Degradable drug sustained-release intrauterine anti-adhesion stent and preparation method thereof

Abstract

The invention relates to a degradable drug sustained-release intrauterine anti-adhesion stent and a preparation method thereof, and belongs to the technical field of medical instruments, the degradable drug sustained-release intrauterine anti-adhesion stent comprises a drug-loading core layer, a sustained-release barrier layer and an antibacterial coating, the drug-loading core layer is formed by compounding a degradable high polymer material and estrogen, the degradable high polymer material is PLGA, the estrogen is 17beta-estradiol, and the sustained-release barrier layer is an anti-bacterial coating. And the loading capacity of the estrogen is 1-10wt% of the total weight of the According to the invention, the anti-adhesion purpose is achieved by physically isolating the uterine cavity wall, the regeneration of the intima is promoted in an estrogen slow release manner, the active repair effect is achieved, the PHMB coating is arranged to inhibit bacteria, and the infection prevention effect is achieved; the clinical pain points that a traditional uterine cavity anti-adhesion support needs to be taken out through a secondary operation, has no active repairing function and has the infection risk and medicine depends on systemic administration are solved in a three-in-one mode of anti-adhesion, repair promoting and anti-infection.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to a degradable drug sustained-release uterine cavity anti-adhesion stent and a preparation method thereof. Background Art

[0002] The intrauterine adhesion stent is a medical device placed in the uterine cavity to prevent or reduce the formation or recurrence of intrauterine adhesions. Its purpose is to serve as a physical barrier between the anterior and posterior uterine walls, preventing them from contacting and adhering to each other during postoperative wound healing, thereby maintaining the uterine cavity's morphology. It supports the uterine cavity, maintaining its normal anatomical shape and volume, preventing deformation, constriction, or occlusion caused by adhesions, promoting endometrial regeneration, and providing a relatively independent space that facilitates the regrowth and coverage of the endometrium in damaged areas. It is primarily used in scenarios such as postoperative intrauterine adhesion separation surgery, resection of moderate to severe endometrial polyps, and resection of larger submucosal uterine myomas.

[0003] The existing traditional silicone-type intrauterine anti-adhesion stent requires a second surgery to remove after use and lacks active repair function. Such traditional stent structures have a high risk of infection, and local estrogen administration relies on systemic medication, which has significant side effects. Therefore, a degradable drug sustained-release intrauterine anti-adhesion stent and a preparation method thereof are proposed. The intrauterine anti-adhesion stent adopts PLGA degradable material, which automatically degrades 6-12 weeks after surgery, eliminating the need for removal surgery, reducing patient pain and medical costs. The core layer is loaded with a 17β-estradiol sustained-release system, which continuously releases estrogen for 28-60 days, directly stimulating endometrial regeneration and reducing the recurrence rate of adhesions. The surface is fixed with a PHMB antibacterial coating with broad-spectrum antibacterial properties, reducing the risk of endometritis, and can locally target sustained-release estrogen to avoid systemic side effects. Summary of the Invention

[0004] The present invention provides a degradable drug-sustained-release intrauterine anti-adhesion stent and a preparation method thereof, which solves the problems raised by the above-mentioned existing background technology. It solves the clinical pain points of traditional intrauterine anti-adhesion stents, such as the need for a second operation to remove them, the lack of active repair function, the risk of infection, and the dependence on systemic drug administration, by adopting a "preventing adhesion, promoting repair, and resisting infection" trinity approach.

[0005] The present invention solves the above technical problems as follows: a degradable drug-sustained-release intrauterine anti-adhesion stent, comprising a drug-loaded core layer, a sustained-release barrier layer, and an antibacterial coating, wherein the drug-loaded core layer is composited with a degradable polymer material and estrogen, wherein the degradable polymer material is PLGA, and the estrogen is 17β-estradiol, and the estrogen loading amount is 1-10 wt% of the total weight of the stent;

[0006] The sustained-release barrier layer wraps the drug-loaded core layer, the sustained-release barrier layer is composed of a degradable film, and the antibacterial coating covers the sustained-release barrier layer, and the antibacterial coating is prepared from a polyhexamethylene biguanide hydrochloride (PHMB) solution;

[0007] The preparation method comprises the following steps:

[0008] S1, preparation of drug-loaded fibers: PLGA was dissolved in an organic solvent, estradiol powder was added, and a uniform spinning solution was obtained by magnetic stirring;

[0009] S2, preparation of drug-loaded fiber membrane, using electrospinning technology to prepare uniform spinning solution into drug-loaded fiber membrane;

[0010] S3, sustained-release membrane coating: spraying PCL solution on the surface of drug-loaded fibers and drying to form a sustained-release barrier layer;

[0011] S4, antibacterial coating construction, spraying PHMB solution on the surface of the sustained-release barrier layer, and curing the coating by UV cross-linking;

[0012] S5, stent molding: hot pressing the composite film into a T-shaped / balloon structure and sterilizing it with gamma rays;

[0013] S6, terminal sterilization, γ-ray irradiation: dose 25 kGy, temperature <40°C.

[0014] On the basis of the above technical solution, the present invention can also be improved as follows.

[0015] Furthermore, in step S1, the organic solvent is dichloromethane, the concentration of PLGA is controlled to be 20 wt%, the 17β-estradiol powder accounts for 8 wt% of the PLGA solid mass, the magnetic stirring parameter is 600 rpm for 2 h, and the ultrasonic dispersion parameter is 40 kHz for 30 min.

[0016] Furthermore, in step S2, the electrospinning parameters are: voltage 18-22 kV, injection speed 1.0 mL / h, receiving distance 15 cm, ambient temperature and humidity 25±2°C, RH<40%.

[0017] Furthermore, in step S2, the spinning solution concentration is 15-25 wt%, and the receiving device is a high-speed rotating drum or aluminum foil, thereby generating a non-woven fiber membrane product with a thickness of 80±10 μm and a fiber diameter of 1-2 μm.

[0018] Furthermore, in step S3, the PCL solution is prepared by dissolving PCL in chloroform with a concentration of 5 wt %. The solution is sprayed by a spray gun with a nozzle diameter of 0.3 mm and evenly sprayed on the surface of the drug-loaded fiber membrane three times, followed by drying for 5 minutes.

[0019] Furthermore, in step S3, the drying equipment is a vacuum drying oven, and the curing is carried out in a vacuum environment at 60°C for 24 hours to form a 30±5 μm dense sustained-release layer.

[0020] Furthermore, in step S4, the PHMB solution is prepared by preparing a 2.5 wt% PHMB aqueous solution containing 0.1% polyethylene glycol viscosity enhancer.

[0021] Furthermore, in step S4, the coating is cured by immersing the stent in PHMB solution (30s) → taking it out and draining it, and then crosslinking it with UV light: wavelength 254nm, intensity 10mW / cm 2 , irradiation for 10 min, drying at 50°C → surface PHMB loading 2.0±0.3 mg / cm 2 .

[0022] Furthermore, in step S5, the hot pressing molding step is specifically as follows: preheating the mold to 70°C (lower than the glass transition temperature Tg of PLGA), placing the composite film material into a T-shaped mold (uterine cavity adaptation size: vertical arm length 30-35mm, horizontal arm width 20-25mm), applying pressure of 0.5MPa, maintaining the pressure for 5min → cooling and demolding.

[0023] The beneficial effects of the present invention are as follows: the present invention provides a degradable drug-release type intrauterine anti-adhesion stent and a preparation method thereof, which has the following advantages:

[0024] 1. It can solve the defect of traditional silicone stents that require a second surgery to remove. This intrauterine anti-adhesion stent uses PLGA biodegradable material and will automatically degrade 6-12 weeks after surgery, eliminating the need for removal surgery and reducing patient pain and medical costs.

[0025] 2. The core layer is loaded with a 17β-estradiol sustained-release system, which continuously releases estrogen for 28-60 days, directly stimulating endometrial regeneration and reducing the recurrence rate of adhesions;

[0026] 3. The surface is fixed with PHMB antibacterial coating, which has broad-spectrum antibacterial properties and reduces the risk of endometritis;

[0027] 4. It has a drug sustained-release function that can locally target and release estrogen, effectively avoiding systemic side effects such as thrombosis and breast irritation;

[0028] 5. The overall soft elastic modulus is 0.5-1.5MPa, which can effectively fit the shape of the uterine cavity and reduce mechanical damage;

[0029] 6. It prevents adhesions by physically isolating the uterine cavity wall, promotes endometrial regeneration through sustained-release estrogen, and has an active repair effect. The PHMB coating is antibacterial, which prevents infection. The "anti-adhesion-promote-repair-anti-infection" trinity approach solves the clinical pain points of traditional uterine cavity anti-adhesion stents, such as the need for a second surgery to remove them, the lack of active repair function, the risk of infection, and the reliance on systemic drug administration.

[0030] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and to implement it according to the contents of the description, the following preferred embodiments of the present invention are described in detail with reference to the accompanying drawings. The specific implementation methods of the present invention are given in detail by the following embodiments and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0032] Figure 1 A flow chart of a degradable drug-releasing intrauterine anti-adhesion stent and a preparation method thereof provided in one embodiment of the present invention;

[0033] Figure 2 This is a schematic structural diagram of a degradable drug-sustained-release intrauterine anti-adhesion stent and a preparation method thereof provided in one embodiment of the present invention.

[0034] In the accompanying drawings, the components represented by the reference numerals are as follows:

[0035] 1. Drug-loaded core layer; 2. Sustained-release barrier layer; 3. Antibacterial coating. DETAILED DESCRIPTION

[0036] The following is combined with Figure 1-2 The principles and features of the present invention are described, and the examples given are only for the purpose of explaining the present invention and are not intended to limit the scope of the present invention. The following paragraphs describe the present invention in more detail by way of example with reference to the accompanying drawings. The advantages and features of the present invention will become more apparent from the following description. It should be noted that the drawings are all in a very simplified form and are not in exact proportions, and are only used for the purpose of conveniently and clearly assisting in illustrating the embodiments of the present invention.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in this specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0038] like Figure 1-2As shown, the present invention provides a degradable drug sustained-release intrauterine anti-adhesion stent, comprising a drug-loaded core layer 1, a sustained-release barrier layer 2, and an antibacterial coating 3. The drug-loaded core layer 1 is composited with a degradable polymer material and estrogen, wherein the degradable polymer material is PLGA, and the degradation cycle is 6-16 weeks. The estrogen is 17β-estradiol, and the release curve satisfies the following requirements: a 24-hour burst rate of <15%, a sustained release time of ≥28 days, and an estrogen loading amount of 1-10 wt% of the total weight of the stent;

[0039] The sustained-release barrier layer 2 wraps the drug-loaded core layer 1, and the sustained-release barrier layer 2 is composed of a degradable film with a thickness of 10-50 μm. The antibacterial coating 3 covers the sustained-release barrier layer 2 and contains polyhexamethylene biguanide hydrochloride (PHMB) or chitosan-silver nanoparticle complex. The antibacterial coating 3 is fixed to the surface of the stent by plasma activation-chemical cross-linking method, and the PHMB loading amount is 0.5-5 mg / cm2. The shape of the stent is T-shaped, balloon-shaped or a uterine cavity-adaptive three-dimensional grid structure, and micropores (pore size 5-20 μm) are provided on the surface.

[0040] The specific working principle and method of use of the present invention are as follows:

[0041] S1, preparation of drug-loaded fibers: PLGA was dissolved in an organic solvent, estradiol powder was added, and a uniform spinning solution was obtained by magnetic stirring. The organic solvent was dichloromethane, the concentration of PLGA was controlled to be 20 wt%, and the 17β-estradiol powder accounted for 8 wt% of the PLGA solid mass. The magnetic stirring parameters were 600 rpm for 2 h, and the ultrasonic dispersion parameters were 40 kHz for 30 min;

[0042] S2, preparation of drug-loaded fiber membrane: a uniform spinning solution was prepared into a drug-loaded fiber membrane by electrospinning technology. The electrospinning parameters were: voltage 18-22 kV, injection rate 1.0 mL / h, receiving distance 15 cm, ambient temperature and humidity 25±2°C, RH <40%, spinning solution concentration 15-25 wt%, and receiving device was a high-speed rotating drum or aluminum foil, thereby producing a non-woven fiber membrane with a thickness of 80±10 μm and a fiber diameter of 1-2 μm.

[0043] S3, sustained-release membrane coating: spraying PCL solution on the surface of the drug-loaded fiber and drying to form a sustained-release barrier layer. The PCL solution is composed of PCL dissolved in chloroform with a concentration of 5 wt%. The spraying is carried out by spraying with a spray gun with a nozzle diameter of 0.3 mm. The drug-loaded fiber membrane surface is evenly sprayed three times, and dried for 5 minutes at intervals. The drying equipment is a vacuum drying oven, and the solution is cured in a vacuum environment at 60°C for 24 hours to form a 30±5 μm film.

[0044] S4, antibacterial coating construction, spraying PHMB solution on the surface of the sustained-release barrier layer, and curing the coating by UV crosslinking to form a dense sustained-release layer. The PHMB solution is a 2.5 wt% PHMB aqueous solution containing 0.1% polyethylene glycol viscosity enhancer. The specific steps of coating curing are as follows: immersing the stent in the PHMB solution (30 s) → taking it out and draining it, and UV crosslinking: wavelength 254 nm, intensity 10 mW / cm 2 , irradiation for 10 min, drying at 50°C → surface PHMB loading 2.0±0.3 mg / cm 2 ;

[0045] S5, stent molding: The composite film is hot-pressed into a T-shaped / balloon structure and sterilized by gamma ray. The hot-pressing molding steps are as follows: preheat the mold to 70°C (below the glass transition temperature (Tg) of PLGA), place the composite film into a T-shaped mold (suitable for uterine cavity: vertical arm length 30-35mm, horizontal arm width 20-25mm), apply pressure of 0.5MPa, maintain pressure for 5 minutes, then cool and demold.

[0046] S6, terminal sterilization, γ-ray irradiation: dose 25 kGy, temperature <40°C.

[0047] Example 1:

[0048] S1, preparation of drug-loaded fibers: PLGA (LA:GA = 75:25) was dissolved in dichloromethane, 17β-estradiol was added (17β-estradiol accounted for 8 wt% of the solid content), and magnetic stirring was performed to obtain a uniform spinning solution;

[0049] S2, electrospinning: voltage 20 kV, injection rate 1 mL / h, receiving distance 15 cm, ambient temperature and humidity 25 ± 2°C, RH < 40%, spinning solution concentration 15-25 wt%, forming an 80 μm thick non-woven fiber membrane on a high-speed rotating drum;

[0050] S3, sustained-release membrane coating: PCL was dissolved in chloroform to a concentration of 5 wt%. The PCL solution was loaded into a spray gun (nozzle diameter 0.3 mm) and evenly sprayed on the surface of the drug-loaded fiber membrane three times (with interval drying for 5 min). The membrane was then cured in a vacuum drying oven at 60 °C for 24 h to form a 30 μm sustained-release layer.

[0051] S4, antibacterial coating construction: 2.5 wt% PHMB aqueous solution (containing 0.1% polyethylene glycol viscosity enhancer) was prepared, the stent was immersed in the PHMB solution (30 s), removed and drained, and UV crosslinked at a wavelength of 254 nm and an intensity of 10 mW / cm 2 , irradiated for 10 min, dried at 50 °C, surface PHMB loading 2.0 ± 0.3 mg / cm 2 ;

[0052] S5, stent molding, hot pressing molding, preheating the mold to 70°C (lower than the glass transition temperature Tg of PLGA), pressurizing to 0.5 MPa, holding the pressure for 5 min, cooling and demolding, thereby hot pressing the composite film into a T-shaped stent (arm length 32 mm, width 24 mm);

[0053] S6, Sterilization, γ-ray irradiation: dose 25 kGy, temperature <40℃ γ-ray sterilization.

[0054] It should be noted that, in this document, relational terms such as first and second are used solely to distinguish one entity or operation from another, and do not necessarily require or imply any actual relationship or order between these entities or operations. Matters not described in detail in this specification are well known to those skilled in the art.

[0055] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in this industry can smoothly implement the present invention as shown in the drawings and described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of protection of the technical solution of the present invention.

Claims

1. A degradable drug sustained-release intrauterine anti-adhesion stent, comprising a drug-loaded core layer (1), a sustained-release barrier layer (2), and an antibacterial coating (3), wherein the drug-loaded core layer (1) is composited with a degradable polymer material and estrogen, wherein the degradable polymer material is PLGA, the estrogen is 17β-estradiol, and the estrogen loading is 1-10wt% of the total weight of the stent; the sustained-release barrier layer (2) wraps the drug-loaded core layer (1), the sustained-release barrier layer (2) is composed of a degradable film, and the antibacterial coating (3) covers the sustained-release barrier layer (2), and the antibacterial coating (3) is prepared from a polyhexamethylene biguanide hydrochloride (PHMB) solution; The preparation method comprises the following steps: S1, preparation of drug-loaded fibers: PLGA was dissolved in an organic solvent, estradiol powder was added, and a uniform spinning solution was obtained by magnetic stirring; S2, preparation of drug-loaded fiber membrane, using electrospinning technology to prepare uniform spinning solution into drug-loaded fiber membrane; S3, sustained-release membrane coating: spraying PCL solution on the surface of drug-loaded fibers and drying to form a sustained-release barrier layer; S4, antibacterial coating construction, spraying PHMB solution on the surface of the sustained-release barrier layer, and curing the coating by UV cross-linking; S5, stent molding: hot pressing the composite film into a T-shaped / balloon structure and sterilizing it with gamma rays; S6, terminal sterilization, γ-ray irradiation: dose 25 kGy, temperature <40°C.

2. The degradable drug-releasing intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S1, the organic solvent is dichloromethane, the concentration of PLGA is controlled to be 20 wt%, the 17β-estradiol powder accounts for 8 wt% of the PLGA solid mass, the magnetic stirring parameter is 600 rpm for 2 h, and the ultrasonic dispersion parameter is 40 kHz for 30 min.

3. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S2, the electrospinning parameters are: voltage 18-22 kV, injection speed 1.0 mL / h, receiving distance 15 cm, ambient temperature and humidity 25±2° C., RH<40%.

4. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S2, the spinning solution concentration is 15-25 wt%, and the receiving device is a high-speed rotating drum or aluminum foil, thereby generating a non-woven fiber membrane product with a thickness of 80±10 μm and a fiber diameter of 1-2 μm.

5. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S3, the PCL solution is prepared by dissolving PCL in chloroform with a concentration of 5 wt %. The solution is sprayed evenly on the surface of the drug-loaded fiber membrane three times with a nozzle diameter of 0.3 mm and then dried for 5 minutes.

6. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S3, the drying equipment is a vacuum drying oven, and the solidification is carried out in a vacuum environment at 60°C for 24 hours to form a 30±5 μm dense sustained-release layer.

7. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S4, the PHMB solution is treated to prepare a 2.5 wt % PHMB aqueous solution containing 0.1 % polyethylene glycol as a viscosity enhancer.

8. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S4, the specific steps of coating curing are as follows:

1. immersing the stent in the PHMB solution for 30 seconds; 2. Take out and drain, and crosslink with UV light: wavelength 254nm, intensity 10mW / cm 2 , irradiation for 10 min, drying at 50 ° C; 3. Surface PHMB loading 2.0 ± 0.3 mg / cm 2 .

9. The degradable drug-sustaining intrauterine anti-adhesion stent according to claim 1, characterized in that: In step S5, the hot pressing molding steps are specifically as follows:

1. preheating the mold to 70° C. and placing the composite film material into the T-shaped mold; 2. applying pressure of 0.5 MPa and maintaining the pressure for 5 minutes; 3. cooling and demoulding.

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