Balloon catheter with microneedles and method of making same

Abstract

The present application relates to a kind of balloon catheter with microneedle and its preparation method, catheter includes catheter main body, balloon and drug-loaded microneedle, balloon is connected at the distal end of catheter main body, buffer layer is provided on the outer circumferential surface of balloon, drug-loaded microneedle is embedded in buffer layer, buffer layer when not being pressed or being pressed pressure is less than set value, drug-loaded microneedle is all located in buffer layer;Method includes pressing down buffer layer from drug-loaded microneedle tip, blows drug-loaded microneedle plane end, so that drug-loaded microneedle all enters buffer layer, buffer layer is attached on the surface of balloon, and balloon is completed folding with less than 4.5atm pressure.The size of balloon of the present application is small after folding, folding does not need to develop additional equipment and process, with great market value;Satisfy drug early burst release, later slow release;Residual microneedle after use will not cause secondary injury to medical workers and sanitation cleaning personnel.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical devices, and relates to a balloon catheter with microneedles for angioplasty operation. BACKGROUND

[0002] Obstruction of human body lumen is a common disease, such as peripheral artery disease (PAD), which generally refers to various arterial diseases other than coronary arteries and intracranial arteries. One of the main methods for treating PAD disease at present is angioplasty, and the instrument used is a balloon catheter. Through the balloon catheter, angioplasty is performed to shape the blood vessel passage, or the balloon catheter is used for pre-expansion, post-expansion, etc. to ensure the blood vessel passage when the stent is released.

[0003] In the process of performing angioplasty through the balloon catheter, the balloon will tear the stenosis of the blood vessel. After the operation is completed, the torn blood vessel wall will proliferate to form new stenosis. The current technology can inhibit the proliferation of the blood vessel through the drug on the drug-loaded balloon, but the ordinary drug-loaded balloon will have 20%-50% drug loss from contacting blood to reaching the lesion site, and such loss is unavoidable in the prior art.

[0004] Microneedle is a new technology emerging in recent years, which has the advantages of minimally invasive, painless, penetrating the epidermis, forming a small channel, and realizing controlled release of drugs. To solve the problem of drug loss in the delivery process of ordinary drug-loaded balloons, some schemes add microneedles to the existing balloon, which has the advantage of reducing drug loss during transportation and sending drugs into the tunica media of the blood vessel with smaller pressure.

[0005] The current microneedle balloon has several common problems. First, before the balloon enters the human body blood vessel, in order to pass through the lesion site while reducing the stimulation to the blood vessel, the balloon needs to be folded. The smaller the folding size, the better the passability. However, the microneedle in the prior art is directly connected to the surface of the balloon. In order to expose the microneedle when it reaches the lesion site, the microneedle needs to be shielded as much as possible after the balloon is folded, which is easy to cause the size of the folded balloon to be too large, so that the balloon cannot smoothly reach the lesion site, such as the patent with publication number CN113018660A. In addition, the microneedle balloon also needs to consider the front burst release and the later slow release of the drug, which is beneficial to the treatment of the disease. SUMMARY

[0006] An object of the present application is to provide a balloon catheter with microneedles,

[0007] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0008] The balloon catheter with microneedles comprises a catheter body, a balloon and drug-loaded microneedles, the balloon is connected to the distal end of the catheter body, a buffer layer is arranged on the outer circumferential surface of the balloon, the drug-loaded microneedles are embedded in the buffer layer, and the tip of one end of the drug-loaded microneedles faces away from the outer circumferential surface of the balloon, and when the buffer layer is not pressed or the pressure is less than a set value, all the drug-loaded microneedles are located in the buffer layer.

[0009] Preferably, the buffer layer is a sponge layer, which is non-toxic and has good biocompatibility.

[0010] Preferably, the apparent density of the buffer layer is 0.01-1.0 g / cm 3 , and more preferably, the apparent density of the buffer layer is 0.1-0.6 g / cm 3 .

[0011] Preferably, the average pore size of the buffer layer is 20 nm-1 mm, and more preferably, the average pore size of the buffer layer is 0.1 um-0.3 mm.

[0012] Preferably, the thickness of the buffer layer is 1 um-3 mm, and more preferably, the thickness of the buffer layer is 10 um-1 mm.

[0013] Preferably, the thickness of the buffer layer is 10 nm-1 mm larger than the length of the drug-loaded microneedles, so that even when the buffer layer is pressed, the drug-loaded microneedles can be located in the buffer layer, and more preferably, the thickness of the buffer layer is 0.1 um-0.1 mm larger than the length of the drug-loaded microneedles.

[0014] Preferably, when the buffer layer is under a pressure of 0-4.5 atm, the drug-loaded microneedles are located in the buffer layer, and the use pressure of the balloon in the blood vessel is usually 6-12 atm, so that the drug-loaded microneedles can be pressed out of the buffer layer and into the blood vessel during use.

[0015] Preferably, the drug-loaded microneedles comprise a microneedle body, the inside and surface of the microneedle body are provided with drugs for inhibiting epithelial cell proliferation, the drugs on the surface of the drug-loaded microneedles can achieve early burst release, and the drugs in the inside of the drug-loaded microneedles can achieve late sustained release with the dissolution of the drug-loaded microneedles.

[0016] The angle of the drug-loaded microneedle tip is preferably 5°-160°, and the sharper the angle of the drug-loaded microneedle tip, the more conducive to piercing into the blood vessel.

[0017] The center line of the drug-loaded microneedle is perpendicular to the outer surface of the balloon at least when the balloon is in a filled state, and all the drug-loaded microneedles are uniformly arranged in this manner to ensure that the tips of the drug-loaded microneedles are directed towards the blood vessel side.

[0018] The face of the drug-loaded microneedle towards the other end of the outer surface of the balloon is a plane, and the plane side of the drug-loaded microneedle is directed towards the balloon, thereby avoiding the drug-loaded microneedle piercing the balloon.

[0019] The catheter body comprises an outer tube and an inner tube arranged inside the outer tube, the distal end of the inner tube protrudes out of the distal end of the outer tube, the proximal end of the balloon is connected to the distal end of the outer tube, and the distal end of the balloon is connected to the distal end of the inner tube, thereby forming a filling channel in communication with the balloon between the outer tube and the inner tube.

[0020] Another object of the present application is to provide a preparation method of a balloon catheter with microneedles.

[0021] To achieve the above object, the technical scheme adopted by the present application is:

[0022] A preparation method of a balloon catheter with microneedles, comprising:

[0023] 1) preparing drug-loaded microneedles,

[0024] 2) arranging the drug-loaded microneedles, and then pressing a buffer layer from the tip of one end of the drug-loaded microneedles to make the tips of the drug-loaded microneedles pierce into the buffer layer,

[0025] 3) blowing the flat end of the other end of the drug-loaded microneedles by airflow to make all the drug-loaded microneedles enter the buffer layer,

[0026] 4) attaching the buffer layer embedded with the drug-loaded microneedles to the surface of the balloon, and the flat end of the other end of the drug-loaded microneedles is directed towards the outer surface of the balloon,

[0027] 5) folding the balloon, and the folding pressure is less than 4.5 atm.

[0028] The preparation of the drug-loaded microneedles comprises: mixing a drug for inhibiting epithelial cell proliferation into raw materials to form a shaped body, and coating the drug for inhibiting epithelial cell proliferation on the surface of the shaped body to form the drug-loaded microneedles.

[0029] Further preferably, the raw material of the drug-loaded microneedle is a degradable material selected from one or more of chitosan, sodium alginate, polyethylene glycol, PPDO, PLGA, PCL, PGA, PLLA, gelatin, PLA, and hyaluronic acid.

[0030] Preferably, the material of the buffer layer is sponge.

[0031] Thanks to the above technical solution, the present application has the following advantages compared with the prior art:

[0032] The folded size of the balloon of the present application is no different from the size of common balloon catheters on the market, and can be widely used in clinical cases, having strong applicability.

[0033] The present application can share existing balloon folding equipment, without the need to develop additional equipment and processes, having great market value.

[0034] The present application realizes burst release of drugs when the microneedle pierces the inner wall of the blood vessel at a minimum cost, and realizes sustained release of drugs after the microneedle balloon catheter is withdrawn from the body.

[0035] The microneedles remaining on the balloon catheter after use will be withdrawn to the inside of the buffer layer due to the recovery of the buffer layer, and will not cause secondary harm to medical workers and sanitation cleaning personnel. BRIEF DESCRIPTION OF DRAWINGS

[0036] FIG. 1 is a structural schematic diagram of the balloon catheter of the present application; Figure 1 FIG. 2 is a schematic diagram of the balloon of the present application;

[0037] FIG. 3 is a schematic diagram of the balloon of the present application; Figure 2a FIG. 4 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 1 ;

[0038] FIG. 5 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 2b FIG. 6 is a schematic diagram of the drug-loaded microneedle of the present application;

[0039] FIG. 7 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 3a FIG. 8 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 1 ;

[0040] FIG. 9 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 3b FIG. 10 is a schematic diagram of the drug-loaded microneedle of the present application;

[0041] FIG. 11 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 4a FIG. 12 is a schematic diagram of the drug-loaded microneedle of the present application;

[0042] FIG. 13 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 4b FIG. 14 is a schematic diagram of the drug-loaded microneedle of the present application;

[0043] FIG. 15 is a schematic diagram of the drug-loaded microneedle of the present application; Figure 5a , 5b FIG. 16 is a schematic diagram of the drug-loaded microneedle of the present application;

[0044] attached Figure 6 The drug release rate determination chart for the present application for seven consecutive days.

[0045] In the above drawings:

[0046] 10, outer tube; 11, inner tube; 12, inflation channel;

[0047] 2, balloon; 20, sponge layer;

[0048] 3, drug-loaded microneedle; 30, tip; 31, flat surface;

[0049] 4, blood vessel. DETAILED DESCRIPTION

[0050] The technical solutions of the present application will be described below in conjunction with the drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0051] In the description of the present application, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer" and the like indicate the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second", "third" are only for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0052] As shown in one of the balloon catheters with microneedles, including catheter body, balloon 2 and drug-loaded microneedle 3. Specifically: Figure 1 The catheter body includes an outer tube 10 and an inner tube 11 disposed inside the outer tube 10. The distal end of the inner tube 11 extends out of the distal end of the outer tube 10. The outer tube 10 and the inner tube 11 are coaxially arranged. The outer tube 10 is used to push the entire catheter body, and the inner tube 11 forms a guide wire channel inside. The inflation channel 12 is formed between the outer tube 10 and the inner tube 11.

[0053] The proximal end of the balloon 2 is connected to the distal end of the outer tube 10, and the distal end of the balloon 2 is connected to the distal end of the inner tube 11. The balloon 2 is in communication with the inflation channel 12 inside, and the balloon 2 is pressed through the inflation channel 12. The structure of the balloon 2 can be a flat balloon, as shown in

[0054] Figure 2a The distal end of the balloon 2 is connected to the distal end of the inner tube 11. The balloon 2 is in communication with the inflation channel 12 inside, and the balloon 2 is pressed through the inflation channel 12. The structure of the balloon 2 can be a flat balloon, as shown in Figure 2b ​​

[0055] In this embodiment, a buffer layer, specifically a sponge layer 20, is disposed on the outer peripheral surface of the balloon 2. The sponge layer 20 is non-toxic and has good biocompatibility. In this embodiment, the apparent density of the sponge layer 20 is 0.01-1.0 g / cm³. 3 With a concentration of 0.1-0.6 g / cm³ 3 The average pore size of the sponge layer 20 is 20nm-1mm, with 0.1um-0.3mm being preferred; the thickness of the sponge layer 20 is 1um-3mm, with 10um-1mm being preferred.

[0056] The drug-loaded microneedle 3 is embedded within the sponge layer 20. The drug-loaded microneedle 3 can be conical in shape, such as... Figure 3a As shown, a combination of conical and cylindrical shapes can also be used, such as... Figure 3b As shown. One end of the drug-loaded microneedle 3 is a pointed tip 30, with an included angle of 5°-160°. The sharper the included angle of the pointed tip 30, the easier it is to penetrate into the blood vessel. Preferably, the included angle of the pointed tip 30 is 10°-120°. The end face of the other end of the drug-loaded microneedle 3 is a plane 31. The centerline of the drug-loaded microneedle 3 is perpendicular to the outer surface of the balloon 2, and the plane 31 of the drug-loaded microneedle 3 faces the outer surface of the balloon 2, which avoids the drug-loaded microneedle 3 puncturing the balloon 2. On the contrary, the pointed tip 30 of the drug-loaded microneedle 3 faces away from the outer surface of the balloon, thus facing the blood vessel.

[0057] In this embodiment: when the sponge layer 20 is not compressed or the pressure is less than a set value, the drug-loaded microneedles 3 are all located within the buffer layer, specifically the pressure value of 0-4.5 atm. Specifically: when the balloon 2 is in a folded state (the common folding method is rolling, i.e., the balloon 2 is rolled up on the surface of the catheter body), the sponge layer 20 is compressed, but the folding pressure is less than the set value of 4.5 atm. At this time, the drug-loaded microneedles 3 are all located within the buffer layer. When the balloon 2 gradually inflates to full expansion, the sponge layer 20 is in its natural state and is not compressed. At this time, the drug-loaded microneedles 3 are also all located within the buffer layer. The thickness of the sponge layer 20 is 10 nm-1 mm greater than the length of the drug-loaded microneedles 3, so that even when the sponge layer 20 is subjected to a certain amount of compression, the drug-loaded microneedles 3 can still be all located within the sponge layer 20. Figure 4a As shown.

[0058] Typically, the inflated balloon 2 operates at a pressure of 6-12 atm within the blood vessel, while the sponge layer 20 experiences no more than 4.5 atm of pressure when the balloon 2 is folded. This folded pressure is significantly lower than the inflated pressure. In clinical use, the compression between the blood vessel and the balloon 2 causes the sponge layer 20 to be compressed, exposing the tip 30 of the drug-loaded microneedle 3 and allowing it to penetrate the blood vessel. Figure 4bAs shown, after the surgery, the balloon 2 is depressurized, and since the pull-out resistance of the drug-loaded microneedle 3 in the blood vessel is greater than the pull-out resistance of the drug-loaded microneedle 3 in the sponge layer 20, the drug-loaded microneedle 3 is pulled out of the sponge layer 20 and left in the blood vessel.

[0059] In the present embodiment: the drug-loaded microneedle 3 comprises a microneedle body, the inside and surface of the microneedle body are provided with the drug for inhibiting epithelial cell proliferation, and the drug on the surface of the drug-loaded microneedle 3 can achieve early burst release, while the drug inside the drug-loaded microneedle 3 achieves late sustained release with the dissolution of the drug-loaded microneedle 3.

[0060] The preparation method of the present embodiment is specifically introduced as follows, which specifically comprises the following steps:

[0061] First, the drug-loaded microneedle 3 is prepared, and the raw material of the drug-loaded microneedle 3 can be a degradable material, including but not limited to chitosan, sodium alginate, polyethylene glycol, PPDO, PLGA, PCL, PGA, PLLA, gelatin, PLA, hyaluronic acid, and the like. After mixing the drug for inhibiting epithelial cell proliferation in the raw material, a shaped body is formed, and then a drug for inhibiting epithelial cell proliferation is coated on the surface of the shaped body to form the drug-loaded microneedle 3.

[0062] Subsequently, the drug-loaded microneedle 3 is arranged, and then the sponge layer 20 is pressed from the tip 30 at one end of the drug-loaded microneedle 3, so that the tip 3 of the drug-loaded microneedle 3 pierces into the sponge layer 20, as shown in Figure 5a As shown, the plane end of the drug-loaded microneedle 3 is blown by air flow, so that the drug-loaded microneedle 3 enters the sponge layer 20 completely, as shown in Figure 5b .

[0063] Then, the sponge layer 20 embedded with the drug-loaded microneedle 3 is adhered to the surface of the balloon 2 by medical quick-drying adhesive 4011, and the plane 30 of the drug-loaded microneedle 3 faces the outer surface of the balloon 2. In order to facilitate the adhesion of the sponge layer 20, the balloon 2 can be in a filled state.

[0064] Finally, the balloon 2 is folded by a balloon folding machine, and the folding pressure is controlled to be less than 4.5 atm.

[0065] Embodiment:

[0066] The sponge layer 20 is made of polyvinyl formal (PVF) medical sponge, and the apparent density of the sponge layer 20 is 0.5 g / cm 3 , the average pore size is 0.2 mm, and the height is 0.01 mm.

[0067] The drug-loaded microneedle 3 is in a conical structure, with a height of about 0.005 mm, and the angle of the tip 30 is 90 degrees. The drug-loaded microneedle 3 is made of PGA, and the blended drug is paclitaxel. The mass ratio of PGA to paclitaxel is 30:1, and at the same time, the surface of the drug-loaded microneedle 3 is covered with a layer of paclitaxel drug, with a thickness of 1 um.

[0068] The balloon catheter prepared by the preparation method of the present embodiment is tested for the size after folding compared with the size of a common vascular intervention balloon after folding, and the results are shown in the following table:

[0069] Balloon outer diameter / length mm Microneedle-bearing balloon collapsed outer diameter size mm Plain balloon collapsed outer diameter size mm 6.0*100 1.1 mm 1.1 mm

[0070] As shown in the above table, when the balloon catheter is folded, the gap existing in the folding of a common balloon is eliminated by extruding the sponge layer. Even if the sponge layer is added, the volume after folding using the same folding device and the same pressure does not exceed the volume of the common balloon after folding.

[0071] The prepared balloon catheter is subjected to continuous seven-day drug release rate determination, and the results are shown in Figure 6 .

[0072] The above embodiments are only for illustrating the technical concept and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made in accordance with the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A method for preparing a balloon catheter with microneedles, characterized in that: The balloon catheter with microneedles includes a catheter body, a balloon, and drug-loaded microneedles. The balloon is connected to the distal end of the catheter body. A buffer layer made of sponge is disposed on the outer peripheral surface of the balloon. The drug-loaded microneedles are embedded in the buffer layer, with the tip of one end of the microneedles pointing away from the outer peripheral surface of the balloon. When the buffer layer is not compressed or the pressure is less than a set value, the drug-loaded microneedles are entirely located within the buffer layer. The preparation method includes: 1) Preparation of drug-loaded microneedles 2) After arranging the drug-loaded microneedles, press a buffer layer down from the tip of one end of the drug-loaded microneedle, causing the tip of the drug-loaded microneedle to pierce into the buffer layer. 3) By blowing airflow onto the flat end of the drug-loaded microneedle, the entire drug-loaded microneedle is allowed to enter the buffer layer. 4) Attach the buffer layer containing the drug-loaded microneedles to the surface of the balloon, with the flat surface of the other end of the drug-loaded microneedles facing the outer surface of the balloon. 5) The balloon is folded with a folding pressure of less than 4.5 atm.

2. The preparation method according to claim 1, characterized in that: The preparation of the drug-loaded microneedles includes: mixing a drug that inhibits epithelial cell proliferation into the raw materials and forming a molded body, and coating the surface of the molded body with the drug that inhibits epithelial cell proliferation to form drug-loaded microneedles.

3. The preparation method according to claim 2, characterized in that: The raw material for the drug-loaded microneedles is a biodegradable material selected from one or more of chitosan, sodium alginate, polyethylene glycol, PPDO, PLGA, PCL, PGA, PLLA, gelatin, PLA, and hyaluronic acid.

4. The preparation method according to claim 1, characterized in that: The apparent density of the buffer layer is 0.01-1.0 g / cm³. 3 ; and / or The buffer layer has an average pore size of 20 nm to 1 mm; and / or The thickness of the buffer layer is 1µm-3mm.

5. The preparation method according to claim 1, characterized in that: The thickness of the buffer layer is 10 nm to 1 mm greater than the length of the drug-loaded microneedles.

6. The preparation method according to claim 1, characterized in that: When the buffer layer is under a pressure of 0-4.5 atm, all the drug-loaded microneedles are located within the buffer layer.

7. The preparation method according to claim 1, characterized in that: The drug-loaded microneedle includes a microneedle body, the interior and surface of which are provided with drugs that inhibit the proliferation of epithelial cells.

8. The preparation method according to claim 1, characterized in that: The included angle of the tip of the drug-loaded microneedle is 5°-160°.

9. The preparation method according to claim 1, characterized in that: At least when the balloon is inflated, the centerline of the drug-loaded microneedle is perpendicular to the outer surface of the balloon.

10. The preparation method according to claim 1 or 9, characterized in that: The surface of the drug-loaded microneedle facing the other end of the outer surface of the balloon is a plane.

11. The preparation method according to claim 1, characterized in that: The catheter body includes an outer tube and an inner tube inserted inside the outer tube. The distal end of the inner tube extends out of the distal end of the outer tube. The proximal end of the balloon is connected to the distal end of the outer tube, and the distal end of the balloon is connected to the distal end of the inner tube. An inflation channel communicating with the balloon is formed between the outer tube and the inner tube.

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