Polydioxanone, preparation method and application thereof

Abstract

The present invention discloses a polydioxanone and its preparation method and application, in particular its application in medical materials (e.g., sutures). The polydioxanone has a specific molecular weight and molecular weight distribution, is highly stable, has a long shelf life, is advantageous for storage and use, and has good processing properties. The polymer fiber prepared using the polydioxanone is easily formed, has high breaking strength, and has good performance in use. The polydioxanone is suitable for preparing surgical sutures and for preparing medical dressings, anti-adhesion materials, orthopedic repair materials, tissue engineering scaffolds, and other medical materials by weaving the fibers. The polydioxanone can also be used to prepare products such as drug carriers, and has good application value. The preparation method of the polydioxanone provided by the present invention is simple to operate, has readily available raw materials, uses a small amount of catalyst, has low cost, is suitable for industrial production, and in particular can obtain polydioxanone with a more regular and narrower molecular weight distribution.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer synthesis, and in particular to polydioxanone and a preparation method and application thereof, in particular to application in medical materials (such as sutures). Background Art

[0002] Polydioxanone (PPDO) is an aliphatic polyester material with excellent biocompatibility, bioabsorbability and biodegradability. Due to the unique ether bond in its molecular chain, its molecular chain is very flexible. The polymer has excellent flexibility, tensile strength, knotting strength and strength retention during degradation. It can be used to prepare surgical sutures, cosmetic lifting threads, orthopedic repair materials (such as screws, fixation bolts, pins, anchors, etc.), hemostatic forceps, tissue engineering scaffolds (such as vascular stents, bile duct stents, tracheal stents, cardiac stents, intestinal stents, etc.), drug carriers, medical adhesives, etc., and has a wide range of applications in biomedical fields such as surgery, tissue engineering, orthopedic repair, plastic surgery, and drug preparation. Summary of the Invention

[0003] The present invention provides polydioxanone and a preparation method and application thereof, in particular application in medical materials (such as sutures).

[0004] In a first aspect of the present invention, a polydioxanone is provided having a molecular weight (particularly a weight-average molecular weight) of 100,000 to 250,000 Da (e.g., 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000, 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000, 240,000, 250,000 Da) and a molecular weight distribution Mw / Mn of 1.01-1.8.

[0005] Specifically, the molecular weight of the polydioxanone can be, for example, 100,000-110,000, 110,000-120,000, 120,000-130,000, 130,000-140,000, 140,000-150,000, 150,000-160,000, 160,000-170,000, 170,000-180,000, 180,000-190,000, 190,000-200,000, 200,000-210,000, 210,000-220,000, 220,000-230,000, 230,000-240,000, or 240,000-250,000 Da.

[0006] Specifically, the molecular weight distribution Mw / Mn of the polydioxanone can be, for example, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.65, 1.70, 1.75, 1.80, especially 1.01-1.4.

[0007] Specifically, the viscosity of the polydioxanone is 0.7-2.5 dL / g (e.g., 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5) (as measured by Ubbelohde viscometry).

[0008] Specifically, the polydioxanone has high stability, and its viscosity, molecular weight, and molecular weight distribution do not change significantly over time. For example, under frozen conditions (e.g., storage below -15°C), within 24 months, the change rate of viscosity, molecular weight, and molecular weight distribution index does not exceed 10.0%; for example, under frozen conditions (e.g., storage below -15°C), within 24 months, the residual monomer mass content in the polydioxanone product does not exceed 1.0%.

[0009] In a second aspect of the present invention, a polymer fiber is provided, which is prepared from a polymer comprising the polydioxanone according to the second aspect.

[0010] Specifically, the polymer fiber is prepared from the polymer comprising the polydioxanone described in the first aspect by a melt spinning method.

[0011] Specifically, the polymer fiber is a monofilament fiber.

[0012] Specifically, the polymer fiber can have a diameter of 0.001-1.500 mm (e.g., 0.001, 0.005, 0.010, 0.020, 0.030, 0.040, 0.050, 0.070, 0.100, 0.150, 0.200, 0.250, 0.350, 0.400, 0.500, 0.600, 0.700, 0.800, 0.900, 1.000, 1.100, 1.200, 1.300, 1.400, 1.500 mm), in particular 0.045-0.700 mm.

[0013] In one embodiment of the present invention, the polymer is composed of the polydioxanone described in the first aspect of the present invention, that is, the polymer fiber is polydioxanone fiber.

[0014] In another embodiment of the present invention, the polymer may also include a polymer composed of polydioxanone and other components other than polydioxanone, such as polylactic acid, polyglycolic acid, polyhydroxyalkanoate, polycaprolactone, polyamide, etc.

[0015] In a third aspect of the present invention, a medical material is provided, which comprises a portion made of the polydioxanone described in the first aspect, or is made of the polydioxanone described in the first aspect.

[0016] In particular, the medical material comprises a portion made of the polymer fiber according to the second aspect, or is made of the polymer fiber according to the second aspect.

[0017] Specifically, the medical materials can be sutures, medical dressings, anti-adhesion materials, orthopedic repair materials (such as screws, fixing bolts, pins, anchors, hoops, bone plates and other orthopedic fixation transpositions), hemostatic forceps, tissue engineering scaffolds (such as vascular stents, bile duct stents, tracheal stents, cardiac stents, intestinal stents, fallopian tube stents, uterine cavity stents, ureteral stents, etc., as well as cell and tissue culture scaffolds), etc.

[0018] In one embodiment of the present invention, the medical material is a suture, which can be used to suture tissues to promote wound healing, ligate blood vessels or tissue stumps, stop bleeding, and be implanted in the face to achieve cosmetic purposes such as lifting and firming, eliminating wrinkles, etc.

[0019] Specifically, according to the structure, the suture thread can be a monofilament or a multifilament (in the form of twisted wire, braided wire, etc.), especially a monofilament suture thread.

[0020] Specifically, according to the shape, the suture line can be a smooth line, a spiral line, a serrated line (such as a unidirectional serrated line, a bidirectional serrated line, a cross serrated line, etc.), a bell line, a fishbone line, etc., especially a smooth line.

[0021] Specifically, the diameter of the suture can be 0.001-1.000 mm (e.g., 0.001, 0.005, 0.010, 0.020, 0.030, 0.040, 0.050, 0.100, 0.200, 0.300, 0.400, 0.500, 0.600, 0.700, 0.800, 0.900, 1.000 mm); more specifically, in one embodiment of the present invention, the suture is a monofilament suture with a diameter of 0.045-0.700 mm (e.g., 0.045, 0.050, 0.070, 0.10 In another embodiment of the present invention, the suture is a multifilament suture with a diameter of 0.001-0.850 mm (e.g., 0.001, 0.005, 0.010, 0.020, 0.030, 0.040, 0.050, 0.070, 0.100, 0.150, 0.200, 0.250, 0.350, 0.400, 0.500, 0.600, 0.700, 0.850 mm).

[0022] Specifically, the breaking strength of the suture thread can be 0.10-100N (e.g., 0.10, 1.0, 2.0, 5.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100N).

[0023] In another embodiment of the present invention, the medical material is a medical dressing, an anti-adhesion material, an orthopedic repair material (such as screws, fixing bolts, pins, anchors, hoops, bone plates and other orthopedic fixation transpositions), a hemostatic forceps, a tissue engineering scaffold (such as a vascular stent, a bile duct stent, a tracheal stent, a cardiac stent, an intestinal stent, a fallopian tube stent, a uterine cavity stent, a ureteral stent, etc., as well as a cell and tissue culture scaffold), which includes a part woven from the polymer fiber described in the third aspect or is woven from the polymer fiber described in the third aspect.

[0024] In the fourth part of the present invention, a drug carrier is provided, which includes a portion made of polydioxanone as described in the first aspect, or is made of polydioxanone as described in the first aspect. The drug carrier can be used to load one or more active pharmaceutical ingredients, such as proteins, polypeptide drugs, nucleic acid drugs, small molecule drugs, etc., to achieve the purpose of sustained release.

[0025] Specifically, the drug carrier can be in any suitable form such as micelles, vesicles, nanoparticles, etc.

[0026] In a fifth aspect of the present invention, a method for preparing the polydioxanone according to the first aspect is provided, comprising the following steps:

[0027] (1) mixing p-dioxanone, a stabilizer and a catalyst to activate the mixture;

[0028] (2) subjecting the system obtained in step (1) to polymerization reaction under vacuum or protective gas;

[0029] or,

[0030] (1) mixing p-dioxanone and a stabilizer and activating the mixture;

[0031] (2) adding a catalyst to the mixed solution obtained in step (1) and performing a polymerization reaction under vacuum or protective gas;

[0032] Optionally, (3) purifying the system obtained in step (2).

[0033] Specifically, the stabilizer is a substance that can make the monomer's activity towards dioxanone uniform and stable. It makes the monomer uniform and stable through dispersion. The stabilizer is selected from one or more of a monohydric alcohol and an organic acid.

[0034] Specifically, the monohydric alcohol has 1 to 30 carbon atoms (especially 4 to 25 carbon atoms); more specifically, the monohydric alcohol is selected from the group consisting of: tetracosanol, octadecanol, cetyl alcohol, tetradecanol, dodecanol and n-butanol.

[0035] Specifically, the organic acid has 1 to 10 carbon atoms, and is preferably selected from: oxalic acid, succinic acid.

[0036] Specifically, the catalyst is a metal compound catalyst, for example, an organotin catalyst, an organoaluminum catalyst, or a titanium catalyst.

[0037] Specifically, the organotin catalyst can be selected from: stannous oxalate, stannous octoate, dioctyltin dilaurate, dibutyltin oxide, tetrabutyltin; especially stannous oxalate and stannous octoate.

[0038] Specifically, the organoaluminum catalyst can be selected from: triethylaluminum, aluminum iodide, nano-aluminum oxide, sodium aluminate; especially triethylaluminum and aluminum iodide.

[0039] Specifically, the titanium catalyst can be selected from: titanium dichloride, titanium dioxide, titanate; especially titanium dichloride.

[0040] Specifically, the molar ratio of p-dioxanone to the stabilizer in step (1) is 200-4000:1 (e.g., 200:1, 500:1, 1000:1, 1500:1, 2000:1, 2500:1, 3000:1, 3500:1, 4000:1), especially 200-3000:1.

[0041] Specifically, the molar ratio of dioxanone to the catalyst is 1000-200000:1 (e.g., 1000:1, 2000:1, 5000:1, 10000:1, 20000:1, 30000:1, 40000:1, 50000:1, 60000:1, 70000:1, 80000:1, 90000:1, 100000:1, 120000:1, 140000:1, 160000:1, 180000:1, 200000:1), in particular, 10000-100000:1.

[0042] In the present invention, the activation step can activate the stabilizer, making the monomer activity uniform and stable, which is beneficial to improving the stability of the polymer. Viscosity measurement of the activated product shows that no polymerization reaction occurs in this step.

[0043] Specifically, step (1) further includes a homogenization step to make the dioxanone, stabilizer (and catalyst, if any) dispersed better and more uniformly, which is conducive to obtaining a highly stable polymer.

[0044] Specifically, the homogenization treatment method can be selected from: one or more combinations of shaking, ultrasound, stirring, especially shaking.

[0045] Specifically, the homogenization time is 5-60 minutes (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes).

[0046] Specifically, the activation temperature in step (1) is 60-150°C (e.g., 60, 80, 100, 110, 120, 130, 140, 150, 160°C), especially 80-150°C.

[0047] Specifically, the activation time in step (1) is less than 30 minutes (e.g., 5, 10, 15, 20, 25 minutes).

[0048] Specifically, the vacuum degree of the vacuum in step (2) is -0.08 to -0.1 MPa.

[0049] Specifically, the protective gas in step (2) can be selected from: nitrogen, argon, helium, etc. or a combination of one or more.

[0050] Specifically, the pressure of the protective gas is 1-20 MPa (eg, 1, 5, 10, 15, 20 MPa), particularly 5-15 MPa.

[0051] Specifically, the polymerization reaction temperature in step (2) is 50-150°C (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150°C), especially 75-150°C.

[0052] Specifically, the polymerization reaction time in step (2) is 24-360 hours (e.g., 24, 48, 60, 72, 84, 96, 120, 144, 168, 192, 216, 240, 280, 320, 360 hours), especially 70-240 hours.

[0053] In a sixth aspect of the present invention, there is provided use of the polydioxanone described in the first aspect in the preparation of polymer fibers, medical materials, and drug carriers.

[0054] Specifically, the polymer fiber, medical material, and drug carrier have the definitions described in the second aspect, third aspect, and fourth aspect of the present invention, respectively.

[0055] In a seventh aspect, the present invention provides use of the polydioxanone described in the first aspect in preparing a drug.

[0056] Specifically, the drug includes one or more active pharmaceutical ingredients loaded in a drug carrier, such as proteins, polypeptide drugs, nucleic acid drugs, small molecule drugs, etc. The drug carrier has the definition described in the fourth aspect of the present invention.

[0057] Molecular weight and molecular weight distribution significantly influence the key properties of PPDO, such as biodegradability, mechanical properties, and crystallization. A narrower molecular weight distribution improves material uniformity, while a narrower melting range leads to higher crystallinity, which in turn benefits the stability and uniformity of processed products. Molecular weights below 100,000 result in poor stability. Molecular weights exceeding 250,000 are too high, leading to excessive melt viscosity and a rubbery appearance. This makes post-polymerization extrusion difficult or requires stringent extrusion conditions, making it unsuitable for industrial production. Furthermore, the extruded material exhibits poor uniformity and processability, hindering subsequent processing operations.

[0058] The polydioxanone provided by the present invention has a specific molecular weight and molecular weight distribution, high stability, a long shelf life, and is convenient for storage and use. It also has good processability. The polymer fibers prepared using it are easy to form, have high breaking strength, and good performance. They are suitable for preparing surgical sutures and for weaving their fibers into medical dressings, anti-adhesion materials, orthopedic repair materials, tissue engineering scaffolds, and other medical materials. They can also be used to prepare products such as drug carriers, and have excellent application value. The preparation method of polydioxanone provided by the present invention is simple to operate, has readily available raw materials, requires a small amount of catalyst, and is low in cost, making it suitable for industrial production. In particular, it can produce polydioxanone with a more regular and narrower molecular weight distribution. DETAILED DESCRIPTION

[0059] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0060] The "polydioxanone" (PPDO) described in the present invention has the following structure:

[0061]

[0062] Here, n represents the degree of polymerization.

[0063] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0064] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0065] Some of the evaluation methods used in the experiments of the embodiment are as follows:

[0066] 1. The PPDO molecular weight and molecular weight distribution detection instruments and methods used in the following examples are as follows:

[0067] The molecular weight and distribution of the prepared PPDO were characterized using a Malvern gel permeation chromatograph (differential refractive index detector, light scattering detector, OminSEC workstation). The chromatographic conditions were as follows:

[0068] I-GUARD-0478 Polar organic guard column, I-MBHMW-3078 Polar organic column, I-MBLMW-3078 Polar organic column; mobile phase: chloroform; flow rate: 0.7 ml / min; column temperature: 35°C.

[0069] PMMA standards purchased from Malvern were used. PMMA 50K and PMMA 95K standards were accurately weighed into 5.0 ml of chloroform, shaken on a shaker for 30 minutes to fully dissolve and set aside. The method was established using PMMA 50K standards to make the RI factor between 10 7 , RALS and LALS in 10 -8 -10 -7 The weight average molecular weight Mw of the PMMA 95K standard is measured using this method. If the measured value is less than 5% of the labeled Mw, it meets the requirements. The absolute molecular weight Mw and molecular weight distribution Mw / Mn of the test sample can be obtained using this method.

[0070] Accurately weigh 25 mg of the PPDO to be tested and place it in a sample vial. Accurately add 5.0 ml of a phenol-tetrachloroethane (V:V = 1:1) solution. Stir at room temperature for 10 minutes, then in an 80°C water bath for 30 minutes. Remove the vial and allow it to cool to room temperature. Filter through a 0.22 μm PTFE filter. The filtrate is used as the test solution. Accurately measure 100 μL of the standard and test solutions, respectively, and measure them by size exclusion chromatography (Chinese Pharmacopoeia 0514 Molecular Exclusion Chromatography). Record the chromatogram. Integrate the chromatographic peaks to determine the molecular weight (Mw) and molecular weight distribution (Mw / Mn) of the PPDO.

[0071] 2. The stability evaluation method of polydioxanone is as follows:

[0072] Polydioxanone was stored in a nitrogen-filled aluminum foil freezer below -15°C. The PPDO polymer was subjected to a 24-month real-time aging test at a temperature below -15°C, with samples collected at two time points for testing: 0 month and 24 months.

[0073] Testing items include viscosity, monomer, molecular weight and molecular weight distribution.

[0074] Viscosity test: The second method of Ubbelohde capillary viscometer in the fourth part 0633 viscosity determination method of the Chinese Pharmacopoeia 2020 edition was used for testing. The solvent was tetrachloroethane and the measurement temperature was 25℃±0.1℃.

[0075] Monomer detection: The determination was carried out using the gas chromatography method 0521 of Part 4 of the Chinese Pharmacopoeia 2020 edition, and the dissolving solvent was hexafluoroisopropanol.

[0076] 3. The PPDO suture performance evaluation method used in the following examples is as follows:

[0077] The PPDO materials were placed into the feed port of the spinning machine respectively, and the temperature of the heating section was set so that the material was completely melted in the melting cavity and then extruded into filaments. After stretching, absorbable surgical sutures made of PPDO were obtained with specifications of 2, 0, 4-0, and 7-0. The suturing performance of the sutures was investigated, among which the breaking strength is the most important performance indicator of the suture. Therefore, the breaking strength test was mainly carried out here. The test method was carried out in accordance with YY 1116-2020 "Absorbable Surgical Sutures". The breaking strength standards of different thread sizes are shown in Table 1.

[0078] Table 1 Standard breaking strength values ​​of sutures of different specifications

[0079]

[0080] Example 1

[0081] PPDO materials with molecular weights of approximately 100,000 but different molecular weight distributions were prepared respectively, and the preparation methods were as follows:

[0082] (1) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of n-butanol and stannous octoate. The mixture was mixed and shaken in a shaker for 30 minutes and activated at 70°C for 10 minutes. The molar ratio of p-dioxanone to stannous octoate was 1000:1, and the molar ratio of p-dioxanone to n-butanol was 200:1. The pressure in the polymerization kettle was maintained at 10 MPa by helium replacement four times. The reactor was heated to 60°C and polymerization was continued for 24 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization kettle.

[0083] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 109854 Da, and the molecular weight distribution (Mw / Mn) was 1.023.

[0084] (2) 400 ml of p-dioxanone (PDO) was added to a polymerization vessel, followed by the addition of n-butanol and stannous octoate. The mixture was mixed and shaken in a shaker for 30 minutes and activated at 60°C for 5 minutes. The molar ratio of p-dioxanone to stannous octoate was 1000:1, and the molar ratio of p-dioxanone to n-butanol was 300:1. The pressure in the polymerization vessel was maintained at 10 MPa by helium replacement four times. The reactor was heated to 50°C and polymerization was continued for 24 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization vessel.

[0085] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 108924 Da, and the molecular weight distribution (Mw / Mn) was 1.701.

[0086] (3) 400 ml of p-dioxanone (PDO) was added to a polymerization vessel, followed by the addition of n-butanol and stannous octoate. The mixture was mixed and shaken in a shaker for 30 minutes and activated at 60°C for 10 minutes. The molar ratio of p-dioxanone to stannous octoate was 500:1, and the molar ratio of p-dioxanone to n-butanol was 500:1. The pressure in the polymerization vessel was maintained at 10 MPa by helium replacement four times. The reactor was heated to 60°C and polymerization was continued for 24 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization vessel.

[0087] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 105679 Da, and the molecular weight distribution (Mw / Mn) was 2.278.

[0088] The stability of the above PPDO materials (real-time aging) was investigated, and the results are summarized in Table 2.

[0089] The performance (breaking strength) of the sutures made of the above-mentioned PPDO materials was investigated, and the results are summarized in Table 3.

[0090] Table 2 Stability test results of PPDO with different molecular weight distributions of about 100,000

[0091]

[0092] Table 3 Breaking strength test results of sutures made of PPDO with a molecular weight of about 100,000 but different molecular weight distributions

[0093]

[0094] Example 2

[0095] PPDO materials with a molecular weight of about 180,000 but different molecular weight distributions were prepared respectively.

[0096] (1) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of octadecyl alcohol and triethylaluminum. The mixture was mixed and shaken in a shaker for 10 minutes and activated at 120°C for 15 minutes. The molar ratio of p-dioxanone to triethylaluminum was 100,000:1, and the molar ratio of p-dioxanone to octadecyl alcohol was 2,000:1. The pressure in the polymerization kettle was maintained at 5 MPa by nitrogen displacement four times. The reactor was heated to 90°C and polymerization was continued for 240 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization kettle.

[0097] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 189562 Da, and the molecular weight distribution (Mw / Mn) was 1.039.

[0098] (2) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of n-butanol and stannous octoate. The mixture was mixed and shaken in a shaker for 10 minutes and activated at 140°C for 20 minutes. The molar ratio of p-dioxanone to stannous octoate was 100,000:1, and the molar ratio of p-dioxanone to n-butanol was 2,900:1. The pressure in the polymerization kettle was maintained at 5 MPa by nitrogen displacement four times. The reactor was heated to 100°C and polymerization was continued for 180 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization kettle.

[0099] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 185469 Da, and the molecular weight distribution (Mw / Mn) was 1.741.

[0100] (3) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of n-butanol and stannous oxalate. The mixture was mixed and shaken in a shaker for 10 minutes and activated at 140°C for 20 minutes. The molar ratio of p-dioxanone to stannous oxalate was 5000:1, and the molar ratio of p-dioxanone to n-butanol was 5000:1. The pressure in the polymerization kettle was maintained at 5 MPa by nitrogen displacement four times. The reactor was heated to 110°C and polymerization was continued for 180 hours. After completion of the polymerization, the resulting PPDO polymer was discharged from the polymerization kettle.

[0101] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 183694 Da, and the molecular weight distribution (Mw / Mn) was 2.369.

[0102] The stability (real-time aging) of the above PPDO materials was investigated, and the results are summarized in Table 4.

[0103] The performance (breaking strength) of the sutures made of the above-mentioned PPDO materials was investigated, and the results are summarized in Table 5.

[0104] Table 4 Stability test results of PPDO with different molecular weight distributions of about 180,000

[0105]

[0106]

[0107] Table 5 Breaking strength test results of sutures made of PPDO with a molecular weight of about 180,000 and different molecular weight distributions

[0108]

[0109] Example 3

[0110] PPDO materials with a molecular weight of about 250,000 but different molecular weight distributions were prepared respectively.

[0111] (1) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of tetradecanol and stannous oxalate. The mixture was mixed and shaken in a shaker for 5 minutes and activated at 150°C for 25 minutes. The molar ratio of p-dioxanone to stannous oxalate was 200,000:1, and the molar ratio of p-dioxanone to tetradecanol was 2900:1. The vacuum in the polymerization kettle was maintained at -0.08 MPa by nitrogen displacement three times. The reactor was heated to 100°C and polymerization was continued for 240 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization kettle.

[0112] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 244894 Da, and the molecular weight distribution (Mw / Mn) was 1.188.

[0113] (2) 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by the addition of n-butanol and stannous oxalate. The mixture was mixed and shaken in a shaker for 5 minutes and activated at 140°C for 25 minutes. The molar ratio of p-dioxanone to stannous oxalate was 200,000:1, and the molar ratio of p-dioxanone to n-butanol was 4,000:1. The vacuum in the polymerization kettle was maintained at -0.08 MPa by nitrogen displacement three times. The reactor was then heated to 100°C and polymerization was continued for 300 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization kettle.

[0114] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 245978 Da, and the molecular weight distribution (Mw / Mn) was 1.711.

[0115] (3) 400 ml of p-dioxanone (PDO) was added to a polymerization vessel, followed by the addition of glycerol and stannous oxalate. The mixture was mixed and shaken in a shaker for 5 minutes and activated at 150°C for 25 minutes. The molar ratio of p-dioxanone to stannous oxalate was 200,000:1, and the molar ratio of p-dioxanone to tetradecanol was 10,000:1. The vacuum in the polymerization vessel was maintained at -0.08 MPa by nitrogen displacement three times. The reactor was heated to 100°C and polymerization was continued for 240 hours. After completion of the polymerization, the resulting polymer, PPDO, was discharged from the polymerization vessel.

[0116] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 245698 Da, and the molecular weight distribution (Mw / Mn) was 2.252.

[0117] The stability (real-time aging) of the above PPDO materials was investigated, and the results are summarized in Table 6.

[0118] The performance (breaking strength) of the sutures made of the above-mentioned PPDO materials was investigated, and the results are summarized in Table 7.

[0119] Table 6 Stability test results of PPDO with different molecular weight distributions of about 250,000

[0120]

[0121]

[0122] Table 7 Breaking strength test results of sutures made of PPDO with a molecular weight of about 250,000 and different molecular weight distributions

[0123]

[0124] As mentioned above, for the detection of monomer percentage content, since there is no relevant literature reporting its content limit requirements, 1.0% is used as its limit index in the embodiments of the present invention (this index is derived from the requirements set by Samyang Company of South Korea for the monomer content in its PPDO material absorbable surgical sutures).

[0125] For viscosity, molecular weight and molecular weight distribution, if the change rate does not exceed 10.0%, it is considered that there is no significant change.

[0126] The results of Examples 1 to 3 show that the real-time aging trends of PPDO show a decrease in viscosity, an increase in monomer content, a decrease in molecular weight, and a broadening of the molecular weight distribution with increasing aging time. Within the molecular weight range of 100,000 to 250,000, PPDO with similar molecular weights exhibited different rates of change in real-time aging. For PPDO with a molecular weight distribution of 1.0 to 1.8, the changes in various indicators remained within acceptable ranges with increasing aging time. For molecular weight distributions greater than 1.8, the changes in various PPDO indicators were significant, exceeding acceptable ranges. This indicates that molecular weight distribution significantly influences PPDO stability, with PPDO with a molecular weight distribution of 1.0 to 1.8 exhibiting excellent 24-month stability.

[0127] PPDO with molecular weights between 100,000 and 250,000, similar in molecular weight but different in molecular weight distribution, was made into sutures. It was found that as the molecular weight distribution widened, its breaking strength continued to decrease, but all met the standard requirements.

[0128] Example 4

[0129] First, 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by n-butanol at a molar ratio of 2500:1. Ultrasonication was performed for 10 minutes, followed by activation at 140°C for 20 minutes. Triethylaluminum was then added to the reaction mixture at a molar ratio of 100,000:1. The reactor was then purged with nitrogen four times to maintain a pressure of 5 MPa. The reactor was then heated to 90°C and polymerization continued for 180 hours. Upon completion of the polymerization, the resulting PPDO polymer was discharged from the reactor.

[0130] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 183698 Da, and the molecular weight distribution (Mw / Mn) was 1.326.

[0131] The stability (real-time aging) of the obtained PPDO and the performance (breaking strength) of the sutures made thereof were investigated. The results are summarized in Table 8.

[0132] Table 8 Results of PPDO stability and suture performance

[0133]

[0134] Example 5

[0135] First, 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by tetracosanol at a molar ratio of 1000:1. The mixture was shaken in a shaker for 60 minutes and activated at 110°C for 15 minutes. Aluminum iodide was added to the reaction mixture at a molar ratio of 20,000:1. The vacuum in the polymerization kettle was maintained at -0.1 MPa by purging with argon four times. The reactor was heated to 75°C and polymerization was continued for 96 hours. After completion of the polymerization, the resulting PPDO polymer was discharged from the reactor.

[0136] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 165890 Da, and the molecular weight distribution (Mw / Mn) was 1.506.

[0137] The stability (real-time aging) of the obtained PPDO and the performance (breaking strength) of the sutures made thereof were investigated. The results are summarized in Table 9.

[0138] Table 9 Results of the stability and suture performance of PPDO

[0139]

[0140] Example 6

[0141] First, 400 ml of p-dioxanone (PDO) was added to a polymerization kettle, followed by hexadecanol at a molar ratio of 500:1. The mixture was stirred for 25 minutes and activated at 80°C for 10 minutes. Titanium dichloride was added to the reaction mixture at a molar ratio of 10,000:1. The reactor was then purged with nitrogen four times to maintain a pressure of 15 MPa. The reactor was then heated to 150°C and polymerization continued for 360 hours. After completion of the polymerization, the resulting PPDO polymer was discharged from the reactor.

[0142] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 139874 Da, and the molecular weight distribution (Mw / Mn) was 1.056.

[0143] The stability (real-time aging) of the obtained PPDO and the performance (breaking strength) of the sutures made thereof were investigated. The results are summarized in Table 10.

[0144] Table 10 Results of PPDO stability and suture performance

[0145]

[0146] The results of Examples 4 to 6 demonstrate that the real-time aging trends of PPDO show a decreasing viscosity, increasing monomer content, decreasing molecular weight, and a broadening of the molecular weight distribution with increasing aging time. PPDO with a molecular weight between 100,000 and 250,000 and a molecular weight distribution of 1.0 to 1.8 exhibited varying rates of real-time aging. With increasing aging time, the changes in various indicators remained within acceptable ranges, demonstrating good 24-month stability.

[0147] PPDO with a molecular weight between 100,000 and 250,000 and a molecular weight distribution of 1.0 to 1.8 is made into sutures, and its breaking strength meets the standard requirements.

[0148] Comparative Example 1

[0149] Compared with Example 3(1), this reaction does not have an activation step. The other conditions remain unchanged. The dioxanone (PDO) monomer is mixed with the stabilizer tetradecanol and the catalyst stannous oxalate for polymerization.

[0150] The molecular weight and molecular weight distribution of the obtained PPDO were characterized, and the weight average molecular weight (Mw) was measured to be 56894 Da, and the molecular weight distribution (Mw / Mn) was 3.025.

[0151] In this comparative example, it can be found from the molecular weight and distribution results of the obtained PPDO that, compared with the molecular weight and distribution of PPDO in Example 3(1), the molecular weight of PPDO in this comparative example is much lower than that of Example 3(1), and its molecular weight distribution is also much wider.

[0152] Comparative Example 2

[0153] Compared with Example 3(1), the molar ratio of 4-dioxanone to tetradecanol was replaced with 100:1, and other conditions remained unchanged.

[0154] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 80289 Da, and the molecular weight distribution (Mw / Mn) was 1.210.

[0155] The stability (real-time aging) of the above PPDO materials was investigated, and the results are summarized in Table 11.

[0156] The performance (breaking strength) of the sutures made of the above-mentioned PPDO materials was investigated, and the results are summarized in Table 12.

[0157] Table 11 PPDO stability test results

[0158]

[0159]

[0160] Table 12 Results of the breaking strength test of sutures made of PPDO

[0161]

[0162] From the molecular weight and distribution results of the obtained PPDO, it can be found that at the ratio of dioxanone to tetradecanol in this comparative example, compared with the molecular weight and distribution of PPDO in Example 3(1), although the molecular weight distribution of PPDO in this comparative example is controlled within a narrower range, the molecular weight of PPDO is much lower than that of Example 3(1).

[0163] Comparative Example 3

[0164] 400 ml of p-dioxanone (PDO) was added to a polymerization vessel, followed by the addition of octadecyl alcohol and triethylaluminum. The mixture was ultrasonically treated for 10 minutes and activated at 140°C for 20 minutes. The molar ratio of p-dioxanone to triethylaluminum was 20,000:1, and the molar ratio of p-dioxanone to octadecyl alcohol was 5,000:1. The reactor was then flushed with nitrogen four times to maintain a pressure of 5 MPa. The reactor was heated to 90°C and polymerization continued for 240 hours. After completion of the polymerization, the resulting PPDO polymer was discharged from the reactor.

[0165] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 298416 Da, and the molecular weight distribution (Mw / Mn) was 1.269.

[0166] The stability (real-time aging) of the above PPDO materials was investigated, and the results are summarized in Table 13.

[0167] When the above-mentioned PPDO material is made into suture thread, the spinning operation cannot be smoothly carried out due to its high viscosity.

[0168] Table 13 PPDO stability test results

[0169]

[0170]

[0171] As mentioned above, for the detection of monomer percentage content, since there is no relevant literature reporting its content limit requirements, 1.0% is used as its limit index in the embodiments of the present invention (this index is derived from the requirements set by Samyang Company of South Korea for the monomer content in its PPDO material absorbable surgical sutures).

[0172] For viscosity, molecular weight and molecular weight distribution, if the change rate does not exceed 10.0%, it is considered that there is no significant change.

[0173] The results in Comparative Example 2 show that when the PPDO molecular weight is less than 100,000 and the molecular weight distribution is between 1.0 and 1.8, the various indicators vary significantly, exceeding acceptable ranges. The PPDO material exhibits poor stability. When manufactured into sutures, the breaking strength was found to be low, failing to meet standard requirements.

[0174] The results in Comparative Example 3 show that when the PPDO molecular weight is greater than 250,000 and the molecular weight distribution is between 1.0 and 1.8, the changes in various indicators are within acceptable ranges. While the PPDO material exhibits good stability, its high molecular weight results in excessive melt viscosity, resulting in a rubbery state. This makes polymer extrusion difficult, and the extruded material exhibits poor uniformity and processability. Consequently, spinning of the PPDO into sutures is unsuccessful.

[0175] If the molecular weight distribution is too broad (for example, exceeding 1.8), the PPDO material will experience a significant degradation rate, adversely affecting its stability. If the molecular weight is too low, the PPDO material will have poor mechanical strength and toughness. Even if it meets spinning requirements, it will not produce yarn properties that meet the application requirements. If the molecular weight is too high, the PPDO material's melt viscosity increases, making processing and molding difficult, and even preventing successful spinning.

[0176] Comparative Example 4

[0177] 400 ml of p-dioxanone (PDO) was added to a polymerization reactor, followed by polyethylene glycol (PEG400) and stannous oxalate. The mixture was shaken in a shaker for 5 minutes and activated at 150°C for 25 minutes. The molar ratio of p-dioxanone to stannous oxalate was 200,000:1, and the molar ratio of p-dioxanone to PEG400 was 6,000:1. The reactor was then flushed with nitrogen three times to maintain a vacuum of -0.08 MPa. The reactor was heated to 100°C and polymerization continued for 240 hours. After completion of the polymerization, the resulting PPDO polymer was discharged from the reactor.

[0178] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 228416 Da, and the molecular weight distribution (Mw / Mn) was 2.342.

[0179] This comparative example uses PEG400, a diol, as a stabilizer. The molecular weight and distribution of the resulting PPDO indicate that, compared to the molecular weight and distribution of PPDO in Example 3(1), although the molecular weight of the PPDO in this comparative example is higher, its molecular weight distribution is not controlled within a narrow range.

[0180] Comparative Example 5

[0181] Compared with Example 3(1), the activation time was adjusted to 30 min, and other conditions remained unchanged.

[0182] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 280259 Da, and the molecular weight distribution (Mw / Mn) was 2.059.

[0183] Comparative Example 6

[0184] Compared with Example 3(1), the activation time was adjusted to 4 h, and other conditions remained unchanged.

[0185] The molecular weight and molecular weight distribution of the obtained PPDO were characterized. The weight average molecular weight (Mw) was measured to be 318534 Da, and the molecular weight distribution (Mw / Mn) was 2.339.

[0186] The reaction time of Comparative Examples 5 and 6 was longer. From the molecular weight and molecular weight distribution of the obtained PPDO, it can be found that the molecular weight of the PPDO obtained in Comparative Examples 5 and 6 was higher than that of the PPDO in Example 3 (1), both exceeding 250,000, and the molecular weight distribution was not controlled within a narrow range.

[0187] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0188] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience, and preference of those skilled in the art.

[0189] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A polydioxanone having a molecular weight of 160,000 to 250,000 Da and a molecular weight distribution Mw / Mn of 1.02 to 1.

4.

2. The polydioxanone according to claim 1, wherein The molecular weight of the polydioxanone is 160,000-170,000 Da, 170,000-180,000 Da, 180,000-190,000 Da, 190,000-200,000 Da, 200,000-210,000 Da, 210,000-220,000 Da, 220,000-230,000 Da, 230,000-240,000 Da or 240,000-250,000 Da.

3. The polydioxanone according to claim 1, wherein The molecular weight distribution Mw / Mn of the polydioxanone is 1.02-1.

2.

4. The polydioxanone according to claim 1, wherein The viscosity of the polydioxanone is 0.7-2.5 dL / g.

5. A polymer fiber made of a polymer, wherein the polymer comprises the polydioxanone according to any one of claims 1 to 4, or consists of the polydioxanone according to any one of claims 1 to 4.

6. A medical material comprising a portion made of the polydioxanone according to any one of claims 1 to 4, or made of the polydioxanone according to any one of claims 1 to 4.

7. The medical material according to claim 6, wherein The medical material is selected from the group consisting of: sutures, medical dressings, anti-adhesion materials, orthopedic repair materials, hemostatic forceps, and tissue engineering scaffolds.

8. The medical material according to claim 6, wherein The medical material is a suture thread, and the diameter of the suture thread is 0.001-1.000 mm.

9. The medical material according to claim 6, wherein The medical material is a suture thread, and the breaking strength of the suture thread is 0.10-100N.

10. The method for preparing polydioxanone according to any one of claims 1 to 4, comprising the following steps: (1) mixing p-dioxanone, a stabilizer and a catalyst to activate the mixture; (2) subjecting the system obtained in step (1) to polymerization reaction under vacuum or protective gas; or, (1) mixing p-dioxanone and a stabilizer and activating the mixture; (2) adding a catalyst to the mixed solution obtained in step (1) and performing a polymerization reaction under vacuum or protective gas; The stabilizer is selected from: one or more monohydric alcohols; The molar ratio of dioxanone to stabilizer is 200-4000:1; The activation time is less than 30 minutes.

11. The preparation method according to claim 10, characterized in that The monohydric alcohol has 1 to 30 carbon atoms.

12. The preparation method according to claim 11, characterized in that The monohydric alcohol is selected from the group consisting of: tetracosanol, stearyl alcohol, hexadecanol, tetradecanol, dodecanol and n-butanol.

13. The preparation method according to claim 10, wherein The catalyst is selected from the group consisting of organotin, organoaluminum and titanium catalysts.

14. The preparation method according to claim 13, wherein The organotin catalyst is selected from the group consisting of stannous oxalate, stannous octoate, dioctyltin dilaurate, dibutyltin oxide, and tetrabutyltin.

15. The preparation method according to claim 13, wherein The organic aluminum catalyst is selected from: triethyl aluminum, aluminum iodide, nano-aluminum oxide, and sodium aluminate.

16. The preparation method according to claim 13, wherein The titanium catalyst is selected from the group consisting of titanium dichloride, titanium dioxide, and titanate.

17. The preparation method according to claim 12, wherein The catalyst is selected from the group consisting of stannous oxalate, stannous octoate, triethylaluminum, aluminum iodide, and titanium dichloride.

18. The preparation method according to any one of claims 10 to 17, characterized in that: In step (1), the molar ratio of p-dioxanone to the catalyst is 1000-200000:

1.

19. The preparation method according to any one of claims 10 to 17, characterized in that: The activation temperature in step (1) is 60-150°C.

20. The preparation method according to any one of claims 10 to 17, characterized in that: The temperature of the polymerization reaction in step (2) is 50-150°C.

21. The preparation method according to claim 20, characterized in that The polymerization reaction time in step (2) is 24-360 hours.

22. The preparation method according to any one of claims 10 to 17, characterized in that: Step (1) also includes a homogenization step.

23. Use of the polydioxanone according to any one of claims 1 to 4 in the preparation of polymer fibers, medical materials or drug carriers.

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