A drug-eluting sinus stent, its preparation method and application

Abstract

This invention discloses a drug-eluting sinus stent, its preparation method, and its application. The drug-eluting sinus stent comprises: a sinusitis treatment drug and a medical-grade, catalyst-free polycaprolactone loaded with the sinusitis treatment drug; the drug loading of the medical-eluting sinus stent is 2-20 wt%; the 24-hour burst release rate of the medical-eluting sinus stent is <10%, and the sustained release time is ≥4 weeks; wherein, the medical-grade, catalyst-free polycaprolactone is prepared by ring-opening polymerization of a diether-bonded oxalamide diol as an initiator and caprolactone. The drug-eluting sinus stent of this invention eliminates the risk of catalyst residue from the source, ensuring the safety of stent implantation. Its controllable degradation performance and sustained drug release effect can meet the needs of postoperative sinus repair, making it suitable for implantation and support in humans or animals, and showing significant promise in the field of postoperative treatment of chronic sinusitis.

Description

Technical Field

[0001] This invention belongs to the field of polyester material technology, specifically relating to a medical drug-loaded sinus stent, its preparation method, and its application. Background Technology

[0002] Chronic sinusitis is a common disease in otolaryngology-head and neck surgery, with complex etiologies and pathophysiological mechanisms. To meet medical needs, fully degradable drug-eluting sinus stents have attracted widespread attention. These stents are coated with a drug that can be released at the lesion site, solving the problem that traditional nasal sprays cannot effectively deliver medication deep into the sinuses to exert their effects. This helps prevent adhesions and polyp formation after femoral artery stenosis (FESS) and reduces inflammation.

[0003] Polycaprolactone (PCL), a commonly used biodegradable polymer material for sinus stents, traditionally relies on metal catalysts such as tin and zinc or organic catalysts for its synthesis. Even trace amounts of these catalysts remaining in the material can still induce chronic inflammation, produce cytotoxicity, and even impose a long-term metabolic burden on organs such as the liver and kidneys after implantation. This makes it particularly unsuitable for long-term implantation in sensitive sites like the sinuses, significantly increasing the risk of postoperative complications. Furthermore, catalyst residues can interfere with the degradation pathway of PCL, leading to unstable degradation rates and complex degradation products. This makes it difficult to accurately match the timeframe for sinus mucosal repair, resulting in premature stent failure or long-term residue, thus affecting tissue repair outcomes. Furthermore, to control catalyst residue, traditional polycaprolactone medical materials require additional purification and testing processes, which not only increases production costs but may also face compliance challenges due to differences in catalyst residue testing standards across different countries and regions, delaying the product's transformation from R&D to clinical application. In contrast, catalyst-free synthesis systems can eliminate the risk of catalyst residue from the source, ensuring the purity of the material's chemical structure and allowing the degradation process to rely solely on its own hydrolysis or enzymatic hydrolysis characteristics, thus achieving predictability of the degradation cycle and products. This also reduces production steps and costs, making it easier to meet the stringent purity requirements of drug regulatory authorities in various countries for medical materials, providing a safer and more accessible material option for medical products such as sinus stents.

[0004] When conventional polycaprolactone (PCL) is used as a sinus stent, it suffers from several performance defects that fail to meet clinical needs: First, its hydrophilicity and biocompatibility are poor. Due to its strong hydrophobicity, it is highly bioinert, resulting in slow cell adhesion and proliferation on the stent surface, delayed tissue repair and vascularization, and an inability to quickly restore sinus physiological function. Second, its crystallization characteristics and mechanical strength are difficult to control. The crystallization rate and degree lack precise control, causing the stent to either deform and break easily under respiratory airflow and sinus physiological activities due to insufficient strength, losing its supporting effect, or to have excessive crystallinity and poor flexibility, resulting in poor adhesion to the sinus mucosa and causing mechanical stimulation and inflammatory reactions. Third, its degradation rate is mismatched with the sinus repair cycle. Too rapid degradation leads to premature stent failure and easy adhesion of newly repaired tissue, while too slow degradation results in long-term residues in the body, interfering with sinus function and increasing the risk of adverse reactions. At the same time, the complex composition of degradation products further aggravates the tissue burden. Fourth, its light transmittance lacks effective control, affecting the accurate assessment of stent position, degradation status, and tissue repair effect in postoperative imaging examinations, which is not conducive to doctors' judgment of the condition. These performance limitations severely restrict the application of conventional PCL materials in the field of sinus stents, and it is urgent to overcome these bottlenecks through material modification. Summary of the Invention

[0005] The main objective of this invention is to provide a medical drug-loaded sinus stent, its preparation method, and its application, so as to overcome the shortcomings of the prior art.

[0006] To achieve the aforementioned objectives, the technical solution adopted by this invention includes:

[0007] This invention provides a medical drug-loaded sinus stent, comprising: a sinusitis treatment drug and a medical catalyst-free polycaprolactone loaded with the sinusitis treatment drug; the drug loading amount of the medical drug-loaded sinus stent is 2~20wt%; the 24-hour burst release rate of the drug in the medical drug-loaded sinus stent is <10%, and the continuous release time is ≥4 weeks;

[0008] The medical-grade catalyst-free polycaprolactone is prepared by ring-opening polymerization of caprolactone with a diether-bonded oxalamide diol as an initiator. This invention also provides a method for preparing the aforementioned medical drug-loaded sinus stent, comprising:

[0009] Medical-grade catalyst-free polycaprolactone was blended with a sinusitis treatment drug to obtain a drug-loaded blend, which was then dried and fed into an injection molding device for injection molding to produce a medical drug-loaded sinus stent. The operating parameters of the injection molding device included: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

[0010] This invention also provides a method for preparing medical-grade catalyst-free polycaprolactone, comprising:

[0011] In a protective atmosphere, oxalate ester and 2-(2-aminoethoxy)ethanol are dissolved in a solvent and subjected to amidation at room temperature for 8-15 h. After recrystallization, a diether bond oxalate amide diol is obtained.

[0012] Furthermore, the diether-bonded oxalamide diol is mixed with caprolactone and subjected to a ring-opening polymerization reaction at 100-150°C for 6-24 hours without a catalyst to obtain medical-grade catalyst-free polycaprolactone.

[0013] The present invention also provides medical-grade catalyst-free polycaprolactone prepared by the aforementioned preparation method.

[0014] This invention also provides a method for preparing a medical catalyst-free polycaprolactone sinus stent material, comprising:

[0015] The previously used medical-grade catalyst-free polycaprolactone was dried and then fed into an injection molding device for injection molding to obtain a medical-grade catalyst-free polycaprolactone sinus stent material. The operating parameters of the injection molding device included: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

[0016] The present invention also provides a medical catalyst-free polycaprolactone sinus stent material prepared by the aforementioned preparation method.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] (1) The present invention uses a novel double ether bond oxalamide diol as an initiator to achieve catalyst-free synthesis of polycaprolactone material, which completely avoids the residual problems of metal or organic catalysts such as tin and zinc in traditional synthesis processes. After implantation into the human body, the material will not cause cytotoxicity, chronic inflammation or organ metabolic burden. It is especially suitable for long-term implantation in sensitive areas such as sinuses, which greatly reduces the risk of postoperative complications.

[0019] (2) By adjusting the ratio of diether bond oxalamide diol to caprolactone monomer and polymerization conditions, the present invention can achieve a wide range of control over the crystallinity, hydrophilicity and hydrophobicity, mechanical strength and degradation behavior of polycaprolactone material. The scaffold material has both excellent tensile strength and high elongation at break, and can provide reliable support during the critical period after surgery. At the same time, its degradation cycle can match the sinus mucosa repair process, avoiding premature failure or long-term residue.

[0020] (3) The medical catalyst-free polycaprolactone in this invention can load sinusitis treatment drugs with a drug loading of 2~20 wt%, a 24-hour burst release rate of less than 10%, and can continuously release drugs for no less than 4 weeks. This controllable release behavior helps to inhibit inflammation, reduce tissue adhesion, promote mucosal repair, and improve postoperative recovery.

[0021] (4) The 100μm film prepared by the medical catalyst-free polycaprolactone in this invention has a visible light transmittance of more than 80%, and some preferred solutions have a transmittance of more than 85%, which is beneficial to observe the position, degradation status and surrounding tissue repair by endoscopy or imaging after surgery, and supports doctors to conduct accurate assessment and follow-up.

[0022] (5) The entire synthesis and molding process of this invention does not require the addition of any catalysts, stabilizers or other auxiliaries. The production process is simplified, the subsequent purification and testing costs are reduced, and it is easier to meet the high purity requirements of domestic and foreign drug regulatory agencies for implantable materials. It accelerates the transformation of products from research and development to clinical application and has significant industrialization advantages and social benefits. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 This is the 1H NMR spectrum of the diether-bonded oxalamide diol of Example 1 of the present invention;

[0025] Figure 2 The above is the 1H NMR spectrum of the catalyst-free polycaprolactone material in Example 2 of this invention;

[0026] Figure 3 This is a stress-strain curve of the catalyst-free polycaprolactone material in Example 2 of the present invention;

[0027] Figure 4 This is a schematic diagram of a tissue sample after implantation of the drug-loaded scaffold prepared in Example 2 of the present invention;

[0028] Figure 5 This is a schematic diagram of a tissue sample taken one month after implantation of the drug-loaded scaffold prepared in Example 2 of the present invention.

[0029] Figure 6 This is a pathological section image of the drug-loaded stent prepared in Example 2 of the present invention after implantation;

[0030] Figure 7This is a pathological section image of the drug-loaded stent prepared in Example 2 of the present invention one month after implantation. Detailed Implementation

[0031] In view of the deficiencies of existing technologies, the inventors of this invention, through long-term research and extensive practice, have proposed the technical solution of this invention. This invention, by developing a novel diether-bonded oxalamide diol that functions as both an initiator and a lactone ring-opening catalyst, achieves catalyst-free synthesis of polycaprolactone. This fundamentally solves the problems of poor biocompatibility, potential toxicity, and inflammatory risks caused by catalyst residues in traditional biodegradable materials, significantly improving the safety of implantable materials in the human body. Simultaneously, the diether-bonded oxalamide diol introduced in this invention allows for the effective regulation of the crystallization ability, degradation behavior, mechanical properties, and drug release characteristics of PCL materials over a wide range. This enables the stent to provide reliable mechanical support during the critical postoperative period and to continuously and stably release therapeutic drugs, thereby inhibiting inflammatory responses, reducing tissue adhesion, and promoting mucosal repair. This technology not only provides a safer and more efficient treatment option for postoperative recovery from sinusitis, reducing patient suffering and economic burden, but also meets the development needs of high-end medical devices for material purity, functionalization, and precision medicine. It provides a new technical path for promoting the clinical application of biodegradable polymer materials in sensitive areas, possessing broad industrial prospects and social benefits.

[0032] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Specifically, as one aspect of the technical solution of the present invention, a medical drug-loaded sinus stent includes: a sinusitis treatment drug and a medical catalyst-free polycaprolactone loaded with the sinusitis treatment drug; the drug loading amount of the medical drug-loaded sinus stent is 2~20wt%; the 24-hour burst release rate of the drug in the medical drug-loaded sinus stent is <10%, and the continuous release time is ≥4 weeks;

[0034] The medical-grade catalyst-free polycaprolactone is prepared by ring-opening polymerization of caprolactone with a diether-bonded oxalamide diol as an initiator.

[0035] In some preferred embodiments, the drug loading of the medical drug-loaded sinus stent is 4~20wt%; the 24-hour burst release rate of the drug in the medical drug-loaded sinus stent is <5%, and the continuous release time is ≥6 weeks.

[0036] In some preferred embodiments, the sinusitis treatment drugs include, but are not limited to, budesonide and / or moxifloxacin hydrochloride.

[0037] In some preferred embodiments, the medical-grade catalyst-free polycaprolactone has a structure as shown in formula (I):

[0038]

[0039] Formula (I)

[0040] In this context, p and q are both independently selected from 10 to 60.

[0041] In some preferred embodiments, the diether-bonded oxalamide diol has a structure as shown in formula (II):

[0042]

[0043] Equation (II).

[0044] In some preferred embodiments, the medical-grade catalyst-free polycaprolactone has a number-average molecular weight of 20,000 to 80,000 g / mol and a molecular weight distribution index of 1.2 to 1.6.

[0045] In some preferred embodiments, the intrinsic viscosity of the medical-grade catalyst-free polycaprolactone is 0.7~1.5 dL / g.

[0046] In some preferred embodiments, the melting temperature of the medical-grade catalyst-free polycaprolactone is 55~75 °C.

[0047] In some preferred embodiments, the medical-grade catalyst-free polycaprolactone has a tensile strength of 30-50 MPa and an elongation at break of 300-800%.

[0048] In some preferred embodiments, the degradation period of the medical catalyst-free polycaprolactone in phosphate buffer (PBS buffer, pH 7.4, 37°C) is 1 to 12 months.

[0049] Furthermore, the degradation period of the medical-grade catalyst-free polycaprolactone in phosphate-buffered saline (PBS buffer, pH 7.4, 37°C) is 1 to 6 months.

[0050] In some preferred embodiments, the visible light transmittance of the 100 μm film formed from the medical-grade catalyst-free polycaprolactone is >80%.

[0051] Furthermore, the visible light transmittance of the 100 μm film formed from the medical-grade catalyst-free polycaprolactone is >85%.

[0052] In some preferred embodiments, the method for preparing the medical-grade catalyst-free polycaprolactone specifically includes:

[0053] In a protective atmosphere, oxalate ester and 2-(2-aminoethoxy)ethanol are dissolved in a solvent and subjected to amidation at room temperature for 8-15 h. After recrystallization, a diether bond oxalate amide diol is obtained.

[0054] Furthermore, the diether-bonded oxalamide diol is mixed with caprolactone and subjected to a ring-opening polymerization reaction at 100-150°C for 6-24 hours without a catalyst to obtain medical-grade catalyst-free polycaprolactone.

[0055] Furthermore, the present invention uses a catalyst-free polycaprolactone obtained by cyclo-opening polymerization of oxalic acid amide diol with a diether bond as an initiator, without the need to add any additional metal or non-metal catalysts.

[0056] Furthermore, the ring-opening polymerization reaction is carried out at a temperature of 110~130℃.

[0057] Furthermore, the ring-opening polymerization reaction takes 8 to 20 hours.

[0058] Furthermore, the oxalate ester includes any one or more combinations of dimethyl oxalate, diethyl oxalate, methyl ethyl oxalate, and dibutyl oxalate, and is not limited thereto.

[0059] Furthermore, the solvent includes any one or more combinations of methanol, ethanol, and acetone, but is not limited thereto.

[0060] Furthermore, the molar ratio of the oxalate ester to 2-(2-aminoethoxy)ethanol is 1:1.95 to 1:2.05.

[0061] Furthermore, the molar ratio of the diether bond oxalamide diol to caprolactone is 1:30 to 1:200.

[0062] Furthermore, the molar ratio of the diether bond oxalamide diol to caprolactone is 1:40 to 1:120.

[0063] The drug-eluting sinus stent of this invention can regulate the hydrophilicity and molecular weight of the resulting polycaprolactone by adjusting factors such as the ratio of diether bond oxalamide diol to caprolactone monomer and the polymerization time during the polymerization process, thereby controlling the overall degradation rate and degradation cycle of the sinus stent product.

[0064] Another aspect of the present invention provides a method for preparing the aforementioned medical drug-eluting sinus stent, comprising:

[0065] Medical-grade catalyst-free polycaprolactone was blended with a sinusitis treatment drug to obtain a drug-loaded blend, which was then dried and fed into an injection molding device for injection molding to produce a medical drug-loaded sinus stent. The operating parameters of the injection molding device included: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

[0066] The medical drug-loaded sinus stent provided by this invention has the functions of no additive residue in the preparation and molding process, better hydrophilicity, faster degradation rate and matching with the drug sustained release cycle, better crystallization ability and mechanical strength to provide mechanical support, and is suitable for postoperative sinus repair and functional reconstruction.

[0067] Another aspect of the present invention provides a method for preparing medical-grade catalyst-free polycaprolactone, comprising:

[0068] In a protective atmosphere, oxalate ester and 2-(2-aminoethoxy)ethanol are dissolved in a solvent and subjected to amidation at room temperature for 8-15 h. After recrystallization, a diether bond oxalate amide diol is obtained.

[0069] Furthermore, the diether-bonded oxalamide diol is mixed with caprolactone and subjected to a ring-opening polymerization reaction at 100-150°C for 6-24 hours without a catalyst to obtain medical-grade catalyst-free polycaprolactone.

[0070] Further, under a protective atmosphere, the oxalate ester is dissolved in a methanol solution with 2-(2-aminoethoxy)ethanol and subjected to an amidation reaction at room temperature for 8-15 hours (preferably 12 hours). The product is then recrystallized from acetone to obtain a diether-bonded oxalate amide diol.

[0071] Another aspect of the present invention provides medical-grade catalyst-free polycaprolactone prepared by the aforementioned preparation method.

[0072] Another aspect of the present invention provides a method for preparing a medical catalyst-free polycaprolactone sinus stent material, comprising:

[0073] The aforementioned medical-grade catalyst-free polycaprolactone was dried and then injected into an injection molding device for injection molding to obtain a medical-grade catalyst-free polycaprolactone sinus stent material. The operating parameters of the injection molding device included: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

[0074] Another aspect of the present invention provides a medical catalyst-free polycaprolactone sinus stent material prepared by the aforementioned preparation method.

[0075] The technical solution of the present invention will be further described in detail below with reference to several preferred embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the invention, and provides detailed implementation methods and specific operation processes. However, the protection scope of the present invention is not limited to the following embodiments.

[0076] Unless otherwise specified, the experimental materials used in the examples below can be purchased from conventional biochemical reagent companies.

[0077] The stents in the embodiments and comparative examples of this invention meet the following requirements: diameter (e.g., 3-5mm, to adapt to different sinus ostium sizes), length (e.g., 8-15mm, to match the needs of different parts such as the maxillary sinus / frontal sinus), and tube wall thickness (e.g., 100-300μm).

[0078] Example 1

[0079] Under nitrogen protection, dimethyl oxalate (11.8 g, 0.1 mol) and 2-(2-aminoethoxy)ethanol (20.0 g, 0.2 mol) were dissolved in 100 mL of anhydrous methanol and reacted at 25 °C for 12 hours. After the reaction, the product was purified three times by recrystallization in icy acetone to obtain high-purity diether-bonded oxalamide diol (as shown below), which was used as the initiator in subsequent examples. The 1H NMR spectrum of the prepared diether-bonded oxalamide diol is shown below. Figure 1 As shown.

[0080]

[0081] Example 2

[0082] The initiator (2.18 g, 0.01 mol) obtained in Example 1 and caprolactone monomer (114 g, 1.0 mol) were added to a reactor at a molar ratio of 1:100 and polymerized at 120°C under nitrogen protection for 18 hours to obtain a catalyst-free polycaprolactone with a number-average molecular weight of 52,000 g / mol and a PDI of 1.2. This was further mixed with the model drug budesonide at a weight ratio of 95:5 at 60°C for 30 minutes to ensure uniform drug dispersion, resulting in a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum-dried at 50°C for 8 hours. Subsequently, they were molded into tubular sinus stents using a micro-injection molding machine. The key injection molding parameters were: barrel temperature 100°C, die temperature 100°C, mold temperature 35°C, and injection pressure 30 MPa.

[0083] The obtained catalyst-free polycaprolactone material has a melting temperature of 68℃, a tensile strength of 50 MPa, and an elongation at break of 800%. When fabricated into a scaffold, its radial compressive strength is approximately 150 kPa, fully meeting the mechanical requirements for sinus support. The catalyst-free polycaprolactone material maintained a quality retention rate of 78% after 6 months. For drug-loaded scaffolds, the quality retention rate exceeded 90% during the 4-week drug release period, with a 24-hour drug burst release rate of only 4.6%, and achieved a stable cumulative release of 82% over the subsequent 28 days, meeting the needs of continuous anti-inflammatory treatment after surgery. A 100 μm thick film prepared from the catalyst-free polycaprolactone material had a visible light transmittance of 85%. Cytotoxicity tests showed that the material extract had a relative proliferation rate of 98% on L929 cells, with a toxicity grade of 0-1.

[0084] The 1H NMR spectrum of the catalyst-free polycaprolactone material prepared in this embodiment is shown below. Figure 2 As shown, the stress-strain curve is as follows: Figure 3 As shown in the diagram, a tissue sample of the prepared drug-loaded scaffold after implantation is presented. Figure 4 As shown in the diagram, a tissue sample was taken one month after implantation of the prepared drug-loaded scaffold. Figure 5 As shown, the pathological section image of the tissue sample after implantation of the prepared drug-loaded scaffold is as follows. Figure 6 As shown, the pathological section of a tissue sample from the prepared drug-loaded scaffold implanted one month after implantation into the maxillary sinus ostium is shown in the figure. Figure 7 As shown.

[0085] Example 3

[0086] The initiator (1.09 g, 0.005 mol) obtained in Example 1 and caprolactone monomer (114 g, 1.0 mol) were added to a reactor at a molar ratio of 1:200 and polymerized at 150°C under nitrogen protection for 6 hours to obtain catalyst-free polycaprolactone with a number average molecular weight of 80,000 g / mol and a PDI of 1.6. This was further mixed with moxifloxacin hydrochloride at a weight ratio of 96:4 at 60°C for 30 minutes to obtain a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum dried at 50°C for 10 hours and then molded into tubular sinus stents using a micro-injection molding machine. The key injection molding parameters were: barrel temperature 120°C, die temperature 120°C, mold temperature 50°C, and injection pressure 50 MPa.

[0087] The obtained catalyst-free polycaprolactone material had a melting temperature of 75℃, a tensile strength of 50 MPa, and an elongation at break of 300%. The radial compressive strength of the scaffold was approximately 180 kPa. The catalyst-free polycaprolactone material maintained 85% of its mass after 12 months. The drug-loaded scaffold maintained over 90% of its mass within 4 weeks, with a 24-hour drug burst release rate of 3.8% and a cumulative drug release of 55% within 28 days. The visible light transmittance of a 100 μm film prepared from the catalyst-free polycaprolactone material was 80%. Cytotoxicity tests showed that the material extract induced a 97% relative proliferation rate in L929 cells, with a toxicity grade of 0.

[0088] Example 4

[0089] The initiator (1.09 g, 0.005 mol) obtained in Example 1 and caprolactone (114 g, 1.0 mol) were added to a reactor at a molar ratio of 1:200 and polymerized at 150°C under nitrogen protection for 10 hours to obtain a catalyst-free polycaprolactone with a number average molecular weight of 80,000 g / mol and a PDI of 1.6. This was further mixed with budesonide at a weight ratio of 92:8 at 60°C for 30 minutes to obtain a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum dried at 50°C for 8 hours and then molded into tubular sinus stents using a micro-injection molding machine. The key injection molding parameters were: barrel temperature 115°C, die head temperature 110°C, mold temperature 45°C, and injection pressure 45 MPa.

[0090] The obtained catalyst-free polycaprolactone material had a melting temperature of 75 °C, a tensile strength of 50 MPa, and an elongation at break of 300%. The radial compressive strength of the fabricated scaffold was approximately 180 kPa. The catalyst-free polycaprolactone material maintained a mass retention of 82% after 6 months. For drug-loaded scaffolds, the mass retention exceeded 92% during the 4-week drug release period, with a 24-hour burst release rate of only 6.2%, and a stable cumulative release of 68% over the subsequent 28 days. The visible light transmittance of a 100 μm thick film prepared from the catalyst-free polycaprolactone material was 81%. Cytotoxicity assays showed that the material extract resulted in a 99% relative proliferation rate of L929 cells.

[0091] Example 5

[0092] The initiator (4.36 g, 0.02 mol) obtained in Example 1 and caprolactone monomer (68.4 g, 0.6 mol) were added to a reactor at a molar ratio of 1:30 and polymerized at 110°C under nitrogen protection for 24 hours to obtain low molecular weight, catalyst-free polycaprolactone with a number average molecular weight of 20,000 g / mol and a PDI of 1.3. This was further mixed with moxifloxacin hydrochloride at a weight ratio of 95:5 at 60°C for 30 minutes to ensure uniform drug dispersion, yielding a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum dried at 50°C for 8 hours. Subsequently, they were molded into sinus stent materials and tubular drug-loaded sinus stents using a micro-injection molding machine. The injection molding parameters were: barrel temperature 90°C, die head temperature 85°C, mold temperature 25°C, and injection pressure 20 MPa.

[0093] The obtained catalyst-free polycaprolactone material has a melting temperature of 55 °C, an elongation at break of 700%, and a radial compressive strength of approximately 100 kPa after being fabricated into a scaffold. The catalyst-free polycaprolactone material exhibits a rapid degradation rate, maintaining 65% of its mass in PBS after 3 months. The drug-loaded scaffold demonstrates a 24-hour burst release rate of 8.0%, with a cumulative drug release of 90% within 14 days, making it suitable for short-term, high-potency treatment. The film prepared from the catalyst-free polycaprolactone material has a light transmittance of 88%.

[0094] Example 6

[0095] The initiator (2.18 g, 0.01 mol) obtained in Example 1 and caprolactone monomer (91.2 g, 0.8 mol) were added to a reactor at a molar ratio of 1:80 and polymerized at 130°C under nitrogen protection for 12 hours to obtain catalyst-free polycaprolactone with a number average molecular weight of 45,000 g / mol and a PDI of 1.4. This was then mixed with budesonide at a weight ratio of 85:15 at 60°C for 30 minutes to ensure uniform drug dispersion, yielding a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum-dried at 50°C for 8 hours. Subsequently, they were molded into sinus stent materials and tubular drug-loaded sinus stents using a micro-injection molding machine. The injection molding parameters were: barrel temperature 110°C, die temperature 105°C, mold temperature 40°C, and injection pressure 40 MPa.

[0096] The obtained catalyst-free polycaprolactone material had a melting temperature of 65℃, a tensile strength of 40 MPa, and an elongation at break of 500%. The radial compressive strength of the scaffold was approximately 130 kPa. The mass retention rate of the catalyst-free polycaprolactone material was 75% after 6 months. The drug-loaded scaffold exhibited a 24-hour burst release rate of 10.0%, with a cumulative drug release of 95% within 4 weeks. The visible light transmittance of a 100 μm film prepared from the catalyst-free polycaprolactone material was 83%. Cytotoxicity assays showed that the material extract induced a relative proliferation rate of 98% in L929 cells, with a toxicity grade of 0-1.

[0097] Example 7

[0098] The initiator (3.27 g, 0.015 mol) obtained in Example 1 and caprolactone monomer (102.6 g, 0.9 mol) were added to a reactor at a molar ratio of 1:60 and polymerized at 140°C under nitrogen protection for 8 hours to obtain catalyst-free polycaprolactone with a number average molecular weight of 60,000 g / mol and a PDI of 1.5. This was then mixed with budesonide at a weight ratio of 82:18 at 60°C for 30 minutes to ensure uniform drug dispersion, yielding a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum-dried at 50°C for 8 hours. Subsequently, they were molded into sinus stent materials and tubular drug-loaded sinus stents using a micro-injection molding machine. The injection molding parameters were: barrel temperature 105°C, die head temperature 100°C, mold temperature 30°C, and injection pressure 25 MPa.

[0099] The obtained catalyst-free polycaprolactone material had a melting temperature of 70℃, a tensile strength of 45 MPa, and an elongation at break of 400%. The radial compressive strength of the scaffold was approximately 140 kPa. The mass retention rate of the catalyst-free polycaprolactone material was 70% after 9 months. The drug-loaded scaffold exhibited a 24-hour burst release rate of 9.8%, with a cumulative drug release of 92% within 4 weeks. The visible light transmittance of a 100 μm film prepared from the catalyst-free polycaprolactone material was 86%. Cytotoxicity assays showed that the material extract induced a relative proliferation rate of 96% in L929 cells, with a toxicity grade of 0.

[0100] Example 8

[0101] The initiator (1.64 g, 0.0075 mol) obtained in Example 1 and caprolactone monomer (125.4 g, 1.1 mol) were added to a reactor at a molar ratio of 1:147 and polymerized at 110°C under nitrogen protection for 20 hours to obtain catalyst-free polycaprolactone with a number average molecular weight of 75,000 g / mol and a PDI of 1.3. This was then mixed with moxifloxacin hydrochloride at a weight ratio of 81:19 at 60°C for 30 minutes to ensure uniform drug dispersion, yielding a drug-loaded blend. The synthesized pure polymer and the drug-loaded blend were vacuum-dried at 50°C for 8 hours. Subsequently, they were molded into sinus stent materials and tubular drug-loaded sinus stents using a micro-injection molding machine. The injection molding parameters were: barrel temperature 95°C, die head temperature 90°C, mold temperature 28°C, and injection pressure 15 MPa.

[0102] The obtained catalyst-free polycaprolactone material had a melting temperature of 72℃, a tensile strength of 48 MPa, and an elongation at break of 350%. The radial compressive strength of the scaffold was approximately 160 kPa. The mass retention rate of the catalyst-free polycaprolactone material was 80% after 3 months. The drug-loaded scaffold exhibited a 24-hour burst release rate of 6.5%, with a cumulative drug release of 83% within 4 weeks. The visible light transmittance of a 100 μm film prepared from the catalyst-free polycaprolactone material was 84%. Cytotoxicity assays showed that the material extract induced a relative proliferation rate of 99% in L929 cells, with a toxicity grade of 0.

[0103] Comparative Example 1

[0104] 1,4-Butanediol (0.01 mol) was used as an initiator and added to a reactor at a molar ratio of 1:100 with caprolactone monomer (114 g, 1.0 mol). 0.05 wt% (based on monomer mass) of stannous octoate was added as a catalyst, and polymerization was carried out at 120°C under nitrogen protection for 18 hours. After the reaction, the resulting polymer was dissolved in chloroform and precipitated in methanol to remove residual metal catalyst as much as possible. This purification step was repeated three times. A polycaprolactone with a number average molecular weight of 50,000 g / mol and a PDI of 1.5 was finally obtained. This was then mixed with budesonide at a weight ratio of 95:5 at 60°C for 30 minutes to obtain a drug-loaded blend. The injection molding process was exactly the same as in Example 2.

[0105] The mechanical properties of the obtained material were comparable to those of Example 2, with a melting temperature of 66°C, a tensile strength of 48 MPa, and an elongation at break of 750%. However, cytotoxicity tests showed that despite repeated purification, the material extract had a relative proliferation rate of only 85% for L929 cells, with a toxicity level of 2, indicating mild cytotoxicity. This was attributed to residual tin catalyst that was difficult to completely remove.

[0106] In drug release tests, the comparative stent exhibited a 24-hour burst drug release rate of up to 25% and a cumulative release of over 95% of the drug within 28 days, demonstrating poor controlled drug release capability. This indicates that traditional catalyst systems not only introduce biosafety risks but may also affect the structural regularity of polymer chains, leading to excessively rapid drug release.

[0107] Comparative Example 2

[0108] Commercially available medical-grade polycaprolactone (product designation Capa™ 6800) was directly purchased. This material was synthesized using a conventional tin catalyst process and subsequently purified. It was then mixed with budesonide at a weight ratio of 95:5 at 60°C for 30 minutes and molded into a tubular sinus stent using the same injection molding process as in Example 2. The commercially available PCL exhibited higher rigidity but insufficient toughness, with a melt temperature of 60°C, a tensile strength of 45 MPa, and an elongation at break of 500%. The radial compressive strength of the stent was approximately 140 kPa. Cytotoxicity testing showed that the relative proliferation rate of its extract was 90%, with a toxicity grade of 1, indicating that its biocompatibility was better than Comparative Example 1, but still inferior to the catalyst-free system of this invention (98%).

[0109] Regarding drug release performance, its loading and controlled-release capabilities for budesonide are significantly reduced: the 24-hour burst release rate is as high as 18%, and more than 95% of the drug is released cumulatively within 21 days, failing to achieve sustained and stable release for up to 4 weeks. This indicates that the molecular structure of commercial PCL is inferior to the specific structure polymer of this invention in terms of drug compatibility and diffusion barrier function, making it difficult to meet the long-term anti-inflammatory treatment needs after sinus surgery.

[0110] The catalyst-free polycaprolactone sinus scaffold material of this invention exhibits significant advantages. Regarding biocompatibility, the relative cell proliferation rate of all embodiments was ≥96%, with a toxicity grade of 0 or 0–1. In contrast, Comparative Examples 1 and 2 showed significant cytotoxicity due to catalyst residues (proliferation rates of 85% and 90%, and toxicity grades of 2 and 1, respectively). In terms of drug controlled release performance, the 24-hour burst release rate of the embodiments was less than 10%, achieving sustained release for more than 4 weeks. Comparative Examples 1 and 2, however, had burst release rates as high as 25% and 18%, respectively, with almost complete drug release within 3 weeks, demonstrating poor controlled release capabilities. Furthermore, this invention fundamentally eliminates the biosafety risks caused by metal residues in traditional processes through catalyst-free synthesis and achieves precise control over degradation behavior and drug release, resulting in significantly superior overall performance compared to traditional catalyst systems and commercial products.

[0111] In addition, the inventors of this case also conducted experiments with other raw materials, process operations, and process conditions described in this specification, referring to the aforementioned embodiments, and obtained relatively ideal results in all cases.

[0112] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A medical drug-eluting sinus stent, characterized in that, include: Sinusitis treatment drugs and medical catalyst-free polycaprolactone loaded with the aforementioned sinusitis treatment drugs; The drug loading capacity of the medical drug-eluting sinus stent is 2-20 wt%; The 24-hour burst release rate of the drug in the medical drug-loaded sinus stent is <10%, and the continuous release time is ≥4 weeks; The medical-grade catalyst-free polycaprolactone is prepared by ring-opening polymerization of a diether-bonded oxalamide diol as an initiator and caprolactone, wherein the diether-bonded oxalamide diol has a structure as shown in formula (II): 。 2. The medical drug-eluting sinus stent according to claim 1, characterized in that: The drug-loaded sinus stent has a drug loading capacity of 4-20 wt%; the 24-hour burst release rate of the drug in the drug-loaded sinus stent is <5%, and the continuous release time is ≥6 weeks.

3. The medical drug-eluting sinus stent according to claim 1, characterized in that: The medications used to treat sinusitis include budesonide and / or moxifloxacin hydrochloride.

4. The medical drug-eluting sinus stent according to claim 1, characterized in that: The medical-grade catalyst-free polycaprolactone has the structure shown in formula (I): ； Formula (I) In this context, p and q are both independently selected from 10 to 60.

5. The medical drug-eluting sinus stent according to claim 1, characterized in that: The medical-grade catalyst-free polycaprolactone has a number-average molecular weight of 20,000~80,000 g / mol and a molecular weight distribution index of 1.2~1.

6. And / or, the intrinsic viscosity of the medical-grade catalyst-free polycaprolactone is 0.7~1.5 dL / g; And / or, the melting temperature of the medical-grade catalyst-free polycaprolactone is 55~75 °C; And / or, the medical-grade catalyst-free polycaprolactone has a tensile strength of 30-50 MPa and an elongation at break of 300-800%.

6. The medical drug-eluting sinus stent according to claim 1, characterized in that: The degradation cycle of the medical-grade catalyst-free polycaprolactone in phosphate buffer is 1 to 12 months. And / or, the visible light transmittance of the 100 μm film formed from the medical catalyst-free polycaprolactone is >80%.

7. The medical drug-eluting sinus stent according to claim 1, characterized in that, The preparation method of the catalyst-free medical polycaprolactone specifically includes: In a protective atmosphere, oxalate ester and 2-(2-aminoethoxy)ethanol are dissolved in a solvent and subjected to amidation at room temperature for 8-15 h. After recrystallization, a diether bond oxalate amide diol is obtained. Furthermore, the diether-bonded oxalamide diol is mixed with caprolactone and subjected to a ring-opening polymerization reaction at 100-150 °C for 6-24 h without a catalyst to obtain medical-grade catalyst-free polycaprolactone.

8. The medical drug-eluting sinus stent according to claim 7, characterized in that: The oxalate ester includes any one or more combinations of dimethyl oxalate, diethyl oxalate, methyl ethyl oxalate, and dibutyl oxalate; and / or, the solvent includes any one or more combinations of methanol, ethanol, and acetone. And / or, the molar ratio of the oxalate ester to 2-(2-aminoethoxy)ethanol is 1:1.95 to 1:2.05; And / or, the molar ratio of the diether-bonded oxalamide diol to caprolactone is 1:30 to 1:

200.

9. The method for preparing a medical drug-eluting sinus stent according to any one of claims 1-8, characterized in that, include: Medical-grade catalyst-free polycaprolactone was blended with a sinusitis treatment drug to obtain a drug-loaded blend, which was then dried and fed into an injection molding device for injection molding to produce a medical drug-loaded sinus stent. The operating parameters of the injection molding device included: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

10. A method for preparing medical-grade catalyst-free polycaprolactone, characterized in that, include: In a protective atmosphere, oxalate ester and 2-(2-aminoethoxy)ethanol are dissolved in a solvent and subjected to amidation at room temperature for 8-15 h. After recrystallization, a diether bond oxalate amide diol is obtained. Furthermore, the diether-bonded oxalamide diol is mixed with caprolactone and subjected to a ring-opening polymerization reaction at 100-150 °C for 6-24 h without a catalyst to obtain medical-grade catalyst-free polycaprolactone.

11. Medical-grade catalyst-free polycaprolactone prepared by the preparation method of claim 10.

12. A method for preparing a medical catalyst-free polycaprolactone sinus stent material, characterized in that, include: The medical-grade catalyst-free polycaprolactone described in claim 11 is dried and then injected into an injection molding device for injection molding to obtain a medical-grade catalyst-free polycaprolactone sinus stent material; wherein the operating parameters of the injection molding device include: barrel temperature of 80~120 ℃, die head temperature of 80~120 ℃, mold temperature of 25~50 ℃, and injection pressure of 10~50 MPa.

13. A medical catalyst-free polycaprolactone sinus stent material prepared by the preparation method of claim 12.

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