Targeting balloon coating capable of prolonging release period in dynamic environment and preparation method thereof

Abstract

The invention relates to the technical field of medical instruments, in particular to a targeted balloon coating capable of prolonging the release period in a dynamic environment and a preparation method of the targeted balloon coating. The renaturable xerogel can be quickly rehydrated after being dried, and a temporary membrane is formed on the inner wall of a blood vessel to resist blood flow scouring. The exosome enhances the vascular endothelium targeting through RGD peptide targeted modification. The polydopamine-hyaluronic acid composite adhesion coating improves the flexibility and adhesion of the coating. Therefore, the drug retention rate within 1 hour after expansion is greater than or equal to 85%, and the vascular endothelium uptake efficiency of the RGD modified exosome is improved by 3 times.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a targeted balloon coating that prolongs the release cycle in a dynamic environment and its preparation method. Background Technology

[0002] In interventional vascular therapy, drug-coated balloons inhibit intimal hyperplasia by rapidly releasing drugs at the plaque site through balloon expansion, and allowing the drugs to continue to infiltrate the vessel wall after the balloon catheter is withdrawn. Drug-coated balloons not only offer advantages such as short drug release time and sustained inhibition of vascular smooth muscle cell proliferation, but also a large contact area and uniform drug release, resulting in good clinical efficacy. However, significant challenges remain in clinical application, including high drug loss rates during delivery, insufficient drug concentration at the target site due to blood flow washout during balloon expansion, and the inability of existing drug delivery systems to actively target vascular lesions. Therefore, improving drug delivery efficiency and targeting capability is a research hotspot in the field of interventional vascular medical devices.

[0003] Dry gel particles, due to their unique three-dimensional porous network structure, excellent biocompatibility, and intelligent responsiveness, have been applied in the field of drug sustained release. Through tunable cross-linking density and pore size, they achieve precise drug release from hours to months, significantly reducing burst release rates. Simultaneously, the lyophilization process provides excellent drug loading flexibility, protecting bioactive molecules while enabling hydrophobic drug loading. Exosomes, vesicles that are key mediators of intercellular communication, have a diameter of approximately 40-200 nm. Exosomes can be recognized by the host as "self," thus acting as active carriers to deliver certain cellular RNA, drug molecules, and other substances into cells. These vesicular bodies offer unique advantages as carriers, such as low immunogenicity, high stability, high efficiency in drug delivery to cells, and a stronger enhanced permeation and retention effect. Therefore, both exosomes and lyosomes have significant potential for future development in disease treatment.

[0004] Patent CN117771260A discloses a drug delivery system for adipose-derived mesenchymal stem cell exosomes loaded with icariin, utilizing the natural targeting properties of exosomes to deliver drugs. However, it does not address the problem of drug retention in dynamic blood flow environments and is only suitable for static lesions such as arthritis. Patent CN109925516A proposes an oxidized hyaluronic acid hydrogel loaded with exosomes for local sustained release from tumors. However, its hydrogel is not dried, failing to meet the instantaneous film-forming requirements of balloon expansion (gelation time 5-60 minutes), and the hydrogel is easily dissolved in the bloodstream, resulting in drug loss. Therefore, there is an urgent need to develop a targeted balloon coating that prolongs the release cycle in dynamic environments to solve the problems of high drug loss rates and lack of targeting in existing drug-coated balloons in clinical applications. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the existing technology, the primary objective of this invention is to provide a targeted balloon coating that prolongs the release cycle in a dynamic environment. This balloon coating utilizes the synergistic effect of drugs, exosomes, and dry gel particles to achieve targeted release and local sustained release of drugs in a dynamic blood flow environment, enabling hydrophobic drugs to better exert their anti-inflammatory, anticoagulant, antithrombotic, antiproliferative, and immunomodulatory functions.

[0006] The objective of this invention is achieved through the following technical solution: In a first aspect, the present invention provides a targeted balloon coating that prolongs the release cycle in a dynamic environment. The balloon coating includes an adhesive coating and a drug coating. The adhesive coating is composed of polydopamine and hyaluronic acid. The drug coating is composed of a drug, exosomes, and reversible dry gel particles. The drug coating is applied on the adhesive coating. In the drug coating, the drug is a hydrophobic drug, and the exosomes are targeted exosomes with surfaces modified by vascular endothelial targeting peptides. After loading the drug, the exosomes are embedded in the three-dimensional network of gel particles, and the drug coating is formed after drying.

[0007] Among them, the reversible dry gel particles hydrate and form a membrane in the blood vessel during balloon dilation, adhering closely to the inner wall.

[0008] Among them, the balloon coating achieves the synergistic effect of targeted release and sustained release of drugs in a dynamic blood flow environment.

[0009] The adhesive coating is used to adhere the drug coating to the surface of the balloon.

[0010] In some embodiments, optionally, the mass ratio of polydopamine to hyaluronic acid is 1:1 to 1:3, and the polydopamine and hyaluronic acid are treated with trehalose at a mass fraction of 3% to 10%.

[0011] The trehalose is used to protect the exosome activity, with an activity retention rate of ≥90% after freeze-drying, and to prevent the coating from cracking when the balloon is folded.

[0012] In some embodiments, the hydrophobic drug may optionally include tubulin inhibitors, mTOR inhibitors, and anti-inflammatory drugs.

[0013] Among them, the microtubule inhibitor drugs include paclitaxel and docetaxel.

[0014] The mTOR inhibitors include sirolimus, zotalimus, and everolimus.

[0015] The anti-inflammatory drugs mentioned include dexamethasone.

[0016] In some embodiments, the vascular endothelial targeting peptide may optionally be an RGD peptide.

[0017] The RGD peptide modification density is 0.5~2 nmol / mg. In some embodiments, optionally, the reversible dry gel particles hydrate within 30 seconds to form a temporary membrane of 1-10 μm, the temporary membrane having a porosity of 60%-80%, maintaining integrity for ≥1 hour under blood flow shear force ≤50 dyn / cm², and degrading for ≤72 hours.

[0018] The reversible dry gel particles can degrade on their own while ensuring long-term drug release, thus avoiding the risk of endothelial hyperplasia caused by retention.

[0019] In some embodiments, optionally, the reproducible dry gel particles are formed by drying a hydrogel after it has been left to stand in a curing solution with a mass fraction of 2%-8%. The hydrogel is made of a biocompatible and degradable material, which is one or a combination of chitosan and its derivatives, sodium alginate, polyvinyl alcohol, polycaprolactone, polylactic acid, hyaluronic acid, gelatin, collagen, and cyclodextrin.

[0020] The drying process is a method that minimizes damage to the drug and has high refolding efficiency. The drying process includes vacuum freeze-drying, vacuum heating drying, or the addition of a desiccant.

[0021] In some embodiments, the balloon coating may optionally possess anti-inflammatory, anticoagulant, antithrombotic, antiproliferative, and immunomodulatory functions.

[0022] Secondly, the present invention provides a method for preparing a targeted balloon coating that prolongs the release cycle in a dynamic environment, comprising the following steps: S1: Exosomes and drugs are mixed, and the mixture is subjected to freeze-thaw treatment using a freeze-thaw method. The freeze-thaw treatment involves freezing at -80°C for 2 hours and then thawing at 37°C for 1 hour, repeated 5-7 times. After freeze-thaw, the mixture is centrifuged, and the supernatant is discarded to obtain drug-loaded exosomes. S2: Mix the hydrogel with the drug-loaded exosomes, add the mixture to a solidification solution with a mass fraction of 2%-8%, let stand for 5-30 minutes, rinse, and centrifuge to obtain undried gel particles loaded with drug-loaded exosomes; S3: The undried drug-loaded exosome-laden gel particles are dried by vacuum freezing, vacuum heating, or by adding a desiccant. After drying, the drug-loaded exosome-laden gel particles are obtained. S4: Spread or spray the adhesive onto the surface of a specific balloon, and then immediately cover it with dry gel particles loaded with drug-loaded exosomes to obtain a drug coating.

[0023] In some embodiments, optionally, the mass ratio of the exosomes to the drug in method S1 is 1:0.2~2; the mass ratio of the hydrogel to the curing solution in method S2 is 1:0.2~1; and the dry gel particles obtained in method S3 are small particles of 30-40 μm, medium particles of 60-80 μm, and large particles of 100-150 μm.

[0024] In some embodiments, the thickness ratio of the drug-loaded exosomes to the adhesive coating may be 1:0.1 to 10.

[0025] Compared with existing technologies, this invention has the following advantages and effects: The reversible dry gel allows for rapid rehydration after drying, forming a temporary membrane on the vascular endothelium to resist blood flow erosion. Exosomes, through RGD peptide targeting modification, enhance endothelial targeting. The polydopamine-hyaluronic acid composite adhesive coating improves coating flexibility and adhesion. This results in a drug retention rate of ≥85% within 1 hour after dilation, and a 3-fold increase in endothelial uptake efficiency of RGD-modified exosomes. Detailed Implementation Example

[0026] This embodiment provides the preparation of adhesive coatings and pharmaceutical coatings.

[0027] 1.1 Preparation of Adhesive Coating Equal volumes of polydopamine solution (PDA, 2 mg / mL) and hyaluronic acid solution (HA, 1% w / v) were mixed at mass ratios of 1:1, 1:2, and 1:3. An equal volume of 10% (w / v) trehalose stock solution was added to the mixture to achieve a final concentration of 5% (w / v). The mixture was vortexed, allowed to stand in the dark for 30 minutes, and then sprayed onto the surface of the balloon. A drug-coated layer was then prepared for later use.

[0028] Table 1 shows the experimental design and test results for the preparation of the adhesive coating: Conclusion: The optimal overall performance is achieved when polydopamine:hyaluronic acid ratio is 1:2 and combined with 5% trehalose.

[0029] 1.2 Optimization of the exosome to drug mass ratio Mix the exosomes and drugs according to the table below to prepare a drug coating for later use.

[0030] Test methods: Encapsulation efficiency: Free drug was separated by ultracentrifugation and quantified by HPLC; Cell uptake: DiI-labeled exosomes were used to detect the fluorescence intensity of HUVEC cells by flow cytometry (normalized compared with the control group); Burst release rate: Drug-loaded exosomes were placed in PBS at 37℃ and the amount of drug released was detected after 1 h.

[0031] Table 2 shows the experimental design and test results for optimizing the exosome to drug mass ratio: Conclusion: When the mass ratio is 1:0.2~2, the encapsulation efficiency is significantly improved (≥78% vs. control 52%), and the burst release rate is reduced by more than 50%, demonstrating the necessity of this ratio range in balancing drug loading and release kinetics.

[0032] 1.3 Verification of the number of freeze-thaw cycles for exosomes and drugs Test methods: Drug loading efficiency: Exosomes were lysed after ultracentrifugation, and the drug content was quantified by HPLC (n=5); Exosome integrity: The proportion of CD63 positive exosomes was detected by flow cytometry (compared to the untreated group). Burst release rate: Drug-loaded exosomes were placed in PBS solution at 37°C, and the amount of free drug was detected by ultrafiltration and centrifugation after 1 hour.

[0033] Table 3 shows the experimental design and test results for verifying the number of freeze-thaw cycles of exosomes and drugs: Conclusion: When the number of freeze-thaw cycles is 5, 6 or 7, the drug loading efficiency is significantly improved, the exosomes are more intact, and the drug burst release rate within 1 hour is lower.

[0034] 1.4 Verification of the ratio of hydrogel to curing solution Test methods: Film integrity: morphology of lyophilized particles after rehydration was observed by scanning electron microscopy; Drug retention rate: residual drug was detected by HPLC after simulated balloon dilation (8 atm, 30 seconds).

[0035] Table 4 shows the experimental design and test results for verifying the ratio of hydrogel to curing solution: Conclusion: A ratio of 1:0.2 to 1 ensures sufficient but not excessive crosslinking, with a rehydration time ≤35 seconds and a drug retention rate ≥75% after expansion. Performance decreases significantly if the ratio exceeds this range.

[0036] 1.5 Screening of dry gel particle size Test methods: Coating uniformity: Thickness variation coefficient (CV value) was calculated by laser confocal scanning; Penetration depth: Distribution measurement of fluorescently labeled particles in an ex vivo blood vessel model.

[0037] Table 5 shows the experimental design and test results for screening the particle size of the dry gel: Conclusion: 30-150 μm particles balance coating uniformity (CV<15%) and tissue penetration requirements; beyond this range, coating quality or degradation rate fails to meet standards.

[0038] 1.6 Optimization of the ratio of drug-loaded exosomes to adhesive coating Test methods: Peeling force: ASTM D4541 standard test; Targeting efficiency: enrichment factor of exosome fluorescence signal in ex vivo blood vessel model (compared to non-targeted group).

[0039] Table 6 shows the experimental design and test results of the optimized ratio of drug-loaded exosomes to adhesive coating: Conclusion: A thickness ratio of 1:0.1 to 10 results in an adhesion force ≥0.38 N / cm and exosome activity ≥88%. Beyond this range, the stability or function of the coating is significantly reduced. Example

[0040] This embodiment provides a drug release curve of the dry gel hydration and a vascular adhesion strength test.

[0041] 2.1 Determination of drug release curve Experimental materials and grouping: 1) Test group: The composite coating prepared according to claim 7 (paclitaxel-loaded exosomes + RGD peptide modification + chitosan dry gel, the adhesive layer is polydopamine / hyaluronic acid mass ratio 1:2, treated with 5% trehalose).

[0042] 2) Control group 1: Paclitaxel exosome coating without added dry gel (others are the same as the test group).

[0043] 3) Control group 2: Paclitaxel dry gel coating without exosomes (others are the same as the test group).

[0044] Each group of coated samples (n=6) was placed in a dynamic release device, and PBS buffer (pH 7.4) at 37℃ was pumped in at a flow rate of 100 mL / min. The eluent was collected. The concentration of paclitaxel was detected by HPLC at 0.5 h, 12 h, 24 h, and 48 h (chromatographic conditions: C18 column, acetonitrile / water = 60 / 40, flow rate 1.0 mL / min, detection wavelength 227 nm). The cumulative release rate (%) was calculated, and the results are shown in Table 7. Table 7 Comparison of cumulative drug release rates among groups (mean ± SD) Conclusion: The burst release rate of the test group in the initial stage (0.5h) and early stage (8h) was significantly lower than that of the control groups (p<0.01), while the test group exhibited sustained-release characteristics within 48h, and the release rates were basically the same within 48h. Adding chitosan dry gel and exosomes can effectively prolong the release period of the drug coating without affecting the final release rate.

[0045] 2.2 Vascular Adhesion Strength Test Fresh porcine coronary arteries (diameter 3.0±0.5 mm) were taken, and each group of coated balloons (n=6) were inflated at a pressure of 6 atm for 30 seconds. The coating peel force (tensile rate 5 mm / min) was measured using a universal testing machine.

[0046] The results are as follows: 1) Test group: 0.47±0.03 N / cm (meets the requirement of claim 1 ≥0.4 N / cm) 2) Group without trehalose: 0.32±0.05 N / cm (visible cracks appeared in the coating) Conclusion: The polydopamine / hyaluronic acid adhesive layer combined with trehalose treatment significantly improved coating integrity (p<0.05). Example

[0047] This embodiment provides a comparison of drug retention rate and targeting in a simulated blood flow environment.

[0048] Experimental Methods: Samples from the test group, control group 1, and control group 2 prepared in section 2.1 were used. Using a parallel plate flow chamber system (shear force set at 50 dyn / cm²), the coated balloons (n=6) of each group were expanded and attached to the inner wall of the silicone vascular model, and continuously perfused with PBS at 37℃ for 1 hour. The perfusion fluid was collected, and the drug concentration was measured to calculate the drug retention rate of the coating. Simultaneously, sections of the vascular model were taken, and the distribution of Cy5-labeled paclitaxel was observed using a confocal microscope (excitation / emission wavelength: 649 / 670 nm).

[0049] Table 8 shows the results of the comparative experiment on drug retention rate and targeting in a simulated blood flow environment: Group Drug retention rate (%) Drug accumulation in the blood vessel wall (μg / cm²) test group 86.4±4.1 12.7±1.8 Control group 1 41.2±5.3 8.3±0.9 Control group 2 63.5±4.7 5.1±1.2 Conclusion: Dry gel particles loaded with drug-loaded exosomes can reduce drug delivery loss, concentrate drugs near the target site, and effectively prolong the duration of drug action. Example

[0050] The difference between the preparation of the adhesive coating and the drug coating provided in this embodiment and that in Example 1 is as follows: The polydopamine and hyaluronic acid are treated with 10% trehalose by mass.

[0051] The reversible dry gel particles hydrate within 30 seconds to form a 10 μm temporary membrane with a porosity of 80%.

[0052] The reproducible dry gel particles are formed by drying hydrogel after it has been left to stand in a curing solution with a mass fraction of 8% for 30 minutes.

[0053] The mass ratio of the exosomes to the drug is 1:2; the mass ratio of the hydrogel to the curing solution is 1:1; the resulting dry gel particles are small particles of 40 μm, medium particles of 80 μm, and large particles of 150 μm.

[0054] The thickness ratio of the drug-loaded exosomes to the adhesive coating is 1:10.

[0055] When the ratio approaches 1:10 (i.e., the adhesive layer is thicker): its advantage lies in maximizing the coating’s robustness and stability in dynamic environments. Example

[0056] The difference between the preparation of the adhesive coating and the drug coating provided in this embodiment and that in Example 1 is as follows: The polydopamine and hyaluronic acid are treated with 3% trehalose by mass.

[0057] The reversible dry gel particles hydrate within 30 seconds to form a 1 μm temporary membrane with a porosity of 60%. The reproducible dry gel particles are formed by drying hydrogel after it has been left to stand in a 2% (w / w) curing solution for 5 minutes.

[0058] The mass ratio of the exosomes to the drug is 1:0.2; the mass ratio of the hydrogel to the curing solution is 1:0.2; the resulting dry gel particles are small particles of 30 μm, medium particles of 60 μm, and large particles of 100 μm.

[0059] The thickness ratio of the drug-loaded exosomes to the adhesive coating is 1:0.1.

[0060] When the ratio approaches 1:0.1 (i.e., the adhesion layer is thinner): its advantage lies in maximizing drug loading.

Claims

1. A targeted balloon coating that prolongs the release cycle in a dynamic environment, characterized in that, The balloon coating comprises an adhesive coating and a drug coating. The adhesive coating is composed of polydopamine and hyaluronic acid. The drug coating is composed of a drug, exosomes, and reversible dry gel particles. The drug coating is applied over the adhesive coating. The drug in the drug coating is a hydrophobic drug, and the exosomes are targeted exosomes with surfaces modified by vascular endothelial targeting peptides. After loading the drug, the exosomes are embedded in the three-dimensional network of gel particles, and the drug coating is formed after drying.

2. The adhesive coating is used to adhere the drug coating to the surface of the balloon.

3. The targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The mass ratio of polydopamine to hyaluronic acid is 1:1 to 1:3, and the polydopamine and hyaluronic acid are treated with trehalose at a mass fraction of 3% to 10%.

4. The targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The hydrophobic drugs include tubulin inhibitors, mTOR inhibitors, and anti-inflammatory drugs.

5. The targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The vascular endothelial targeting peptide is the RGD peptide.

6. A targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The reversible dry gel particles hydrate within 30 seconds to form a temporary membrane of 1~10μm, the temporary membrane having a porosity of 60%~80%, maintaining its integrity for ≥1 hour under blood flow shear force ≤50 dyn / cm², and degrading for ≤72 hours.

7. The targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The reversible dry gel particles are formed by drying a hydrogel after it has been left to stand in a curing solution with a mass fraction of 2%-8%. The hydrogel is made of a biocompatible and degradable material, which is one or a combination of chitosan and its derivatives, sodium alginate, polyvinyl alcohol, polycaprolactone, polylactic acid, hyaluronic acid, gelatin, collagen and cyclodextrin.

8. The targeted balloon coating for extending the release cycle in a dynamic environment according to claim 1, characterized in that, The balloon coating has functions including anti-inflammatory, anticoagulant, antithrombotic, antiproliferative, and immunomodulatory effects.

9. A method for preparing a targeted balloon coating that prolongs the release cycle in a dynamic environment, as described in claims 1 to 6, characterized in that, Includes the following steps: S1: Exosomes and drugs are mixed, and the mixture is subjected to freeze-thaw treatment using a freeze-thaw method. The freeze-thaw treatment involves freezing at -80°C for 2 hours and then thawing at 37°C for 1 hour, repeated 5-7 times. After freeze-thaw, the mixture is centrifuged, and the supernatant is discarded to obtain drug-loaded exosomes. S2: Mix the hydrogel with the drug-loaded exosomes, add the mixture to a solidification solution with a mass fraction of 2%-8%, let stand for 5-30 minutes, rinse, and centrifuge to obtain undried gel particles loaded with drug-loaded exosomes; S3: The undried drug-loaded exosome-laden gel particles are dried by vacuum freezing, vacuum heating, or by adding a desiccant. After drying, the drug-loaded exosome-laden gel particles are obtained. S4: Spread or spray the adhesive onto the surface of a specific balloon, and then immediately cover it with dry gel particles loaded with drug-loaded exosomes to obtain a drug coating.

10. A method for preparing a targeted balloon coating that prolongs the release cycle in a dynamic environment, as described in claim 8, characterized in that, In method S1, the mass ratio of exosomes to the drug is 1:0.2~2; in method S2, the mass ratio of hydrogel to the curing solution is 1:0.2~1; and in method S3, the dry gel particles obtained are small particles of 30-40 μm, medium particles of 60-80 μm, and large particles of 100-150 μm.

11. The method for preparing a targeted balloon coating that prolongs the release cycle in a dynamic environment according to claim 8, characterized in that, The thickness ratio of the drug-loaded exosomes to the adhesive coating is 1:0.1~10.