye, is a general term for a range of eye diseases caused by pathological changes in the tear film, resulting in a lack of proper moistening of the cornea and conjunctiva. The etiology and pathophysiology of dry eye are complex, and clinically, it is primarily managed through medication, physical therapy, punctal embolization, and surgery. Punctal embolization involves blocking the tear ducts with punctal or ductal plugs to increase tear volume, improve ocular symptoms and signs, and reduce the levels of inflammatory factors on the ocular surface.

[0003] Punctal plugs are typically cylindrical and placed completely within the tear duct, directly at the punctum opening, with some extending into the vertical portion of the duct. They are held in place by tension within the duct. Due to their shallow placement, punctal plugs are relatively easy to install and remove. Punctal plugs can be categorized as either degradable or non-degradable based on their duration of action. Degradable plugs generally last 2 to 6 months, necessitating frequent insertion. Degradable and hydrogel-based punctal plugs are typically inserted dry into the canaliculus. Due to their hard surface, they can easily damage the tear duct mucosa during insertion, leading to adverse reactions such as chronic inflammation and scarring. Non-degradable punctal plugs are commonly made of materials such as silicone, hydroxyethyl methacrylate, polyethylene, and hydrophilic acrylic acid. Representative products include the Herrick Lacrimal Plug and Smart Plug. These products are placed within the canaliculus and cannot be observed under a slit lamp. If the plug becomes dislodged, it can be difficult to retrieve and may even require surgical removal.

[0004] Currently, the common punctal plug products on the market are mostly made of medical silicone, which is elastic. The mainstream shape is a top-cover type punctal plug. The main body includes a cap (sometimes called a collar) and a rod (or anchor), with a central blind hole in the middle to facilitate the fixation of the implant device. However, since the punctal plug is close to the ocular surface, it is easy to cause ocular surface irritation symptoms or the patient's misoperation and fall off. This is often related to factors such as the size, structure, hardness, apparent quality and the location of the punctum plug. In addition, in order to adapt to the size of different puncta, punctal plugs are provided in multiple sizes. However, in actual application, punctal plugs made of silicone cannot fit well with the punctum. If the punctal plug is too large, it will easily lead to implantation difficulties and relaxation of the punctal muscles. If the punctal plug is too small, it cannot be well fixed on the punctum and is easy to fall out.

[0005] Chinese patent CN115651131A discloses a method for preparing a secondary expansion tear plug, which selects cationic monomers such as methacryloylpropyltrimethylammonium chloride and dimethylaminoethyl methacrylate for polymerization, and then polymerizes with anionic monomers such as polymethacrylic acid and polystyrene sulfonic acid to prepare a hydrogel tear plug. Before and during implantation, the hydrogel absorbs water and swells to become soft, and swells again after implantation to play a fixing role. However, the patent uses a photoinitiator ammonium persulfate in the hydrogel polymerization process. Ammonium persulfate is irritating and corrosive to the skin and mucous membranes. If the skin is in long-term contact, it may cause allergic dermatitis. In addition, the tear plug in the patent is cylindrical. After being implanted in the lacrimal canaliculus, since its head is lower than the tear point, a dead cavity will be formed at the top and the tear point, which can easily lead to the accumulation of bacteria and cause complications such as dacryoductitis, and there is a risk of displacement. In addition, tear plugs are small in size and require high precision, with the overall size no larger than a sesame seed. If chemical cross-linking agents are directly used to cross-link polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, cellulose, etc., the cross-linking agent has poor dispersion in the matrix, resulting in uneven cross-linking and local "burning". The prepared tear plugs have poor precision, and the appearance size and swelling rate are uncontrollable. Summary of the Invention

[0006] In order to solve the above technical problems, the present invention provides a polyvinyl alcohol hydrogel tear plug, which is prepared by physical chemical double cross-linking and shaping technology (DCS technology). The obtained polyvinyl alcohol hydrogel tear plug has precise size and stable performance, and has the advantages of reducing the irritation of the tear plug to the skin and reducing complications such as dacryoductitis after implantation; it can also expand rapidly to prevent displacement and falling off after implantation, thereby improving the safety of the tear plug.

[0007] The technical solution of the present invention is achieved as follows:

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

[0009] Furthermore, the two ends of the tear plug are respectively provided with a cap structure and an anchor structure, with a conical shaft structure in the middle, and no central blind hole is provided.

[0010] Furthermore, the length of the tear 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 1.0-1.4 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, and 0.2 mm.

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

[0014] Furthermore, the height of the conical structure is 0.4-0.8 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, and 0.8 mm.

[0015] Furthermore, the diameter of the largest surface of the anchor structure is 0.8-1.5 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 0.6-1.4 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, and 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, at least three circular ribs are provided on the tapered shaft structure.

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

[0020] The present invention uses an injection molding process to form a polyvinyl alcohol hydrogel punctal plug by first physically crosslinking it and then chemically crosslinking it in a mold. Once implanted, the plug absorbs tears, rapidly expands, and secures itself to the designed size in the punctum, preventing it from falling off.

[0021] In a second aspect, the present invention provides a method for preparing a polyvinyl alcohol hydrogel punctal plug, the preparation method comprising the following steps:

[0022] (1) degassing the polyvinyl alcohol aqueous solution, injecting it into a mold, and freezing and thawing it to prepare a physically cross-linked polyvinyl alcohol hydrogel punctal plug;

[0023] (2) The punctal plug prepared in step (1) is taken out from the mold, and is placed in a crosslinking agent solution for immersion and crosslinking to obtain the polyvinyl alcohol hydrogel punctal plug.

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

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

[0026] In step (1), the polyvinyl alcohol aqueous solution is prepared by weighing polyvinyl alcohol, adding it into water, and stirring until the polyvinyl alcohol is completely dissolved.

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

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

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

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

[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°C, 25°C, 27°C, 30°C, 35°C, 37°C, 40°C, 45°C, 47°C or 50°C.

[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 freezing and thawing process is repeated 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times or 10 times.

[0035] Furthermore, the cross-linking agent solution in step (2) is prepared by adding a cross-linking agent into a catalyst solution.

[0036] Furthermore, the mass volume concentration of the crosslinker in the crosslinker 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 cross-linking agent is an epoxide, such as ethylene oxide, propylene oxide, 1,2-butylene oxide, 1,4-butylene oxide, 1,4-butanediol diglycidyl ether, 1,2,3,4-diepoxybutane, glycerol tri(1,2-epoxy)propyl ether, etc.

[0038] Furthermore, the mass concentration of the catalyst solution is 10% to 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, 3 hours.

[0042] Furthermore, the soaking temperature is 2-10°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 immersion conditions of the polyvinyl alcohol hydrogel tear plug in the crosslinker solution and immersing it at low temperature, the crosslinker can be easily penetrated 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 cross-linking reaction is 60-80°C, for example: 60°C, 65°C, 70°C, 75°C, 80°C.

[0046] The present invention subjects the polyvinyl alcohol solution to a physical crosslinking process of first freezing and thawing to obtain a preliminarily formed tear plug, and then performs chemical crosslinking in a crosslinking agent and catalyst solution system. By controlling the degree of crosslinking within a suitable range, the structure of the prepared tear plug can be made stable while having a suitable swelling rate. This effectively solves the problems of the tear plug being deformed and lost during clinical use if the crosslinking degree of the polyvinyl alcohol hydrogel tear plug is too low, resulting in a low initial dry size and excessive softness after swelling; and the problem of the tear plug being too high and harder in initial dry size and easily scratching the lacrimal duct mucosa during implantation if the crosslinking degree of the hydrogel is too high, and the swelling rate is too low, which is not conducive to rapid occlusion of the tear punctum. This is more conducive to clinical application.

[0047] Furthermore, after the cross-linking reaction, cleaning and shaping treatment processes are also included.

[0048] Furthermore, the cleaning is to use an acidic solution to wash away the crosslinking agent solution in the punctal plug, and then wash at least once with injection water to wash away 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 solution and acidic citrate buffer solution.

[0050] Furthermore, the excipient treatment is to soak the cleaned punctal plug in an excipient 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 performed in 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, 24 hours.

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

[0055] Furthermore, the concentrations of the gradient immersion 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 of the excipient solution is water.

[0058] In the prior art, hydrogel punctal plugs are usually dried directly after being obtained, which easily leads to the destruction of the porous structure of the hydrogel, making the structure compact and resulting in low expansion effect. However, the present invention uses an excipient solution to treat the punctal plug before drying, which can better fix the pore structure of the polyvinyl alcohol hydrogel. Specifically, by soaking the punctal plug with a gradient concentration from low to high, the water in the gel can be slowly replaced, which is conducive to the steady solidification of the porous structure in the gel, so that it maintains a better shape during the drying process, and is conducive to its expansion to a predetermined size in a shorter time after implantation, achieving the technical effect of rapid expansion and reducing the risk of dislocation caused by inappropriate punctal plug size.

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

[0060] Furthermore, the drying is vacuum drying.

[0061] Furthermore, the drying temperature is 30-70°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] In a third aspect, the present invention provides a use of a polyvinyl alcohol hydrogel punctal plug in the preparation of a medical device 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 liquid can be water for injection or physiological saline, or a solution containing one or more ophthalmic therapeutic drugs.

[0065] Furthermore, the ophthalmic therapeutic 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] Beneficial effects of the present invention:

[0067] 1. The present invention adopts a double cross-linking shaping process, and obtains a preliminary formed tear plug through physical cross-linking by freeze-thawing first, and then controls the cross-linking degree of the hydrogel by low-temperature immersion and high-temperature chemical cross-linking. The low-temperature immersion allows the cross-linking agent to slowly penetrate into the interior of the polyvinyl alcohol hydrogel, preventing the cross-linking reaction from occurring too quickly, thereby improving the uniformity of the subsequent high-temperature cross-linking, so that the prepared tear plug has a stable structure and a suitable swelling rate, maintaining the uniformity of the overall cross-linking degree and the stability of the hydrogel, not easy to deform, and more conducive to clinical application.

[0068] 2. The present invention obtains a physically cross-linked tear plug by freeze-thawing in a mold, and 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 the metal mold by a strong alkaline catalyst, circumvents the risk of introducing heavy metals into the product during the processing and manufacturing process, and increases the reusable time of the mold. On the other hand, it enables the tear plug to achieve long-term effective clinical effects after implantation, reducing the foreign body sensation caused by traditional silicone tear plugs.

[0069] 3. The present invention uses excipient gradient immersion treatment for the cross-linked punctal plug, which helps to solidify the porous structure in the gel and maintain a better shape during the drying process of the punctal plug, which is beneficial for it to expand to a predetermined size in a shorter time after implantation, achieving the technical effect of rapid expansion and reducing the risk of dislocation due to inappropriate punctal plug size.

[0070] 4. The present invention eliminates the central blind hole in the structural design of the punctal plug, which can avoid dead space accumulation in the punctal plug and thus reduce the risk of bacterial infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 Shown is a schematic diagram of a polyvinyl alcohol hydrogel punctal plug of the present invention;

[0072] Figure 2 is the punctal plug of Example 4;

[0073] Figure 3 This is the tear point plug of Comparative Example 5.

[0074] The components in the figure are marked as follows: 1-cap structure, 2-conical shaft structure, 3-circular rib, 4-anchor structure. DETAILED DESCRIPTION

[0075] The technical solution of the present invention will be further described below in conjunction with the embodiments and drawings, and the advantages and features of the present invention will become clearer as the description proceeds. However, it should be understood that the embodiments are merely illustrative and do not limit the scope of the present invention.

[0076] It should be noted that the experimental methods used in the following examples are conventional methods in the art unless otherwise specified. Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention relates.

[0077] Example 1 Preparation of Punctal Plug Sample 1

[0078] The punctal plug has a length of 1.1 mm, a cap structure 1 with a diameter of 1.0 mm and a thickness of 0.1 mm. The tapered shaft structure 2 has a minimum diameter of 0.4 mm and a height of 0.4 mm, and contains three circular ribs 4 on its surface. The anchor structure 3 has a maximum diameter of 0.8 mm and a height of 0.6 mm, with a bottom taper of 35°. A stainless steel mold was prepared based on the shape of the punctal plug.

[0079] Weigh 20g of polyvinyl alcohol (99-100% alcoholysis; viscosity 22-30mPa·s) and add purified water to a total mass of 100g. Stir at 90°C until the polyvinyl alcohol is completely dissolved. After centrifugation and degassing, inject it into a stainless steel mold for the punctal plug. The mold is placed in a -70°C environment and frozen for 4 hours. Remove it and thaw it at 20°C for 6 hours. Repeat the freeze-thaw operation three times. The punctal plug after freeze-thaw is removed from the mold and immersed in a 3% (w / v) 1,4-butanediol diglycidyl ether crosslinker solution (prepared by weighing 0.6g of 1,4-butanediol diglycidyl ether and adding it to 20mL of 10wt% sodium hydroxide solution). Soak it at 2°C for 3 hours and crosslink it at 60°C for 3 hours. After removal, the punctal plug was soaked and cleaned with a pH 6.5 phosphate buffer for 24 hours, and then washed three times with injection water. The punctal plug was then soaked in 30%, 60%, 80%, and 100% n-butanol in sequence, with each gradient concentration soaked for 6 hours. After soaking, the punctal plug was taken out and placed in a vacuum oven at 70°C for 4 hours. After trimming and cutting, the punctal plug was obtained. The schematic diagram of its structure is shown below. Figure 1 shown.

[0080] Example 2 Preparation of Punctal Plug Sample 2

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

[0082] Weigh 50 g of polyvinyl alcohol (alcoholization degree 98-99%; viscosity 5.2-6.0 mPa·s) and add purified water to a total mass of 100 g. Stir at 100°C until the polyvinyl alcohol is completely dissolved. After centrifugation and degassing, inject it into the stainless steel mold of the tear plug. Place the mold in a -5°C environment and freeze it for 24 hours. Take it out and thaw it at 50°C for 20 minutes. Repeat the above freeze-thaw operation 10 times. Remove the frozen and thawed tear plug from the mold and immerse it in a 3% (W / V) propylene oxide solution (prepared by weighing 0.6 g of propylene oxide and adding it to 20 mL of 40 wt% sodium hydroxide solution), soak it at 10°C for 30 minutes, and cross-link it at 60°C for 3 hours. After taking it out, soak it in 5mM hydrochloric acid solution for 8 hours, and wash it with injection water 4 times. Then, soak the tear plug in 15%, 50%, 85%, and 100% acetone in sequence, soaking each gradient concentration for 1 hour. After soaking, take it out and place it in a vacuum oven, dry it at 60℃ for 8 hours, and trim and cut it to obtain the tear plug.

[0083] Example 3 Preparation of Punctal Plug Sample 3

[0084] The punctal plug has a length of 1.77 mm, a cap structure 1 with a diameter of 1.2 mm, and a thickness of 0.12 mm. The tapered shaft structure 2 has a minimum diameter of 0.4 mm and a height of 0.65 mm, and contains three circular ribs 4 on its surface. The anchor structure 3 has a maximum diameter of 1.0 mm and a height of 1.0 mm, with a bottom taper of 49.53°. A stainless steel mold was prepared based on the shape of the punctal plug.

[0085] Weigh 20g of polyvinyl alcohol (99-100% alcoholysis; viscosity 78-88mPa·s) and add purified water to a total mass of 100g. Stir at 95°C until the polyvinyl alcohol is completely dissolved. After centrifugation and degassing, inject it into a stainless steel mold for the punctal plug. The mold is placed in a -20°C environment and frozen for 8 hours. Remove it and thaw it at 37°C for 1 hour. Repeat the freeze-thaw operation 6 times. The punctal plug after freeze-thaw is removed from the mold and immersed 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 it at 5°C for 3 hours and cross-link it at 60°C for 3 hours. After taking it out, soak it in 0.01% citric acid solution for 6 hours, and wash it with injection water for 3 times. Then, soak the tear plug in 25%, 50%, 75%, and 100% isopropyl alcohol in sequence, soaking it in each gradient concentration for 2 hours. After soaking, take it out and place it in a vacuum oven, dry it at 30°C for 24 hours, and trim and cut it to obtain the tear plug.

[0086] Example 4 Preparation of Punctal Plug Sample 4

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

[0088] Weigh 30 g of polyvinyl alcohol (99-100% alcoholysis degree; 78-88 mPa·s) and add purified water to a total mass of 100 g. Stir at 98°C until the polyvinyl alcohol is completely dissolved. After centrifugation and degassing, inject it into a stainless steel mold for the punctal plug. Place the mold in a -18°C environment and freeze it for 16 hours. Remove it and thaw it at 25°C for 2 hours. Repeat the freeze-thaw operation 5 times. Remove the punctal plug from the mold after freeze-thawing and immerse it in a 5% (W / V) 1,2,3,4-diepoxybutane solution (prepared by weighing 1.0 g of 1,2,3,4-diepoxybutane and adding it to 20 mL of 15 wt% sodium hydroxide solution), soak it at 8°C for 2 hours, and crosslink it at 80°C for 0.5 hours. After taking it out, soak it in 5mM acetic acid solution for 8 hours, and wash it with injection water 4 times. Then, soak the tear plug in 25%, 50%, 75%, and 100% ethanol, soaking for 1.5 hours in each gradient concentration. After soaking, take it out and place it in a vacuum oven, dry it at 40℃ for 15 hours, and trim and cut it to obtain the tear plug.

[0089] Comparative Example 1 Preparation of Punctal Plug Comparative Sample 1

[0090] The tear plug mold is consistent with the mold used in Example 4. 30 g of polyvinyl alcohol (alcoholysis degree 99-100%; viscosity 78-88 mPa·s) is weighed, and purified water is added to a total mass of 100 g. The mixture is stirred at 98°C until the polyvinyl alcohol is completely dissolved. After centrifugal degassing, it is injected into the stainless steel mold of the tear plug. The mold is placed in a -18°C environment and frozen for 16 hours. It is taken out and thawed at 25°C for 2 hours. The above freeze-thaw operation is repeated 5 times. After the last thawing is completed, the tear plug is placed in 25%, 50%, 75%, and 100% ethanol for 1.5 hours at each gradient concentration. After soaking, it is taken out and placed in a vacuum oven and dried at 40°C for 15 hours. The tear plug is obtained after trimming and cutting.

[0091] Comparative Example 2 Preparation of Punctal Plug Comparative Sample 2

[0092] The mold for the punctal plug is consistent with the mold used in Example 4. The material of the punctal plug is common medical silicone rubber. Glue A and glue B (silicone rubber brand Nusil, Inc. MED 4870) are mixed in a mass ratio of 1:1, injected into the mold, cured at 150°C for 2h, and trimmed and cut to obtain the punctal plug.

[0093] Comparative Example 3 Preparation of Punctal Plug Comparative Sample 3

[0094] The appearance of the punctal plug is consistent with that of Example 4, except that the cap structure 1 and the shaft structure 2 are provided with a central blind hole with a diameter of 200 μm and a depth of 800 μm. The preparation process of the punctal plug is consistent with that of Example 4.

[0095] Comparative Example 4 Preparation of Punctal Plug Comparative Sample 4

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

[0097] Comparative Example 5 Preparation of Punctal Plug Comparative Sample 5

[0098] The tear plug mold is consistent with the mold used in Example 4. 30 g of polyvinyl alcohol (alcoholization degree 99-100%; viscosity 78-88 mPa·s) is weighed, and purified water is added to a total mass of 100 g. The mixture is stirred at 98°C until the polyvinyl alcohol is completely dissolved. 1.0 g of 1,2,3,4-diepoxybutane and 2 mL of 15 wt% sodium hydroxide solution are weighed and mixed. The mixture is added to the polyvinyl alcohol solution, mixed evenly, and centrifuged for degassing. The mixture is injected into the stainless steel mold of the tear plug, and the mold is placed at 80°C for crosslinking for 0.5 h. The tear plug was placed in a -18°C environment and frozen for 16 hours, taken out and thawed at 25°C for 2 hours; the above freeze-thaw operation was repeated 5 times. After the last thawing was completed, the tear plug was taken out and soaked and cleaned with 5mM acetic acid solution for 8 hours, and washed with injection water 4 times. The tear plug was placed in 25%, 50%, 75%, and 100% ethanol and soaked for 1.5 hours in each gradient concentration. After soaking, it was taken out and placed in a vacuum oven, dried at 40°C for 15 hours, and trimmed and cut to obtain the tear plug.

[0099] Comparative Example 6 Preparation of Punctal Plug Comparative Sample 6

[0100] The mold for the tear plug is consistent with the mold used in Example 4. 30 g of polyvinyl alcohol (alcoholization degree 99-100%; viscosity 78-88 mPa·s) is weighed and purified water is added to a total mass of 100 g. Stir at 98°C until the polyvinyl alcohol is completely dissolved. After centrifugal degassing, it is injected into the stainless steel mold of the tear plug. The mold is placed in a -18°C environment and frozen for 16 hours. It is taken out and thawed at 25°C for 2 hours. The freeze-thaw operation is repeated 5 times. The frozen and thawed tear plug is removed from the mold and immersed in a 5% (W / V) 1,2,3,4-diepoxybutane solution (prepared by weighing 1.0 g of 1,2,3,4-diepoxybutane and adding it to 20 mL of 15 wt% sodium hydroxide solution), soaked at 8°C for 2 hours, and cross-linked at 80°C for 0.5 hours. After removal, it is soaked and cleaned with a 5 mM acetic acid solution for 8 hours and washed 4 times with water for injection. Take it out and place it in a vacuum oven, dry it at 40°C for 15 hours, and then trim and cut it to obtain the tear plug.

[0101] Comparative Example 7 Preparation of Punctal Plug Comparative Sample 7

[0102] The mold for the tear plug is consistent with the mold used in Example 4. 30 g of polyvinyl alcohol (alcoholization degree 99-100%; viscosity 78-88 mPa·s) is weighed and purified water is added to a total mass of 100 g. Stir at 98°C until the polyvinyl alcohol is completely dissolved. After centrifugal degassing, it is injected into the stainless steel mold of the tear plug. The mold is placed in a -18°C environment and frozen for 16 hours. It is taken out and thawed at 25°C for 2 hours. The freeze-thaw operation is repeated 5 times. The frozen and thawed tear plug is removed from the mold and immersed in a 10% (W / V) 1,2,3,4-diepoxybutane solution (prepared by weighing 2.0 g of 1,2,3,4-diepoxybutane and adding it to 20 mL of 15 wt% sodium hydroxide solution), soaked at 8°C for 2 hours, and cross-linked at 80°C for 0.5 hours. After removal, the punctal plug was soaked and cleaned with 5mM acetic acid solution for 8 hours, and then washed four times with injection water. The punctal plug was then soaked in 25%, 50%, 75%, and 100% ethanol, with each gradient concentration soaking for 1.5 hours. After soaking, the punctal plug was removed and placed in a vacuum oven, dried at 40°C for 15 hours, and trimmed and cut to obtain the punctal plug.

[0103] Performance testing

[0104] Material hardness testing

[0105] According to the sample requirements for hardness testing, hardness test specimens of Examples 1 to 4 and Comparative Examples 1 to 2, 4 to 7 were prepared. The specimens were repeatedly swollen for 2 days before testing began. The test was carried out with reference to GB / T2411-2008. The height of the Shore hardness tester (Type A) on the bracket was adjusted to begin calibration of the Shore hardness tester. When the lower pressure plate of the Shore hardness tester was in full contact with the glass sheet, the pointer on the reading disk should indicate "100". When the pointer completely left the glass sheet, the pointer should indicate "0". The maximum allowable deviation is ±1 Shore hardness value. Two layers of thin sheet specimens were placed on top of each other on the test platform. The pressure needle was at least 12 mm away from the edge of the specimen. The Shore hardness tester was pressed onto the specimen under the action of the specified weight in a steady and impact-free manner. The reading was taken immediately 15 seconds after the lower pressure plate was in full contact with the specimen. The hardness was measured three times at different points on the specimen at a distance of more than 6 mm, and the arithmetic mean was taken. The test results are shown in Table 1.

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

[0107]

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

[0109] Comparative Example 1 only performed physical crosslinking by freeze-thaw, and the hardness of its material was significantly lower than that of the double-crosslinked material of Example 4, which was first physically crosslinked and then chemically crosslinked. This is because the entanglement of the molecular segments of the physical crosslinking is not as tight as that of the double crosslinking, resulting in low hardness, easy deformation during use, and the risk of falling off. Comparative Examples 4 and 5, respectively, performed only chemical crosslinking and first chemical crosslinking and then physical crosslinking. Although their hardnesses were similar to the average hardness of the material in Example 4, because the chemical crosslinking method was co-crosslinking, which was significantly different from the low-temperature immersion followed by high-temperature crosslinking in the present application, as the co-crosslinking reaction proceeded, the viscosity of the system would further increase, making it increasingly difficult to disperse the small amount of crosslinking agent solution. As a result, the prepared material was unevenly crosslinked, resulting in significantly different hardnesses at different locations on the material. This is also reflected in the large differences in hardness of the three sets of parallel data for Comparative Examples 4-5 in Table 1.

[0110] In addition, the appearance of the prepared punctal plug can also reflect the uniformity of cross-linking. Figure 2As can be seen from the figure, the punctal plug prepared in Example 4 has a complete appearance and stable size, indicating that the hardness and stability of the punctal plug can be improved by first performing physical crosslinking by freeze-thawing and then performing chemical crosslinking; while the punctal plug prepared in Comparative Example 5 (see Figure 3 ), its appearance has undergone a certain degree of deformation. 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 has poor dispersion in the polyvinyl alcohol solution with higher viscosity, which can easily lead to uneven cross-linking of the tear plug and eventually shrinkage 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, 4-7 were prepared according to the specimen requirements for the elongation at break test. The tests were conducted in accordance with GB / T528-2009. The specimens were prepared into dumbbell-shaped strips using a Type 2 cutter, with a narrow portion 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 protocol used was "Tensile Strength - Maximum 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 of different tear plug materials

[0114] Sample name Elongation at break / % 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 can be seen in Table 2, the polyvinyl alcohol hydrogel crosslinked first physically and then chemically in Example 4 exhibited a higher elongation at break than the polyvinyl alcohol hydrogel crosslinked only chemically in Comparative Example 1. Furthermore, compared to the polyvinyl alcohol hydrogel crosslinked only chemically in Comparative Example 4 and the polyvinyl alcohol hydrogel crosslinked first chemically and then physically in Comparative Example 5, the polyvinyl alcohol hydrogel crosslinked first physically and then chemically in Example 4 exhibited a slightly higher elongation at break, indicating that the polyvinyl alcohol hydrogel crosslinked first physically and then chemically possessed greater 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, combined with the hardness test results in Table 1, it can be seen that the polyvinyl alcohol material offers both softness and toughness. Medical silicone rubber products typically have an elongation at break greater than 250%, a value that can be met by polyvinyl alcohol hydrogels.

[0116] Punctal plug extraction test

[0117] The tear plug samples prepared in Examples 3 to 4 and Comparative Examples 1, 4 to 5 are dried in a vacuum oven at 60°C ± 5°C to constant weight. Before weighing, the sample is cooled to room temperature in a vacuum state or in a sealed container containing an active desiccant, and the weighing accuracy is ± 0.1 mg (m1). The sample is placed in an extraction sleeve, and purified water of about 70% of its capacity is added to the flask. If necessary, zeolite can be placed in the flask. Place the round-bottom flask on a heating jacket, insert the extraction sleeve into the Soxhlet extractor, and then connect the extractor to the flask, and insert a condenser on top. Turn on the water source and start heating. The extraction should be carried out for at least 4 hours. When the solvent has cooled to room temperature, remove the sample from the extraction sleeve. Dry the sample according to the above method and weigh it to an accuracy of ± 0.1 mg (m2). Calculate the loss (expressed as a percentage) of the amount dissolved in purified water according to formula (1), and the final stability of the sample is expressed by the loss;

[0118]

[0119] Where:

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

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

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

[0123] Sample name Example 3 Example 4 Comparative Example 1 Comparative Example 4 Comparative Example 5 Amount of loss 28％ 21％ 99％ 45％ 40％

[0124] As can be seen from Table 3, the loss amounts of the tear plugs of Examples 3-4 were 28% and 21%, respectively, indicating that they were partially dissolved. However, due to the uniform cross-linking and high degree of cross-linking, the extraction loss amount was relatively low; the loss amount of Comparative Example 1 was 99%, indicating that the tear plug sample of Comparative Example 1 was almost completely dissolved. This was because Comparative Example 1 only underwent physical cross-linking by freeze-thaw, and it was difficult to exist stably in a high-temperature water bath, so it was completely dissolved; and the loss amounts of the tear plug samples of Comparative Examples 4 and 5 were above 40%, indicating that only chemical cross-linking, or chemical cross-linking followed by physical cross-linking, was difficult to effectively achieve uniform cross-linking of the tear plugs. Therefore, the method of chemical cross-linking only or chemical cross-linking followed by physical cross-linking is not suitable for the preparation of tear plugs with small sizes and high dimensional accuracy requirements. The aforementioned method will result in uneven mixing of the cross-linking agent, which will lead to the problem of low degree of cross-linking and low stability of the tear plugs.

[0125] Punctal plug swelling test

[0126] The minimum diameter at the tapered axis of the punctal plugs was used as the observation object to measure the swelling equilibrium time and dimensional change before and after swelling. The minimum diameter at the tapered axis 2 of the dry punctal plugs from Examples 1-2, Example 4, and Comparative Examples 1-2, 4-7 was measured using a reading microscope. The samples were then immersed in 37°C saline and the swelling size of the samples was observed at intervals using a microscope. When the punctal plugs no longer changed in size, the punctal plugs reached swelling equilibrium. The time required for swelling equilibrium was recorded. The results are shown in Table 4.

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

[0128] Sample name Initial state size / μm Swelling equilibrium size / μm Swelling equilibrium time / min 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 the polyvinyl alcohol tear plug is mainly related to factors such as the size of the hydrogel, the content of polyvinyl alcohol, the cross-linking density of the hydrogel, and the ionic strength of the swelling solution. It can be seen from Table 4 that the swelling equilibrium time of Example 1 is 5 minutes, while the swelling equilibrium time of Example 2 is 10 minutes, indicating that when the swelling system is the same, the lower the polyvinyl alcohol content and the smaller the size, the faster the swelling rate. Example 1, Example 2 and Example 4 can all reach swelling equilibrium within 15 minutes, indicating that the tear plug prepared by the double cross-linking shaping process of the present invention can expand rapidly and meet the requirements of clinical use. The size of the initial state of Comparative Example 1 after drying (330 μm) is smaller than the initial size of Example 4 (379 μm), and there is a risk of falling off from the tear point before swelling equilibrium. In addition, although Comparative Example 1 can also reach swelling equilibrium in 10 minutes, since it is only physically cross-linked, the cross-linking density is small, the material is soft, and the stability is poor, which is not conducive to clinical application. The tear plug of Comparative Example 2 is made of silicone and does not have swelling properties, so its size remains basically unchanged; the initial size of the tear plug of Comparative Example 4-5 after drying is significantly larger than the initial size of Example 4, which makes it difficult to implant into the tear punctum and easily irritates the lacrimal mucosa, causing complications such as inflammation. In addition, it takes 20 minutes to reach swelling equilibrium, making it difficult to quickly and effectively block the tear punctum; the only difference between Example 4 and Comparative Example 6 is that Comparative Example 6 does not use excipients for shaping, and the dry size of Comparative Example 6 is slightly smaller than that of Example 4, and the swelling time is slightly longer than that of Example 4, that is, the swelling rate of Example 4 is faster, indicating that the use of excipients for treatment is more conducive to the formation of the pore structure of the tear plug, so the tear punctum can be quickly blocked during the implantation process. However, Comparative Example 7 has a large dry size (468 μm) due to its high degree of chemical cross-linking, and also has the defect of being difficult to implant into the tear point. At the same time, its swelling rate is slow, and it takes about 30 minutes to reach swelling equilibrium. This is mainly because as the degree of cross-linking increases, the distance between the entanglement points of molecules decreases, and the number of hydroxyl groups combined with water becomes less, which is not conducive to rapid swelling.

[0130] Punctal plug microbial attachment and growth detection

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

[0132] Table 5 Results of microbial attachment and growth test on different punctal plug samples

[0133] Sample name Example 4 Comparative Example 2 Comparative Example 3 Growth - - +

[0134] Note: “+” indicates microbial growth, “-” indicates no microbial growth.

[0135] As shown in Table 5, microbial growth occurred in Comparative Example 3, which had a central hole. This was primarily due to the presence of a central hole with a diameter of 200 μm and a depth of 800 μm, which allowed bacteria to survive and multiply in the fluid accumulated within the central hole. However, the punctal plugs in Example 4 and Comparative Example 2 eliminated the central hole, thus preventing fluid accumulation. Consequently, no bacterial growth was observed during the experiment, which is more conducive to future clinical applications.

[0136] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within 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 scope of protection of the present invention.

Claims

1. A polyvinyl alcohol hydrogel punctal plug, characterized in that: The tear point plug is prepared by a double cross-linking shaping process of first physical cross-linking and then chemical cross-linking.

2. The polyvinyl alcohol hydrogel punctal plug according to claim 1, characterized in that: The two ends of the tear point plug are respectively provided with a cap structure and an anchor structure, with a tapered shaft structure in the middle and no central blind hole.

3. The polyvinyl alcohol hydrogel punctal plug according to claim 1 or 2, characterized in that: The length of the punctal plug is 1.1 to 2.2 mm, and the diameter of the cap structure is 1.0 to 1.4 mm; and / or, The thickness of the cap structure is 0.1 to 0.2 mm; and / or, The tapered shaft structure has a minimum diameter of 0.4 to 0.8 mm and a height of 0.4 to 0.8 mm; and / or The anchor structure has a maximum diameter of 0.8 to 1.5 mm and a height of 0.6 to 1.4 mm; and / or The bottom taper of the anchor structure is 35° to 50°; Preferably, at least three circular ribs are provided on the tapered shaft structure; and the circular ribs are connected by arc transitions.

4. The method for preparing the polyvinyl alcohol hydrogel punctal plug according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: (1) degassing the polyvinyl alcohol aqueous solution, injecting it into a mold, and freezing and thawing it to prepare a physically cross-linked polyvinyl alcohol hydrogel punctal plug; (2) The punctal plug prepared in step (1) is taken out from the mold, and is placed in a crosslinking agent solution for immersion and crosslinking to obtain the polyvinyl alcohol hydrogel punctal plug.

5. The preparation method according to claim 4, characterized in that: The mass concentration of the polyvinyl alcohol aqueous solution in step (1) is 20-50%; Preferably, the freeze-thaw process is: freezing the mold at -70 to -5°C for 4 to 24 hours, and then thawing at 20 to 50°C for 20 to 240 minutes; Preferably, the freezing and thawing process is repeated 3 to 10 times.

6. The preparation method according to claim 4, characterized in that: In step (2), the crosslinking agent solution is prepared by adding the crosslinking agent to the catalyst solution; Preferably, the mass volume concentration of the crosslinking agent in the crosslinking agent solution is 3%-6%; Preferably, the cross-linking agent is an epoxide, and the catalyst is an alkali metal hydroxide or an alkali metal carbonate.

7. The preparation method according to claim 4, characterized in that: In step (2), the soaking time is 0.5 to 3 hours; and / or the soaking temperature is 2 to 10° C.; Preferably, the cross-linking time is 0.5 to 3 hours; and / or the cross-linking temperature is 60 to 80°C.

8. The preparation method according to any one of claims 4 to 7, characterized in that: In the step (2), after the soaking and cross-linking, the steps of washing 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 to 24 hours; Preferably, after the excipient is soaked, a drying step is further included; preferably, the drying is vacuum drying, the drying temperature is 30 to 70° C., and the drying time is 4 to 24 hours.

9. The preparation method according to claim 8, characterized in that: The excipient soaking is a gradient soaking; preferably, the concentration of the gradient soaking is 15-30%, 50-60%, 70-85% and 100%; Preferably, the soaking time of each gradient is 1 to 6 hours.

10. Use of the punctal plug according to any one of claims 1 to 3 or the punctal plug prepared by the method according to any one of claims 4 to 9 in preparing a medical device for treating eye diseases.

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