A self-expanding traceable lacrimal plug and its preparation method and application

Abstract

The application relates to a self-expanding traceable lacrimal canaliculus plug and a preparation method and application thereof, the preparation method comprising the following steps: raw material pretreatment, injection molding and post-treatment; the mixed material is subjected to segmented temperature control injection molding treatment to obtain a precursor product, and is subjected to circulation soaking-drying post-treatment, through synergistic optimization of a formula and a process, the technical problems of poor hydrophilicity, low expansion ratio, no traceability and great difficulty in micro-size molding of the existing PPDO lacrimal canaliculus plug are solved, the lacrimal canaliculus plug has excellent morphological stability, biocompatibility and visual traceability, can meet the clinical treatment requirements of dry eye, and has the advantages of simple process and industrialized mass production.

Description

Technical Field

[0001] This invention relates to the field of medical devices, and in particular to a self-expanding traceable lacrimal canaliculus plug, its preparation method, and its application. Background Technology

[0002] Dry eye syndrome is the most common chronic ocular surface disease in ophthalmology clinics, and its global prevalence is increasing year by year. Moderate to severe cases can cause persistent ocular surface damage and decreased vision, seriously affecting the quality of life. Lacrimal canaliculus occlusion is a first-line minimally invasive treatment for moderate to severe dry eye syndrome. By implanting an occluder to block the lacrimal duct, reducing tear drainage and prolonging the residence time of the body's own tears on the ocular surface, it has the advantages of high efficiency and few side effects, and has been widely used in clinical practice.

[0003] Poly(p-dioxanone) (PPDO) exhibits excellent biocompatibility and controllable degradation, making it an ideal matrix material for preparing lacrimal canaliculus occluders. However, existing technologies suffer from several key drawbacks: pure PPDO has poor hydrophilicity and lacks stable self-expansion properties, leading to easy slippage after implantation; existing modification methods cannot balance high expansion ratio with structural stability. Furthermore, the clinically applicable 0.3mm diameter ultrafine cylindrical products are difficult to mold, with existing processes exhibiting low precision and poor mass production stability, and a lack of suitable dedicated injection molding solutions. Finally, existing products lack compliant visualization and traceability capabilities, making clinical follow-up difficult, and existing traceability methods pose biosafety risks.

[0004] Existing technologies for the modification, molding, and tracer design of PPDO lacrimal canaliculus occluders are mostly fragmented and single solutions, failing to form a complete system of synergistic optimization. They cannot simultaneously meet the multiple requirements of clinical performance, biosafety, and industrial mass production. There is an urgent need to develop corresponding self-expanding traceable lacrimal canaliculus occluders and their preparation methods. Summary of the Invention

[0005] To address the challenges of injection molding micro-sized PPDO cylinders and provide a suitable injection molding method for achieving high precision, high yield, and industrial-scale production, while further optimizing the product's expansion properties through post-processing to meet clinical treatment needs, this invention provides a method for preparing a self-expanding traceable lacrimal canaliculus plug, comprising the following steps: Raw material pretreatment: Take raw material poly(p-dioxanone) (PPDO), hydrophilic substances, inorganic particles and colorant, vacuum dry, mix evenly to obtain premix; Injection molding: The premixed material is added to the screw injection molding machine for temperature-controlled injection molding. After the injection molding is completed, it is held at room temperature for 3-5 minutes, and then the mold is opened to obtain the lacrimal canaliculus plug precursor. The working conditions of the temperature-controlled injection molding include: the hopper preheating temperature is 60-80℃, the heating end temperature is 110-140℃, and the injection end temperature is 110-120℃. Post-processing: The lacrimal canaliculus plug precursor was soaked and dried to obtain a self-expanding traceable lacrimal canaliculus plug.

[0006] In one embodiment, the drying process includes at least three drying operations.

[0007] In one embodiment, the hydrophilic material includes at least one of polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG).

[0008] Poly(p-dioxanone) is a hydrophobic substance, while polyethylene glycol, polyvinylpyrrolidone, and inorganic particles are all hydrophilic substances. Poor interfacial compatibility is a common problem, and with the increase of the amount added, it is easier for agglomeration to occur, leading to structural collapse. At the same time, high-temperature molding of polymeric substances can lead to thermal decomposition, resulting in a decline in performance. This invention uses a low-temperature screw, which has excellent processing performance at a temperature far below the thermal decomposition temperature of the materials, and solves the compatibility problem between materials, avoiding product failure caused by morphological collapse.

[0009] To solve the injection molding challenge of micro-sized PPDO cylinders, this invention first preheats the hopper to 60-80°C: preventing premature melting and agglomeration of the raw material, ensuring uniform material feeding, and maintaining a low moisture content in the material system to improve injection molding performance; the heating end is 110-140°C (gradient heating): ensuring the PPDO just melts, preventing degradation of hydrophilic substances, and ensuring sufficient melt fluidity; the injection end is 110-120°C: slightly higher than the melting point of PPDO (110°C), maintaining optimal fluidity when the melt enters the mold, while rapidly cooling and solidifying; and a longer holding time at room temperature completely compensates for the shrinkage difference between the high-filler system and pure PPDO, thoroughly eliminating shrinkage cavities and bubbles.

[0010] In one embodiment, the polyethylene glycol has a molecular weight of 4,000 to 20,000.

[0011] In one embodiment, the inorganic particles include at least one of sodium chloride, potassium chloride, potassium sulfate, and sodium sulfate.

[0012] In one embodiment, the colorant includes at least one of D&C Violet 2, D&C Green 6, and [phthalocyanine (2-)]copper.

[0013] In one embodiment, the mass ratio of the poly(p-dioxanone): the hydrophilic substance: the inorganic particles: the colorant is (50~70): (5~20): (20~40): (0.01~1).

[0014] In one embodiment, the intrinsic viscosity of the polydioxanone is 2.0~2.5 dL / g.

[0015] In one embodiment, the inorganic particles have a particle size of 10~50μm.

[0016] In one embodiment, the soaking is performed by soaking in purified water for 20-30 minutes, and the drying temperature is 55-65°C.

[0017] In a second aspect, the present invention also provides a self-expanding traceable lacrimal canaliculus plug obtained by the above preparation method, wherein the self-expanding traceable lacrimal canaliculus plug is a cylinder with a diameter of 0.3 mm and a length of 1.8 to 2.2 mm.

[0018] A third aspect of the present invention also provides the use of the self-expanding tracerable lacrimal canaliculus plug obtained by the above preparation method or the above self-expanding tracerable lacrimal canaliculus plug in the preparation of a medical device for treating dry eye syndrome.

[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) Through the synergistic optimization of the formulation system, the present invention fits tightly with the lacrimal canaliculus after implantation, solving the core pain points of existing products that are easy to slip off and cannot balance expansion performance and structural stability.

[0020] (2) This preparation method gives the lacrimal canaliculus plug obvious visualization function, clear imaging, and can accurately monitor the implantation position and degradation process of the plug. There is no biosafety risk, which greatly reduces the difficulty of clinical operation and follow-up.

[0021] (3) The lacrimal canaliculus plug prepared by this method has an in vivo degradation cycle that matches the treatment needs of dry eye syndrome. It can be completely metabolized and excreted without the need for a second surgery to remove it. Detailed Implementation

[0022] This invention provides a self-expanding traceable lacrimal canaliculus occluder, which achieves high water-swelling performance, excellent mechanical stability and visual traceability through synergistic optimization of the formulation system, and meets the biocompatibility standards for medical implantation.

[0023] To facilitate understanding of the present invention, a more complete description will be given below with reference to relevant embodiments. Preferred embodiments of the invention are shown in the embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the disclosure of the present invention will be achieved.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] Unless otherwise specified, all reagents, materials, and equipment used in this embodiment are commercially available; unless otherwise specified, all test methods are conventional test methods in this field.

[0026] Example 1 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment is composed of the following raw materials by weight: 70 parts PPDO (intrinsic viscosity 2.2 dL / g), 10 parts PEG (molecular weight 10000), 20 parts sodium chloride (particle size 20~30 μm), and D&C Violet NO.2 colorant, which are dried and then uniformly mixed, with a colorant content of 0.03 parts.

[0027] In this embodiment, the mass ratio of poly(p-dioxanone): hydrophilic substance: inorganic particles: colorant is 70:10:20:0.03.

[0028] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0029] (3) Soak the sample prepared in step (2) in purified water at room temperature for 30 minutes, take it out and dry it at 60°C. Repeat the soaking-drying operation three times to obtain the self-expanding traceable lacrimal tubule plug.

[0030] Example 2 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment is composed of the following raw materials by weight: 60 parts of PPDO (intrinsic viscosity 2.2dL / g), 10 parts of PEG (molecular weight 10000), 30 parts of sodium chloride (particle size 20~30μm), and D&C Violet NO.2 colorant, which are dried and uniformly mixed, with a colorant content of 0.03 parts.

[0031] In this embodiment, the mass ratio of poly(p-dioxanone): hydrophilic substance: inorganic particles: colorant is 60:10:30:0.03.

[0032] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0033] (3) Soak the sample prepared in step (2) in purified water at room temperature for 30 minutes, take it out and dry it at 60°C. Repeat the soaking-drying operation three times to obtain the self-expanding traceable lacrimal tubule plug.

[0034] Example 3 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment is composed of the following raw materials by weight: 50 parts of PPDO (intrinsic viscosity 2.2dL / g), 10 parts of PEG (molecular weight 10000), 40 parts of sodium chloride (particle size 20~30μm), and D&C Violet NO.2 colorant, which are dried and then uniformly mixed, with a colorant content of 0.03 parts.

[0035] In this embodiment, the mass ratio of poly(p-dioxanone): hydrophilic substance: inorganic particles: colorant is 50:10:40:0.03.

[0036] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0037] (3) Soak the sample prepared in step (2) in purified water at room temperature for 30 minutes, take it out and dry it at 60°C. Repeat the soaking-drying operation three times to obtain the self-expanding traceable lacrimal tubule plug.

[0038] Example 4 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment, by weight, consists of the following raw material components: 60 parts PPDO (intrinsic viscosity 2.2 dL / g), 20 parts PEG (molecular weight 10000), 20 parts sodium chloride (particle size 20~30 μm), and D&C Violet NO.2 colorant, which are dried and then uniformly mixed, with a colorant content of 0.03 parts.

[0039] In this embodiment, the mass ratio of poly(p-dioxanone): hydrophilic substance: inorganic particles: colorant is 60:20:20:0.03.

[0040] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0041] (3) Soak the sample prepared in step (2) in purified water at room temperature for 30 minutes, take it out and dry it at 60°C. Repeat the soaking-drying operation three times to obtain the self-expanding traceable lacrimal tubule plug.

[0042] Comparative Example 1 (1) Poly(p-dioxanone) cyclohexanone (PPDO, intrinsic viscosity 2.2 dL / g) was placed in a micro screw injection molding machine and injected under controlled temperature. The hopper preheating temperature was 60℃, the heating end temperature was 115℃, and the injection end temperature was 113℃. After holding the mold at room temperature for 4 minutes, a lacrimal canaliculus plug was obtained. The size and structure were cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0043] Comparative Example 2 (1) 100 parts of poly(p-dioxane)cyclohexanone (PPDO) (intrinsic viscosity 2.2 dL / g) were dried and mixed evenly with D&C Violet NO.2 colorant, and the colorant content was 0.03 parts; (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 115°C, and the injection end temperature is 113°C. After being placed in the mold and kept under pressure at room temperature for 4 minutes, a traceable lacrimal tubule plug is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0044] Comparative Example 3 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment has the following raw material components by weight: 70 parts of PPDO (intrinsic viscosity 2.2dL / g), 30 parts of PEG (molecular weight 10000), and D&C Violet NO.2 colorant, which are dried and uniformly mixed, with a colorant content of 0.03 parts.

[0045] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0046] Comparative Example 4 (1) The self-expanding traceable lacrimal canaliculus plug of this embodiment is composed of the following raw materials by weight: 70 parts of PPDO (intrinsic viscosity 2.2 dL / g), 30 parts of sodium chloride (particle size 20~30 μm), and D&C Violet NO.22 colorant, which is dried and then uniformly mixed, with a colorant content of 0.03 parts.

[0047] (2) The mixed particles obtained in step (1) are placed in a micro screw injection molding machine for temperature-controlled injection molding. The hopper preheating temperature is 60°C, the heating end temperature is 125°C, and the injection end temperature is 115°C. After being placed in the mold and held under pressure at room temperature for 4 minutes, the lacrimal canaliculus plug precursor is obtained. The size and structure are cylinders with a diameter of 0.3 mm and a length of 2.0 mm.

[0048] (3) Soak the sample prepared in step (2) in purified water at room temperature for 30 minutes, take it out and dry it at 60°C. Repeat the soaking-drying operation three times to obtain the finished product of traceable lacrimal canaliculus plug.

[0049] Implementation effect evaluation The performance of the samples prepared in the examples and comparative examples was tested using the following methods: 1. Volume expansion rate test: The dry sample was immersed in physiological saline at 37℃, and the sample volume was measured at 30 min, 2 h, and 24 h. The volume expansion rate was calculated as follows: Volume expansion rate = (Volume after immersion - Dry volume) / Dry volume × 100%; 2. Morphological retention test: Observe the appearance of the sample after soaking for 24 hours under a 10x magnifying glass, and count the percentage of samples without cracks or disintegration, which is the morphological retention rate. 3. Tracer performance test: The tube was wiped and the sample was examined under a 10x magnifying glass to evaluate the clarity of the development; 4. Cytotoxicity test: The cytotoxicity of the samples was tested according to GB / T 16886.5-2017 standard; 5. In vitro degradation test: The dry sample was placed in PBS solution at 37°C and the mass was tested after 15 days, 30 days and 60 days. The degradation rate was calculated as follows: Degradation rate = (initial weight - test weight) / initial weight × 100%.

[0050] The test results are shown in Table 1.

[0051] Table 1

[0052] The test results show that the samples prepared in Examples 1-4 of this invention all exhibited a 24-hour volume expansion rate exceeding 100%, significantly higher than that of pure PPDO and PPDO / PEG, PPDO / NaCl samples in Comparative Examples 1-4. Furthermore, when only hydrophilic substances or inorganic particles are added to the system, the morphology is difficult to maintain due to interfacial incompatibility, resulting in a very low expansion rate. However, when hydrophilic substances and inorganic particles are added simultaneously and subjected to a soaking-drying cycle, the material system forms a self-expanding system with a framework support, hydrophilic water absorption, and a porous network working together, exhibiting excellent morphological stability; clear imaging, meeting clinical tracking requirements; good rapid expansion effect, preventing slippage and failure after implantation due to size mismatch; and grade 1 cytotoxicity, demonstrating excellent biocompatibility. In contrast, the pure PPDO sample in Comparative Example 1 showed almost no water-induced swelling and no tracking function, while the sample in Comparative Example 2 only showed tracking without expansion, failing to meet clinical application needs. The present invention allows for controllable adjustment of the degradation rates of different components, better meeting the needs of different patients in clinical practice, fully demonstrating the significant technological advancements of this invention.

[0053] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0054] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing a self-expanding traceable lacrimal canaliculus plug, characterized in that, Includes the following steps: Raw material pretreatment: Take raw material poly(p-dioxanone), hydrophilic substances, inorganic particles and colorant, vacuum dry, mix evenly to obtain premix; Injection molding: The premixed material is added to the screw injection molding machine for temperature-controlled injection molding. After the injection molding is completed, it is held at room temperature for 3-5 minutes, and then the mold is opened to obtain the lacrimal canaliculus plug precursor. The working conditions of the temperature-controlled injection molding include: the hopper preheating temperature is 60-80℃, the heating end temperature is 110-140℃, and the injection end temperature is 110-120℃. Post-processing: The lacrimal canaliculus plug precursor was soaked and dried to obtain a self-expanding traceable lacrimal canaliculus plug.

2. The preparation method according to claim 1, characterized in that, The hydrophilic substance includes at least one of polyvinylpyrrolidone and polyethylene glycol.

3. The preparation method according to claim 1, characterized in that, The inorganic particles include at least one of sodium chloride, potassium chloride, potassium sulfate, and sodium sulfate.

4. The preparation method according to claim 1, characterized in that, The colorant includes at least one of D&C Violet 2, D&C Green 6, and [phthalocyanine (2-)]copper.

5. The preparation method according to claim 1, characterized in that, According to the mass ratio, the poly(p-dioxanone): the hydrophilic substance: the inorganic particles: the colorant is (50~70): (5~20): (20~40): (0.01~1).

6. The preparation method according to claim 1, characterized in that, The intrinsic viscosity of the poly(p-dioxanone) is 2.0~2.5 dL / g.

7. The preparation method according to claim 1, characterized in that, In the raw material pretreatment, the moisture content after vacuum drying is ≤200ppm.

8. The preparation method according to claim 1, characterized in that, The inorganic particles have a particle size of 10~50μm.

9. The self-expanding traceable lacrimal canaliculus plug obtained by the preparation method according to any one of claims 1-8, characterized in that, The self-expanding traceable lacrimal canaliculus plug is a cylinder with a diameter of 0.3 mm and a length of 1.8~2.2 mm.

10. The use of the self-expanding tracerable lacrimal canaliculus plug obtained by the preparation method according to any one of claims 1-8 or the self-expanding tracerable lacrimal canaliculus plug according to claim 9 in the preparation of a medical device for treating dry eye syndrome.

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