A high-permeability drug-coated balloon, its preparation method and application

Abstract

This invention discloses a high-permeability drug-coated balloon, its preparation method, and its application, belonging to the technical field of cardiovascular disease treatment materials. The preparation method includes the following steps: pre-treating sponge spicules, then sequentially placing them in sodium hydroxide solution and hydrochloric acid solution for ultrasonication, washing, and drying; preparing a silane coupling agent hydrolysate; preparing a sponge spicule dispersion; heating the sponge spicule dispersion and adding the silane coupling agent hydrolysate for stirring and reaction to obtain surface-modified sponge spicules; mixing the drug with the surface-modified sponge spicules and adding anhydrous ethanol for dispersion grafting to obtain drug-loaded sponge spicules; dissolving the drug-loaded sponge spicules in shellac ethanol solution for homogenization and spin coating, and drying to obtain the final product. This invention also discloses the high-permeability drug-coated balloon prepared by the above method and its application. The high-permeability drug-coated balloon of this invention has advantages such as low drug dosage, high-efficiency drug delivery, and low toxicity, and has broad application prospects.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of cardiovascular disease treatment materials, and particularly relates to a high-permeability drug coating balloon as well as a preparation method and application thereof. BACKGROUND

[0002] Cardiovascular diseases seriously endanger the health and safety of people, among which, atherosclerosis is one of important driving factors of cardiovascular diseases, and preventing and treating atherosclerosis is an important means to reduce the incidence of cardiovascular diseases. Drug-coated balloons (DCB) are a way of treating atherosclerosis by intervention without implantation, which can effectively avoid the risk of restenosis caused by material implantation, but due to blood flushing and drug residue and other factors, the drug utilization rate of DCB is not very high.

[0003] Sponges are ancient porous filter-feeding animals on earth, and the bone needles formed by biological mineralization in the sponges are called sponge spicules. The sponge spicules and skeletons together constitute the skeleton of the sponges and play a role in supporting the sponges. Studies have found that the sponge spicules have good mechanical properties, high mechanical strength, and sharp structures at the ends, which have a function similar to microneedles, can be retained in the stratum corneum for a long time to form a large number of microchannels, and effectively promote the absorption of drugs or active ingredients. At present, the researches mainly focus on the fields of optical properties, nanostructure, bionics and transdermal drug delivery.

[0004] As a unique biological material, the chemical properties and physical structures of the sponge spicules are incompatible with the drugs and coating materials used in the drug-coated balloons, which can cause uneven drug release, coating shedding or performance degradation. How to prepare a coating balloon with high drug utilization rate and high permeability is a necessary method to solve the problems existing in the treatment of drug-coated balloons. SUMMARY

[0005] The problems to be solved by the present application are to provide a high-permeability drug coating balloon as well as a preparation method and application thereof, to endow the drug coating balloon with low drug dosage, high-efficiency drug delivery and low toxicity and side effects, and to solve the problems of low drug utilization rate and high drug loss rate.

[0006] To solve the technical problems, a preparation method of a high-permeability drug coating balloon is provided, which comprises the following steps:

[0007] (1) After pretreatment, the sponge spicules are sequentially placed in a sodium hydroxide solution and a hydrochloric acid solution for ultrasonic treatment, washing and drying, to obtain sponge spicules with activated surface silicon hydroxyl groups;

[0008] (2) A silane coupling agent, water and anhydrous ethanol are mixed to prepare a silane coupling agent hydrolysis solution;

[0009] (3) mixing the sponge bone needle with surface silicon hydroxyl activated with anhydrous ethanol and ultrasonic, to obtain a sponge bone needle dispersion liquid;

[0010] (4) heating the sponge bone needle dispersion liquid and adding a silane coupling agent hydrolysis liquid to stir and react, washing and drying, to obtain a surface modified sponge bone needle;

[0011] (5) mixing the drug with the surface modified sponge bone needle and adding anhydrous ethanol to disperse and graft, to obtain a drug loaded sponge bone needle;

[0012] (6) dissolving the drug loaded sponge bone needle in a shellac ethanol solution to perform uniform glue spin coating, and after drying, a high permeability drug coating balloon is obtained.

[0013] The beneficial effects of the technical scheme of the present application are as follows: in the present application, the pretreated sponge bone needle is sequentially treated with sodium hydroxide and hydrochloric acid, the sodium hydroxide treatment can remove the oil stains and impurities on the surface of the sponge bone needle, and then the hydrochloric acid etching further cleans and increases the roughness of the surface of the bone needle, and introduces or enhances the presence of silicon hydroxyl (Si-OH), thereby providing active sites for subsequent chemical reactions; the sponge bone needle with surface silicon hydroxyl activated is uniformly dispersed in anhydrous ethanol, which helps to reduce the agglomeration of the sponge bone needle and improve the efficiency of the subsequent reaction; by heating the sponge bone needle dispersion liquid and adding a silane coupling agent, the hydrolysis product of the silane coupling agent is promoted to react with the silicon hydroxyl on the surface of the sponge bone needle, thereby firmly introducing the corresponding functional groups; then through the interaction between the drug groups and the corresponding functional groups, the effective loading of the drug on the surface of the sponge bone needle is realized, thereby improving the stability and targeting of the drug; finally, it is dissolved in a shellac ethanol solution, the shellac has good film forming property and biocompatibility, and as a coating material, it can protect the drug loaded sponge bone needle and control the release rate of the drug, and the high permeability drug coating balloon obtained ultimately is uniform, smooth, and has good sealing property and drug permeability.

[0014] Preferably, the step (1) comprises the following steps: grinding the sponge bone needle for 2-4 min and performing centrifugal treatment at 3500-4500 r / min, then placing it in a sodium hydroxide solution with a molar concentration of 1-4 mol / L for ultrasonic treatment for 30-40 min, washing and drying, then placing it in a hydrochloric acid solution with a volume concentration of 4-6% for ultrasonic treatment for 30-40 min, washing and drying, to obtain the sponge bone needle with surface silicon hydroxyl activated.

[0015] The sponge bone needle is ground to further break the size of the sponge bone needle, and different sizes of the sponge bone needles are separated by the centrifugal force, so that the sponge bone needle with a small size and a needle tip structure can be obtained.

[0016] More preferably, the step (1) comprises the following steps: the sponge bone needle is ground for 3 min and subjected to centrifugal treatment at 4000 r / min, then is placed in a sodium hydroxide solution with a molar concentration of 1 mol / L for ultrasonic treatment for 40 min, is washed and dried, is placed in a hydrochloric acid solution with a volume concentration of 5% for ultrasonic treatment for 40 min, is washed and dried, and the sponge bone needle with activated surface silicon hydroxyl is obtained.

[0017] Preferably, in the step (2), the silane coupling agent is (3-aminopropyl)triethoxysilane; and the volume ratio of the silane coupling agent, water and anhydrous ethanol is 1:1:5-7.

[0018] More preferably, in the step (2), the silane coupling agent is (3-aminopropyl)triethoxysilane; and the volume ratio of the silane coupling agent, water and anhydrous ethanol is 1:1:6.

[0019] Preferably, in the step (3), the material-liquid ratio of the sponge bone needle with activated surface silicon hydroxyl and anhydrous ethanol is 0.1 g:10-15 mL; and the ultrasonic treatment time is 10-20 min.

[0020] More preferably, in the step (3), the material-liquid ratio of the sponge bone needle with activated surface silicon hydroxyl and anhydrous ethanol is 0.1 g:13 mL; and the ultrasonic treatment time is 15 min.

[0021] Preferably, in the step (4), the heating temperature is 85-95 ℃; the volume ratio of the sponge bone needle dispersion liquid and the silane coupling agent hydrolysate is 10-15:5-10; the stirring reaction temperature is 55-65 ℃, and the time is 5-7 h.

[0022] More preferably, in the step (4), the heating temperature is 90 ℃; the volume ratio of the sponge bone needle dispersion liquid and the silane coupling agent hydrolysate is 13:8; the stirring reaction temperature is 60 ℃, and the time is 6 h.

[0023] Preferably, in the step (5), the mass ratio of the drug and the surface-modified sponge bone needle is 0.1:2-3; the dispersion grafting temperature is 25-30 ℃, and the time is 10-15 min.

[0024] More preferably, in the step (5), the mass ratio of the drug and the surface-modified sponge bone needle is 0.1:2.8; the dispersion grafting temperature is 30 ℃, and the time is 10 min.

[0025] More preferably, the drug is colchicine, pravastatin or paclitaxel; the drug grafting rate of the drug-loaded sponge bone needle is 6-7%.

[0026] The beneficial effects of the technical scheme of the present application are as follows: when the drug is colchicine, the amide in colchicine can be combined with the amino group on the modified sponge bone needle to realize the dispersion grafting of colchicine, and the specific process is as follows:

[0027]

[0028] More preferably, the drug grafting rate of the drug-loaded sponge bone needle is 6.955%.

[0029] Preferably, step (6) comprises the following steps: dissolving the drug-loaded sponge bone needle in a shellac ethanol solution with a mass concentration of 90-110 mg / mL, so that the mass concentration of the drug-loaded sponge bone needle is 9-10 mg / mL, to obtain a mixed solution; using a spin coater to spin coat the mixed solution at 300-500 r / min for 10-15 s, and then spin coat the mixed solution at 1500-2500 r / min for 25-35 s, and the high-permeability drug-coated balloon is obtained after drying.

[0030] More preferably, step (6) comprises the following steps: dissolving the drug-loaded sponge bone needle in a shellac ethanol solution with a mass concentration of 100 mg / mL, so that the mass concentration of the drug-loaded sponge bone needle is 9.5 mg / mL, to obtain a mixed solution; using a spin coater to spin coat the mixed solution at 350 r / min for 12 s, and then spin coat the mixed solution at 2000 r / min for 30 s, and the high-permeability drug-coated balloon is obtained after drying.

[0031] More preferably, the mass of the drug-loaded sponge bone needle on the high-permeability drug-coated balloon is 3 μg / mm 2 .

[0032] More preferably, the thickness of the high-permeability drug-coated balloon is 1-3 μm.

[0033] The present application also provides a high-permeability drug-coated balloon prepared by the above preparation method.

[0034] The present application also provides the use of the above high-permeability drug-coated balloon in the preparation of materials for treating atherosclerosis.

[0035] The present application has the following beneficial effects:

[0036] The high-permeability drug coating balloon of the application uses shellac as an excipient, which helps the adhesion of the drug-loaded bone needles and the balloon after mixing with the sponge bone needles, and when the drug coating balloon reaches the injury site, the sponge bone needles with good mechanical properties can penetrate into the intima of the blood vessel to form micropores and promote drug absorption, thereby improving the drug utilization rate. The high-permeability drug coating balloon of the application can increase the drug utilization rate by nearly 1.8 times, has the advantages of low drug dosage, high efficiency of drug administration and low toxic side effects, solves the problems of low drug utilization rate and drug loss, and has wide application prospect and practical value. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 It is a transmission electron micrograph of the bee sponge bone needle;

[0038] Figure 2 It is a 40 times optical microscope graph of the bee sponge bone needle after different pretreatments, wherein (a) is the bee sponge bone needle without pretreatment in the comparative example 4; (b) is the bee sponge bone needle pretreated in the comparative example 1; (c) is the bee sponge bone needle pretreated in the comparative example 2; (d) is the bee sponge bone needle pretreated in the example 1;

[0039] Figure 3 It is a 100 times optical microscope graph of the bee sponge bone needle pretreated in the example 1;

[0040] Figure 4 It is a 3D graph of the high-permeability drug coating balloon prepared in the example 1, wherein (a) is the Imaris 3D reconstructed image after confocal layer scanning; (b) is the coating thickness construction result graph of Imaris;

[0041] Figure 5 It is an Imaris reconstructed graph, wherein (a) is the 3D result graph of the hydrogel confocal layer scanning after the coating of the bone needle is administered; (b) is the 3D result graph of the hydrogel confocal layer scanning after the coating without bone needle is administered;

[0042] Figure 6 It is a result graph of the in-vitro drug release experiment of the drug-loaded sponge bone needle, wherein (a) is a standard curve graph of colchicine; (b) is a drug release curve graph of the drug-loaded sponge bone needle. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical scheme and advantages of the application more clear and obvious, the application will be further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain the application and are not used to limit the application, that is, the described examples are only a part of the examples of the application, but not all the examples.

[0044] Therefore, the following detailed description of the embodiments of the application provided is not intended to limit the scope of the claimed application, but merely represent selected embodiments of the application. Based upon the embodiments of the application, all other embodiments that would be obtained by one of ordinary skill in the art from the embodiments of the application, without having to do creative work, are within the scope of the application.

[0045] The features and performances of the application are further described in detail below in combination with the embodiments. The sponge spicules are Chondrocladia spicules, provided by Xi'an Misen Biological Technology Co., Ltd.; the shellac is provided by Shanghai Maikelin Biochemical Technology Co., Ltd.; and the colchicine is provided by Shanghai Yinn Chemical Technology Co., Ltd.

[0046] Embodiment 1

[0047] A preparation method of a high-permeability drug-coated balloon, comprising the following steps:

[0048] (1) After grinding the Chondrocladia spicules for 3 min and centrifuging at 4000 r / min, the Chondrocladia spicules are placed in a 1 mol / L sodium hydroxide solution for ultrasonic treatment for 40 min, washed with deionized water for 2 times and anhydrous ethanol for 1 time, and then dried in an oven at 37℃, and then placed in a 5% hydrochloric acid solution for ultrasonic treatment for 40 min, washed with deionized water for 2 times and anhydrous ethanol for 1 time, and then dried in an oven at 37℃, to obtain the sponge spicules with activated surface silicon hydroxyl groups;

[0049] (2) A silane coupling agent hydrolysis solution is prepared by mixing (3-aminopropyl) triethoxysilane, RO water and anhydrous ethanol according to a volume ratio of 1:1:6;

[0050] (3) 0.1 g of the sponge spicules with activated surface silicon hydroxyl groups is mixed with 13 mL of anhydrous ethanol and ultrasonically treated for 15 min, to obtain a sponge spicule dispersion;

[0051] (4) The sponge spicule dispersion is heated in a water bath under stirring, 8 mL of the silane coupling agent hydrolysis solution is added dropwise when the temperature is stabilized to 90℃, and then stirring reaction is performed at 60℃ for 6 h, and then the sponge spicules are washed with anhydrous ethanol for 3 times and deionized water for 1 time, and then dried in an oven at 37℃, to obtain the sponge spicules with surface amino modification;

[0052] (5) 0.005 g of colchicine is mixed with 0.14 g of the sponge spicules with surface amino modification, 2 mL of anhydrous ethanol is added, and then dispersed grafting is performed at 1000 r / min for 10 min at 30℃, and then stirring is performed at room temperature until the ethanol volatilizes, to obtain drug-loaded sponge spicules;

[0053] (6) Take 100 mg of shellac and dissolve it in 1 mL of anhydrous ethanol to obtain a shellac ethanol solution with a mass concentration of 100 mg / mL; dissolve the drug-loaded sponge bone needles in the shellac ethanol solution with a mass concentration of 100 mg / mL to obtain a mixed solution with a drug-loaded sponge bone needle mass concentration of 9.5 mg / mL; place the PU disc on the suction disc of a spin coater, tightly fix the PU disc on the suction disc by opening the vacuum pump, use a pipette to drop 100 μL of the mixed solution onto the center of the disc, start the spin coater, spin at 350 r / min for 12 s, and then spin at 2000 r / min for 30 s; dry in a 37℃ oven to obtain a high-permeability drug-coated balloon.

[0054] The high-permeability drug-coated balloon prepared by the preparation method has a drug grafting rate of 6.955% on the drug-loaded sponge bone needles, and the mass of the drug-loaded sponge bone needles on the high-permeability drug-coated balloon is 3 μg / mm 2 .

[0055] Example 2

[0056] A preparation method of a high-permeability drug-coated balloon, comprising the following steps:

[0057] (1) Grind the sponge bone needles for 2 min and centrifuge at 4500 r / min, then place them in a 4 mol / L sodium hydroxide solution and ultrasonic for 30 min, wash twice with deionized water and once with anhydrous ethanol, dry in a 37℃ oven, then place them in a 6% hydrochloric acid solution and ultrasonic for 30 min, wash twice with deionized water and once with anhydrous ethanol, dry in a 37℃ oven, to obtain sponge bone needles with activated surface silicon hydroxyl groups;

[0058] (2) Mix (3-aminopropyl) triethoxysilane, RO water and anhydrous ethanol according to a volume ratio of 1:1:5 to prepare a silane coupling agent hydrolysis solution;

[0059] (3) Mix 0.1 g of sponge bone needles with activated surface silicon hydroxyl groups with 10 mL of anhydrous ethanol and ultrasonic for 10 min to obtain a sponge bone needle dispersion;

[0060] (4) Under stirring, heat the sponge bone needle dispersion in a water bath, when the temperature is stable at 85℃, drop 5 mL of the silane coupling agent hydrolysis solution, then stir at 55℃ for 7 h, wash repeatedly with anhydrous ethanol 3 times and with RO water once, and dry in a 37℃ oven to obtain sponge bone needles with amino-modified surfaces;

[0061] (5) 0.005 g of colchicine was mixed with 0.10 g of surface amino-modified sponge bone needles and added to 1 mL of anhydrous ethanol, and dispersed grafting was carried out at 1000 r / min for 15 min at 30℃, and then stirring was carried out at room temperature until the ethanol volatilized, to obtain drug-loaded sponge bone needles;

[0062] (6) 90 mg of shellac was dissolved in 1 mL of anhydrous ethanol to obtain a shellac ethanol solution with a mass concentration of 90 mg / mL; the drug-loaded sponge bone needles were dissolved in the shellac ethanol solution with a mass concentration of 90 mg / mL to obtain a mixed solution with a drug-loaded sponge bone needle mass concentration of 9.5 mg / mL; the PU disc was placed on the suction disc of the spin coater, and the vacuum pump was opened to tightly fix the PU disc on the suction disc; 100 μL of the mixed solution was taken by a pipette and dropped onto the center of the disc; the spin coater was started, and spin coating was carried out at 300 r / min for 15 s and then at 1500 r / min for 35 s; after drying in a 37℃ oven, a high-permeability drug coating balloon was obtained.

[0063] Example 3

[0064] A preparation method of a high-permeability drug coating balloon, comprising the following steps:

[0065] (1) The bee sponge bone needles were ground for 4 min and centrifuged at 3500 r / min, then placed in a 2 mol / L sodium hydroxide solution and ultrasonicated for 40 min; washed twice with deionized water, once with anhydrous ethanol, and then dried in a 37℃ oven; then placed in a 4% hydrochloric acid solution and ultrasonicated for 30 min; washed twice with deionized water, once with anhydrous ethanol, and then dried in a 37℃ oven, to obtain surface silicon hydroxyl activated sponge bone needles;

[0066] (2) (3-Aminopropyl)triethoxysilane, RO water and anhydrous ethanol were mixed according to a volume ratio of 1:1:7 to prepare a silane coupling agent hydrolysis solution;

[0067] (3) 0.1 g of surface silicon hydroxyl activated sponge bone needles were mixed with 15 mL of anhydrous ethanol and ultrasonicated for 20 min, to obtain a sponge bone needle dispersion;

[0068] (4) The sponge bone needle dispersion was heated in a water bath under stirring, and when the temperature stabilized to 95℃, 10 mL of the silane coupling agent hydrolysis solution was added dropwise, and then stirring was carried out at 65℃ for 5 h; washed repeatedly with anhydrous ethanol 3 times and with RO water 1 time, and then dried in a 37℃ oven, to obtain surface amino-modified sponge bone needles;

[0069] (5) 0.005 g of colchicine was mixed with 0.15 g of surface amino-modified sponge bone needles and added to 2 mL of anhydrous ethanol, and dispersed grafting was carried out at 1000 r / min for 10 min at 30°C, and then stirring was carried out at room temperature until the ethanol evaporated, to obtain drug-loaded sponge bone needles;

[0070] (6) 110 mg of shellac was dissolved in 1 mL of anhydrous ethanol to obtain a shellac ethanol solution with a mass concentration of 110 mg / mL; the drug-loaded sponge bone needles were dissolved in the shellac ethanol solution with a mass concentration of 110 mg / mL to obtain a mixed solution with a drug-loaded sponge bone needle mass concentration of 9.5 mg / mL; the PU disc was placed on the suction disc of the spin coater, and the vacuum pump was turned on to tightly fix the PU disc on the suction disc; 100 μL of the mixed solution was taken by a pipette and dropped onto the center of the disc; the spin coater was turned on, and spin coating was carried out at 500 r / min for 10 s and then at 2500 r / min for 25 s; after drying in a 37°C oven, a high-permeability drug coating balloon was obtained.

[0071] Comparative Example 1

[0072] A method for preparing a high-permeability drug coating balloon, compared with Example 1, the difference is that step (1) is: the bee sponge bone needles are ground for 3 min and subjected to centrifugal treatment at 1000 r / min, then placed in a 1 mol / L sodium hydroxide solution and ultrasonicated for 40 min, washed with deionized water twice and anhydrous ethanol once, and then dried in a 37°C oven; then placed in a 5% hydrochloric acid solution and ultrasonicated for 40 min, washed with deionized water twice and anhydrous ethanol once, and then dried in a 37°C oven, to obtain surface silicon hydroxyl activated sponge bone needles; the remaining steps are the same as those of Example 1.

[0073] Comparative Example 2

[0074] A method for preparing a high-permeability drug coating balloon, compared with Example 1, the difference is that step (1) is: the bee sponge bone needles are ground for 3 min and subjected to centrifugal treatment at 2000 r / min, then placed in a 1 mol / L sodium hydroxide solution and ultrasonicated for 40 min, washed with deionized water twice and anhydrous ethanol once, and then dried in a 37°C oven; then placed in a 5% hydrochloric acid solution and ultrasonicated for 40 min, washed with deionized water twice and anhydrous ethanol once, and then dried in a 37°C oven, to obtain surface silicon hydroxyl activated sponge bone needles; the remaining steps are the same as those of Example 1.

[0075] Comparative Example 3

[0076] A preparation method of a high-permeability drug coating balloon, compared with example 1, the difference is that step (1) is: the bee sponge bone needle is ground for 3 min, then placed in a 1 mol / L sodium hydroxide solution, ultrasonic for 40 min, centrifugal washed with deionized water for 2 times, centrifugal washed with anhydrous ethanol for 1 time, then placed in a 37℃ oven for drying, then placed in a 5% hydrochloric acid solution, ultrasonic for 40 min, centrifugal washed with deionized water for 2 times, centrifugal washed with anhydrous ethanol for 1 time, then placed in a 37℃ oven for drying, to obtain the surface silicon hydroxyl activated sponge bone needle; the rest of the steps are the same as example 1.

[0077] Comparative example 4

[0078] A preparation method of a high-permeability drug coating balloon, compared with example 1, the difference is that step (1) is: the bee sponge bone needle is placed in a 1 mol / L sodium hydroxide solution, ultrasonic for 40 min, centrifugal washed with deionized water for 2 times, centrifugal washed with anhydrous ethanol for 1 time, then placed in a 37℃ oven for drying, then placed in a 5% hydrochloric acid solution, ultrasonic for 40 min, centrifugal washed with deionized water for 2 times, centrifugal washed with anhydrous ethanol for 1 time, then placed in a 37℃ oven for drying, to obtain the surface silicon hydroxyl activated sponge bone needle; the rest of the steps are the same as example 1.

[0079] Comparative example 5

[0080] A preparation method of a drug coating balloon, comprising the following steps:

[0081] 100mg of shellac is dissolved in 1mL of anhydrous ethanol to obtain a shellac ethanol solution with a mass concentration of 100mg / mL; 0.005g of colchicine is dissolved in the shellac ethanol solution with a mass concentration of 100mg / mL to obtain a mixed solution with a colchicine mass concentration of 9.5mg / mL; the PU disc is placed on the suction disc of the glue uniformizer, the vacuum pump is turned on to tightly fix the PU disc on the suction disc, 100μL of the mixed solution is sucked by the pipette and dropped onto the center of the disc, the glue uniformizer is turned on, and the disc is spin-coated at 350r / min for 12s and then at 2000r / min for 30s, and then dried in a 37℃ oven to obtain the drug coating balloon.

[0082] Experimental example

[0083] 1, the morphology of the bee sponge bone needle is analyzed by transmission electron microscope, as shown in Figure 1 , the bee sponge bone needle is a uniaxial bone needle, and the two ends are sharp needle-like structures.

[0084] 2. The bee sponge spicules of Examples 1 and 2 (pretreated by grinding and centrifuging) and Comparative Examples 4 (untreated) were observed and analyzed using an optical microscope. The spicule length was measured using ImageJ. The results are as follows: Figures 2-3 As shown. From Figure 2 The results of 40x optical microscopy showed that the size of the sponge spicule raw material (Comparative Example 4) ranged from 1 to 200 μm, with a small number of spicules measuring 1 to 5 μm in length; the size of the ground spicules centrifuged at 1000 r / min (Comparative Example 1) ranged from 1 to 80 μm, with a low density of spicules containing needle-like structures after fracture; the size of the ground spicules centrifuged at 2000 r / min (Comparative Example 2) ranged from 1 to 50 μm, with more than half of them lacking needle-like structures after fracture; the size of the ground spicules centrifuged at 4000 r / min (Example 1) ranged from 1 to 10 μm, and most of them contained needle-like structures after fracture; further observation of the ground spicules centrifuged at 4000 r / min (Example 1) using a 100x optical microscope revealed... Figure 3 As shown, most of the ground bone needles centrifuged at 4000 r / min exhibited a fine needle-like structure, with the size of the broken, needle-like bone needles being approximately 1–5 μm. Analysis results indicate that if the spongy bone needles are too long, a large amount of the bone needle coating will lie flat, failing to achieve a vertical position; if they are too short, they cannot penetrate the vascular intima, thus affecting the treatment effect. Grinding the bone needles for 3 minutes to break them into smaller pieces, followed by centrifugation at 4000 r / min, yields small spongy bone needles with a needle-like structure, which is beneficial for subsequent use.

[0085] 3. Confocal scanning was performed on the high-permeability drug-coated balloon prepared in Example 1, and the 3D layer scan was reconstructed using Imaris software. The results are as follows: Figure 4 As shown. From Figure 4 As can be seen in Figure (a), the surface of the high-permeability drug-coated balloon prepared by this invention is relatively uniform, the drug-loaded sponge needles are evenly distributed in the coating, and some of the drug-loaded sponge needles are vertical in the coating; Figure 4 As shown in (b), Imaris constructed a side view image to characterize the coating thickness; the coating thickness was measured using Image J, and the results showed that the average thickness of the high-permeability drug-coated balloon was 2.778 μm.

[0086] 4. Fluorescent carbon dots were used to replace colchicine in Example 1 and Comparative Example 5, and drug penetration analysis was performed on 15% GelMa hydrogel to simulate drug administration. After confocal chromatography, 3D reconstruction was performed using Imaris. ImageJ analysis of the average fluorescence intensity of the fluorescent carbon dots penetrating into the hydrogel showed that the fluorescence intensity of the hydrogel with the non-spiculated coating (Comparative Example 5) was 140.322, while the average fluorescence intensity of the hydrogel with the spiculated coating (Example 1) was 243.586, approximately 1.73 times that of the hydrogel without the spiculated coating. The results are as follows... Figure 5 As shown, the sponge bone needles in the coating can significantly promote drug penetration.

[0087] 5. To investigate whether the drug release from the prepared drug-loaded sponge bone needles (COL-SHS) at different time points meets the concentration requirements for the treatment of atherosclerosis, an in vitro drug release experiment was conducted on COL-SHS: 30 mg of COL-SHS was weighed and placed in 20 mL of 10% PBS buffer solution, and the solution was shaken at 37°C for drug release. At different time points (15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 30 h, 36 h, and 48 h), 6 mL of the drug release solution was collected and aliquoted into two centrifuge tubes. Then, 6 mL of PBS buffer solution was added to the drug release system. The absorbance of the drug release solutions obtained at different time points was measured using a UV spectrophotometer.

[0088] Because the solubility of colchicine (COL) differs significantly between ethanol and PBS solutions, it is necessary to determine the relationship between COL concentration and absorbance in PBS solvent before investigating the COL content in PBS solution. A colchicine standard solution was prepared using 10% PBS as the solvent, and the absorbance was measured at 350 nm. The relationship between the colchicine solution using PBS as the solvent and absorbance was obtained, as shown in the following figures. Figure 6 As shown in (a). Based on the colchicine solution standard curve using PBS as the solvent, the concentration of COL in the sample solution at different time points can be measured, and the drug release rate at each time point can be calculated using the following cumulative release rate formula:

[0089]

[0090] In the above formula, E r COL cumulative release rate, %; V e V0 is the PBS replacement volume, 6 mL; V0 is the total drug release volume, 20 mL; C i denoted as , where is the concentration of the released fluid at the time of the i-th replacement sampling; m is the mass of the drug contained in the drug-loaded bone needle; and n is the number of PBS replacements.

[0091] The COL-SHS in-vitro drug release curve was plotted with the drug release time as the horizontal coordinate and the measured cumulative release rate and drug release amount as the double vertical coordinates, and the results are shown in Table 1. Figure 6 (b) shown.

[0092] The cumulative drug release results show that the drug release amount of COL-SHS in PBS is slowly released with time, and the drug release tends to be stable after 30 h, the highest drug release amount is about 1358 μg, the highest cumulative drug release rate is about 60%, and the drug release effect is good.

[0093] The present application is illustrated according to the above examples, and it should be understood that the above examples do not limit the present application in any form, and any technical solutions obtained by equivalent replacement or equivalent transformation fall within the scope of the present application.

Claims

1. A method of making a high permeation drug coated balloon, characterized in that, The preparation method comprises the following steps: (1) the sponge bone needle is pretreated, and then is sequentially placed in a sodium hydroxide solution and a hydrochloric acid solution for ultrasonic treatment, washing and drying to obtain a sponge bone needle with activated surface silicon hydroxyl groups; (2) a silane coupling agent, water and anhydrous ethanol are mixed to prepare a silane coupling agent hydrolysis solution; (3) the sponge bone needle with activated surface silicon hydroxyl groups is mixed with anhydrous ethanol and is subjected to ultrasonic treatment to obtain a sponge bone needle dispersion solution; (4) the sponge bone needle dispersion solution is heated, and the silane coupling agent hydrolysis solution is added for stirring reaction, and then the sponge bone needle is washed and dried to obtain a surface-modified sponge bone needle; (5) a drug is mixed with the surface-modified sponge bone needle, and anhydrous ethanol is added for dispersion grafting to obtain a drug-loaded sponge bone needle; (6) the drug-loaded sponge bone needle is dissolved in a shellac ethanol solution for uniform coating and spin coating, and then is dried to obtain a high-permeability drug coating balloon.

2. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (1), the sponge bone needle is ground for 2-4 min and is subjected to centrifugal treatment at 3500-4500 r / min, and then is placed in a sodium hydroxide solution with a molar concentration of 1-4 mol / L for ultrasonic treatment for 30-40 min, and then is washed and dried, and then is placed in a hydrochloric acid solution with a volume concentration of 4-6% for ultrasonic treatment for 30-40 min, and then is washed and dried to obtain the sponge bone needle with activated surface silicon hydroxyl groups.

3. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (2), the silane coupling agent is (3-aminopropyl) triethoxysilane; and the volume ratio of the silane coupling agent, water and anhydrous ethanol is 1:1:5-7.

4. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (3), the material-to-liquid ratio of the sponge bone needle with activated surface silicon hydroxyl groups to anhydrous ethanol is 0.1 g:10-15 mL; and the ultrasonic treatment time is 10-20 min.

5. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (4), the heating temperature is 85-95 ℃; the volume ratio of the sponge bone needle dispersion solution to the silane coupling agent hydrolysis solution is 10-15:5-10; the stirring reaction temperature is 55-65 ℃, and the stirring reaction time is 5-7 h.

6. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (5), the mass ratio of the drug to the surface-modified sponge bone needle is 0.1:2-3; the dispersion grafting temperature is 25-30 ℃, and the dispersion grafting time is 10-15 min.

7. The method of claim 1 or 6, wherein the high permeability drug coating balloon is prepared by the steps of: The drug is colchicine, pravastatin or paclitaxel; and the drug grafting rate of the drug-loaded sponge bone needle is 6-7%.

8. The method of claim 1, wherein the high permeation drug coating balloon is prepared by the steps of: In the step (6), the drug-loaded sponge bone needle is dissolved in a shellac ethanol solution with a mass concentration of 90-110 mg / mL to obtain a mixed solution, in which the mass concentration of the drug-loaded sponge bone needle is 9-10 mg / mL; the mixed solution is spin coated by using a uniform coating machine at 300-500 r / min for 10-15 s and then at 1500-2500 r / min for 25-35 s, and then is dried to obtain the high-permeability drug coating balloon.

9. The high-permeability drug coating balloon prepared by using the preparation method in any one of claims 1-8.

10. The high-permeability drug coating balloon in claim 9 is used for preparing a material for treating atherosclerosis.

Images