Absorbable gelatin sponge embolization strip for fallopian tube interventional embolization

Abstract

The invention relates to an absorbable gelatin sponge embolism strip for fallopian tube interventional embolism, which comprises a composite matrix formed by crosslinking gelatin and chitosan through genipin, and the composite matrix has a two-stage pore structure; the embedded developing-degrading adjusting particles are dispersed; the anti-inflammatory drug units are fixed on the inner walls of the micropores through amido bonds. According to the structure, physical anchoring and drug sustained release are achieved through two-stage pores, the PLGA-barium sulfate particles provide a degradable developing function, and the anti-inflammatory drug is triggered to be released in a reducing environment. Compared with an existing stainless steel spring ring, the embolism strip can be completely degraded and absorbed, displacement risks and tissue reaction are avoided, developing is clear and free of interference, a controllable degradation period of 3-6 months can be achieved by adjusting the gelatin / chitosan proportion, and different temporary birth control requirements are met.

Description

Technical Field

[0001] The invention relates to the technical field of medical devices, in particular to an absorbable gelatin sponge embolization strip used for fallopian tube interventional embolization. Background Art

[0002] Tubal embolization is an interventional treatment for fallopian tube problems. Its principle is: by placing embolic materials, such as micro-coils, gel-like substances, etc. in the fallopian tubes, the fallopian tubes are blocked, thereby preventing the fluid in the fallopian tubes from entering the uterine cavity, avoiding the impact on embryo implantation, etc. It can also be used to block blood supply during tubal pregnancy to achieve the treatment goal.

[0003] At present, the commonly used embolic material in clinical practice is stainless steel coil, which has the following disadvantages: 1. There is a risk of displacement; 2. It may cause tissue reaction; 3. It interferes with imaging; 4. It is non-absorbable. Therefore, we propose an absorbable gelatin sponge embolic strip for fallopian tube interventional embolization. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide an absorbable gelatin sponge embolization strip for fallopian tube interventional embolization, which can effectively solve the problems raised in the above-mentioned background technology.

[0005] In order to solve the above problems, the technical solution adopted by the present invention is: an absorbable gelatin sponge embolization strip for fallopian tube interventional embolization, comprising: a composite matrix: composed of gelatin and chitosan in a mass ratio of 6:4-7:3, cross-linked with 0.5%-1.0% genipin to form a cylinder with a diameter of 1-3mm, a length of 10-30mm, and a dual-level pore structure; the dual-level pore structure of the composite matrix is divided into: Through macropores 100-200μm, porosity ≥85%, The drug storage micropores are 5-10μm, and the inner wall roughness Ra≤0.5μm; Development-degradation regulating microparticles: composed of PLGA wrapped with barium sulfate, with a particle size of 1-5 μm, dispersed and embedded in the pore network of the composite matrix, accounting for 3%-4% of the weight of the composite matrix, and the encapsulation method adopts other existing technologies such as emulsified solvent evaporation method or spray drying method; Anti-inflammatory drug unit: It is composed of dexamethasone and disulfide-crosslinked N-succinyl chitosan microspheres. The crosslinking reaction conditions adopt existing technology and are fixed to the inner wall of the drug storage micropores through amide bonds. When GSH ≥ 10 μM, the release rate is ≥ 4 times that of a neutral environment.

[0006] As a further preferred embodiment of the present invention, the molar ratio of lactic acid to glycolic acid in the PLGA is 85:15.

[0007] As a further preferred embodiment of the present invention, the disulfide bond density is 0.8 - 1.5 mmol / g.

[0008] As a further preferred embodiment of the present invention, the amide bond fixation is carried out by EDC / NHS-mediated coupling.

[0009] Compared with the prior art, the present invention provides an absorbable gelatin sponge embolization strip for fallopian tube interventional embolization, which has the following beneficial effects: The present invention promotes the ingrowth of fibroblasts through the dual-porosity of the composite matrix to form physical anchoring, avoiding the displacement of the embolization strip. The anti-inflammatory drug unit is triggered to release in the inflammatory environment, and the TNF-α inhibition rate reaches 85%, significantly reducing the tissue inflammatory response. The barium sulfate particles are evenly embedded in the pores by PLGA wrapping, and the imaging attenuation linearity R² = 0.97. The imaging during the operation is clear and disappears synchronously with the degradation of the material, without residual interference. The gelatin / chitosan matrix + PLGA particles are completely degradable, and the degradation rate at 3 months is 65%. The degradation rate can be controlled by adjusting the ratio of gelatin / chitosan, and it can meet the temporary contraception needs of 3 - 6 months. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 It is a schematic diagram of the material structure of the present invention; Figure 2 It is a schematic diagram of finding the fallopian tube embolization position under angiography; Figure 3 It is a schematic diagram of performing fallopian tube embolization of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0011] The following will describe the content of the present invention in conjunction with embodiments. It should be understood that the embodiments described in the present invention are used to more clearly illustrate the present invention, rather than limiting the scope of the present invention.

[0012] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values and individual point values of each range, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0013] Referring to Figures 1-3 , the present invention provides an absorbable gelatin sponge embolization strip for fallopian tube interventional embolization, including: Composite matrix: composed of gelatin and chitosan in a mass ratio of 6:4 - 7:3, crosslinked by 0.5% - 1.0% genipin to form a cylinder with a diameter of 1 - 3 mm and a length of 10 - 30 mm, and having a dual-porosity structure; the dual-porosity structure of the composite matrix is divided into: The through-hole has a diameter of 100 - 200 μm and a porosity of ≥ 85%, which is used for fibroblasts to grow in and form physical anchoring. The drug storage micropores have a diameter of 5 - 10 μm and an inner wall roughness Ra ≤ 0.5 μm, which are used to fix anti-inflammatory drug units. The imaging - degradation regulating microparticles: composed of PLGA - coated barium sulfate (particle size 1 - 5 μm), are dispersed and embedded in the pore network of the composite matrix, accounting for 3% - 4% of the weight of the composite matrix. The anti-inflammatory drug unit: composed of dexamethasone - crosslinked N - succinyl chitosan microspheres with disulfide bonds, is fixed to the inner wall of the drug storage micropores through amide bonds; the release rate is ≥ 4 times that in a neutral environment when GSH ≥ 10 μM.

[0014] As a further preferred embodiment of the present invention, the molar ratio of lactic acid to glycolic acid in the PLGA is 85:15.

[0015] As a further preferred embodiment of the present invention, the disulfide bond density is 0.8 - 1.5 mmol / g, and the GSH - triggering efficiency ≥ 90%.

[0016] As a further preferred embodiment of the present invention, the amide bond fixation is carried out by EDC / NHS - mediated coupling, and the bonding efficiency ≥ 85%.

[0017] As a further preferred embodiment of the present invention, it further includes VEGF microspheres crosslinked with phosphazene bonds (-P(=N - CH3)-N<), which are co - triggered for release at pH ≤ 6.0 and 37 °C.

[0018] As a further preferred embodiment of the present invention, the preparation method of the absorbable gelatin sponge embolization strip includes: Synthesis of disulfide - bond microspheres: N - Succinyl chitosan reacts with bis(N - succinimidyl) 3,3'-dithiodipropionate (DTSP) to form a disulfide - bond cross - linked network. Dexamethasone is loaded by dialysis (drug loading rate ≥ 80%). Matrix compounding: vacuum impregnation with PLGA - barium sulfate microparticles → activation of micropores with EDC / NHS → fixation of drug - loaded microspheres.

[0019] The operation steps are as follows: S1. Improve the preoperative examination, clarify the diagnosis, and exclude surgical contraindications.

[0020] S2. The patient lies supine on the operating table, is routinely disinfected and draped, and is locally anesthetized.

[0021] S3. Insert a catheter into the uterine cavity through the vagina and cervix, inject a contrast agent, and clarify the morphology, course, and hydrosalpinx of the fallopian tube.

[0022] S4. Selectively insert the microcatheter into the fallopian tube opening, deliver the absorbable gelatin sponge embolization strip to the appropriate position of the fallopian tube, and perform angiography again to confirm the effect of the absorbable gelatin sponge embolization strip.

[0023] S5. After the operation, observe whether there is bleeding at the puncture site. Generally, the patient needs to be observed for several hours to one day.

[0024] S6. Explain the post-operative precautions.

[0025] Post-operative precautions: S1. Rest for 1 - 2 weeks, avoid heavy physical labor and strenuous exercise; S2. Keep the vulva clean. Sexual intercourse and sitz baths are prohibited within 2 weeks after the operation to prevent infection; S3. Take antibiotics and other drugs as prescribed by the doctor to prevent infection for 3 - 5 days.

[0026] S4. There may be mild pain in the lower abdomen, a small amount of vaginal bleeding, etc., which generally will gradually relieve. If the symptoms are severe or do not relieve continuously, seek medical attention in time.

[0027] As a specific embodiment 1 of the present invention: The material parameters are as follows: Matrix: Gelatin: Chitosan = 6.5:3.5, crosslinked with 0.75% genipin; Particles: PLGA(85:15)-Barium sulfate (particle size 3μm, content 4%); Drug unit: Disulfide bond-crosslinked N-succinyl chitosan microspheres (disulfide bond density 1.2 mmol / g), loaded with dexamethasone (drug loading rate 85%); The preparation process is as follows: Step 1. Matrix molding: Gelatin / chitosan solution + 1% ammonium bicarbonate, directional freezing at -20°C → gradient pores (macropores 150μm / micropores 8μm); Step 2. Particle embedding: Vacuum impregnation of PLGA-barium sulfate dispersion (0.1MPa×30min) → pore filling rate 92%; Step 3. Drug fixation: Activate the inner wall of the micropores with EDC / NHS → form an amide bond with the carboxyl group of the drug-loaded microspheres (bonding efficiency 88%).

[0028] As a specific embodiment 2 of the present invention: The material parameters are as follows: Matrix: Gelatin: Chitosan = 6:4, crosslinked with 0.75% genipin, 40% chitosan. The proportion increase is expected to degrade slower than that in Embodiment 1 and is suitable for slightly longer-term birth control; Particles: PLGA(85:15)-Barium sulfate (particle size 3μm, content 4%); Drug unit: Disulfide-crosslinked N-succinyl chitosan microspheres (disulfide bond density 1.2 mmol / g), loaded with dexamethasone (drug loading rate 85%); The preparation process is as follows: Step 1, matrix forming: Gelatin / chitosan solution + 1% ammonium bicarbonate, directional freezing at -20°C → gradient pores (macropores 150 μm / micropores 8 μm); Step 2, particle embedding: Vacuum impregnation of PLGA-barium sulfate dispersion (0.1 MPa × 30 min) → pore filling rate 92%; Step 3, drug fixation: Activation of the inner wall of micropores with EDC / NHS → formation of amide bonds with the carboxyl groups of drug-loaded microspheres (bonding efficiency 88%).

[0029] This is a specific Example 3 of the present invention: The material parameters are as follows: Matrix: Gelatin:chitosan = 7:3, crosslinked with 0.75% genipin, 30% chitosan, the proportion is decreased compared with Example 1, and it is expected to degrade faster, suitable for short-term birth control; Particles: PLGA(85:15)-barium sulfate (particle size 3 μm, content 4%); Drug unit: Disulfide-crosslinked N-succinyl chitosan microspheres (disulfide bond density 1.2 mmol / g), loaded with dexamethasone (drug loading rate 85%); The preparation process is as follows: Step 1, matrix forming: Gelatin / chitosan solution + 1% ammonium bicarbonate, directional freezing at -20°C → gradient pores (macropores 150 μm / micropores 8 μm); Step 2, particle embedding: Vacuum impregnation of PLGA-barium sulfate dispersion (0.1 MPa × 30 min) → pore filling rate 92%; Step 3, drug fixation: Activation of the inner wall of micropores with EDC / NHS → formation of amide bonds with the carboxyl groups of drug-loaded microspheres (bonding efficiency 88%).

[0030] Rabbits were selected as the biological model for verification in the examples, the sample size was ≥10 per group, and the experimental data comparison table is as follows: Index Example 1 Example 2 Example 3 Ratio of gelatin to chitosan 6.5:3.5 6:4 7:3 Degradation rate at 3 months 65% ± 3% 50% ± 4% 80% ± 3% Degradation rate at 6 months 90% ± 5% 70% ± 5% 95% ± 2% GSH-triggered drug release rate Increased by 4.2 times Increased by 4 times Increased by 4.5 times Inhibition rate of TNF-a at 3 months (inflammatory model experiment) 85% ± 2% 88% ± 3% 82% ± 3% Developing attenuation linearity (X-ray attenuation calibration) R²=0.97 R²=0.96 R²=0.98 Recommended birth control duration 3-4 months 4-6 months 2-3 months Temporary birth control option Example 3 (short-term): High degradation rate (80% in 3 months), suitable for birth control for 2 - 3 months.

[0031] Example 1 (medium-term): Benchmark degradation rate (65% in 3 months), suitable for standard birth control for 3 - 4 months.

[0032] Example 2 (long-term): Low degradation rate (50% in 3 months), suitable for birth control for 4 - 6 months.

[0033] The technical solutions between various embodiments can be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions results in contradictions or is impossible to implement, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0034] The above are only the preferred embodiments of the present invention, and do not limit the patent scope of the present invention accordingly. Any equivalent structural transformation made under the inventive concept of the present invention by using the content of the specification and drawings of the present invention, or directly / indirectly applied in other related technical fields, is included in the patent protection scope of the present invention.

Claims

1. An absorbable gelatin sponge embolization strip for fallopian tube interventional embolization, characterized in that, Comprising: Composite matrix: composed of gelatin and chitosan in a mass ratio of 6:4 to 7:3, cross-linked by 0.5%-1.0% genipin to form a cylinder with a diameter of 1-3 mm and a length of 10-30 mm, and having a dual-porosity structure; the dual-porosity structure of the composite matrix is divided into: Through-pores with a diameter of 100-200 μm and a porosity of ≥85%, Drug-storing micropores with a diameter of 5-10 μm and an inner wall roughness Ra ≤ 0.5 μm; Imaging-degradation regulating microparticles: composed of PLGA-coated barium sulfate with a particle size of 1-5 μm, dispersed and embedded in the pore network of the composite matrix, accounting for 3%-4% of the weight of the composite matrix; Anti-inflammatory drug unit: composed of dexamethasone and N-succinyl chitosan microspheres cross-linked by disulfide bonds, and fixed to the inner wall of the drug-storing micropores through amide bonds.

2. The absorbable gelatin sponge embolization strip for fallopian tube interventional embolization according to claim 1, wherein, The molar ratio of lactic acid to glycolic acid in the PLGA is 85:

15.

3. The absorbable gelatin sponge embolization strip for fallopian tube interventional embolization according to claim 1, characterized in that, The disulfide bond density is 0.8-1.5 mmol / g.

4. The absorbable gelatin sponge embolization strip for fallopian tube interventional embolization according to claim 1, characterized in that, The amide bond fixation is carried out by EDC / NHS-mediated coupling.

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