WO2014044082A1

WO2014044082A1 - Arsenic trioxide controllable-releasing balloon and preparing method thereof

Info

Publication number: WO2014044082A1
Application number: PCT/CN2013/080528
Authority: WO
Inventors: 霍勇; 马晓意; 马丽娟
Original assignee: 北京美中双和医疗器械有限公司
Priority date: 2012-09-21
Filing date: 2013-07-31
Publication date: 2014-03-27
Also published as: CN102974026A

Abstract

An arsenic trioxide controllable-releasing balloon and a preparing method thereof. The arsenic trioxide and a slow-releasing layer are coated on the surface of the balloon. Even minitype concave holes (21) which restrain releasing of the arsenic trioxide are formed on the slow-releasing layer. The size of the concave holes (21) is adjusted, so that the concave holes (21) are expanded to form micro holes in the process of expanding the balloon, the arsenic trioxide is quickly released on a vascular wall and is evenly distributed on the surface of the vascular wall, thereby further restraining cell proliferation, and achieving the effect of restraining vessel restenosis.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a drug balloon, and more particularly to a arsenic trioxide controlled release balloon for PTCA surgery and a bare stent and a preparation method thereof. BACKGROUND ART Arsenic trioxide (As ₂ 0 ₃ ) is a main component of traditional Chinese medicine arsenic, and it has been used for treating various diseases such as malignant tumors in medical research in China.

As a drug, natural arsenic compounds have been used in China for more than a thousand years. In the 1970s, blood physicians used As ₂ 0 _{3 to} treat promyelocytic leukemia, and achieved remarkable results. In recent years, As ₂ 0 ₃ has also been used for the treatment of solid tumors. Zhang Zhuoqi et al. and Shao Jianwei et al. found that it has anti-proliferative, pro-apoptotic and cell cycle-blocking effects on VSMCs, which may be important for reducing the number of cells in the neointima in the vascular stent implantation site and reducing the thickness of the intima. significance.

Coronary Atherosclerotic Heart Disease (coronary heart disease) is the most common type of heart disease. It is caused by abnormal lipid metabolism in the body, which causes the lipid in the blood to settle on the smooth inner membrane of the artery. Less and more accumulation of plaques, these plaques gradually increase the arterial stenosis, blood flow is blocked, resulting in cardiac ischemia, angina, and even sudden death.

Percutaneous Transluminal Coronary Angioplasty is a cardiac catheter technique, multi-finger coronary balloon dilatation, which is the most mature interventional technique for all coronary heart disease. Specifically, through the femoral artery at the base of the thigh or the radial artery on the wrist, a balloon catheter, a stent or other instruments are placed into the coronary artery through vascular puncture to achieve the purpose of relieving coronary artery stenosis and reconstruct coronary flow.

Drug Coated Balloon is a catheter-delivered drug delivery device. This concept was proposed by Harvey Wolinsky in 1991 to prevent restenosis after vascular balloon dilation. The mechanism of action is to inhibit the proliferation of the intima of the blood vessel by carrying the drug. When the drug coated on the surface of the balloon reaches the lesion, the balloon is expanded by pressurizing the balloon, and the drug is coated at the same time. This is sustained release, allowing the blood vessel wall to take up the drug sufficiently to inhibit the occurrence of restenosis. The drug balloon method eliminates the need for radiation therapy and allows the drug to be delivered to all areas of the balloon without the use of polymers or other sustained release techniques.

At present, most common drug balloons are paclitaxel and rapamycin as drug coatings, of which paclitaxel is the first Applied to the drug balloon, it was found that the uptake and bioavailability of the blood vessel wall after paclitaxel single exposure was significantly higher than that of rapamycin, so the paclitaxel drug balloon was also marketed earlier in Europe. In 2004, Dr. Scheller published an animal experiment on the effective prevention of restenosis in drug balloons in (: ir _CU lati _0n ), the clinical trial results of the PACC0CATH drug balloon, which showed that the paclitaxel drug balloon is in common with the normal balloon. In terms of late lumen loss, restenosis rate, and major cardiovascular event rates, drug balloons are superior to ordinary balloons.

Studies have also shown that the obvious advantages of drug balloons are mainly reflected in the treatment of in-stent restenosis. Whether it is to treat restenosis of bare stents or restenosis of drug-coated stents, the advantages of drug balloons have been recognized. The balloon carries as much drug as possible, while ensuring that the drug is not washed away by the flowing blood during the delivery of the balloon through the catheter to the lesion, becoming a key bottleneck restricting the development of technology in the field, high-dose paclitaxel drug balloon Balloons coated with new drugs are also under study and have important research significance.

As ₂ 0 ₃ is a water-soluble drug. Due to the difference in solubility of the commonly used polymer carrier, the drug and the carrier are two-phase separated during the spraying process, such as the arsenic trioxide spraying technology disclosed in CN200510023714. 5 patent and CN1413594A patent. , the agent and the carrier are mixed in a solvent and sprayed together. However, As ₂ 0 _{3 has a high} density and is easy to precipitate, so that the content and uniformity of the drug after spraying are limited, and irregular channels are formed between the drugs in the polymer coating, which makes the stability of drug release difficult to control. The inhibition effect of restenosis is poor, and the risk of clinical treatment is increased, so the drug release control of the ideal and effective drug balloon is necessary.

At present, the existing drug balloons generally use paclitaxel, rapamycin, heparin and the like as drugs, such as patent 20101239216A, 200920205723. X, 200910084768. 0, 200710150413. 8, also in the balloon material into the pharmaceutical ingredients, so that It gradually releases drugs, such as the international application W08911882A. Some of the balloon's spherical structure is unique in design, and the outer surface of the balloon is designed to have a non-planar structure with irregularities to enhance drug adsorption, or to use the balloon's own three-fold fold or Four-fold folding, forming a drug storage chamber at the flap, such as patent 201010121627. 4, 200920268650. 9, also changing the main structure of the balloon catheter, changing the traditional balloon structure into an eccentric hollow balloon catheter, or forming A plurality of lumen balloon catheters have a guidewire lumen, a balloon expansion lumen, and a drug delivery lumen, such as patent 201010520201. 6, 201110261928. However, in the above patents, the arsenic trioxide drug is discarded in the drug selection, and its application in the field is still a blank, and the drug is located on the surface of the coating, so that the drug of the balloon product itself has non-intraoperative drugs. Loss and uneven administration, at the same time, changes in the structure of the balloon sphere also increase the risk of the product used in clinical surgery, thus affecting the therapeutic effect of the product.

Therefore, existing drug balloons are not well suited to the needs of clinical use. It can be seen that there is still a need for a convenient, efficient and cost-effective drug balloon in the market.

Thus, the inventors have proposed a controllable release of arsenic trioxide and a preparation method thereof by virtue of years of experience and practice in related industries to overcome the drawbacks of the prior art. SUMMARY OF THE INVENTION An object of the present invention is to provide a controlled release arsenic trioxide balloon and a preparation method thereof, which are coated with a polymer coating on the surface of the balloon body, and have a concave pore structure on the surface of the polymer coating layer. The arsenic trioxide drug is sprayed on the arsenic trioxide drug particles to fill the concave pores, so that the adsorption amount of the arsenic trioxide drug is greatly improved, and the loss rate of the drug carried by the balloon is greatly reduced during the balloon transportation process. .

Another object of the present invention is to provide a controlled release arsenic trioxide balloon and a preparation method thereof, which can be effectively used in PCTA surgery and in combination with a bare stent, and is a convenient, efficient and cost-effective drug balloon.

The object of the present invention is achieved by a controlled release arsenic trioxide balloon, wherein the arsenic trioxide controlled release balloon comprises: a balloon body, a arsenic trioxide drug, and a polymer coating for controlling the release of arsenic trioxide drug, wherein the polymer The surface of the coating has concave holes, and only arsenic trioxide is released quickly during the expansion process.

In a preferred embodiment of the present invention, the polymer coating is sprayed on the surface of the balloon body, the surface of the polymer coating has a plurality of concave holes, and the plurality of concave holes are spaced apart from each other, and the arsenic trioxide drug particles are sprayed on the polymerization. On the coating, the arsenic trioxide drug particles are filled in a plurality of recessed holes, and the arsenic trioxide drug particles in each recess form an independent particle group, so that the drugs are isolated from each other, like "islands", making the drug controllable freed.

00 ug/mm ² , The arsenic trioxide content is 0. 10-2. 00 ug/mm ² , The ratio of the weight of the arsenic trioxide is 0. 50-1. 00 ug / mm ² ; the ratio of the weight of the arsenic trioxide drug to the weight of the polymer coating is 0.1. 9. 9 to 9. 9 : 0. 00 00 um, preferably particle size size. 01至50. 00 um, the optimum particle size is 0. 05-50. 00 um

In a preferred embodiment of the invention, the polymer coating is made of a degradable material or a non-degradable material.

In a preferred embodiment of the present invention, the polymer coating is made of one of polyurethane and a copolymer thereof. In a preferred embodiment of the invention, the material of the balloon body is a nylon or nylon elastomer.

In a preferred embodiment of the invention, the plurality of recessed holes in the surface of the polymer coating layer are needled recessed holes; and the balloon has a vacuum flap.

In a preferred embodiment of the present invention, the coating surface recesses distributed balloon 4-8 / mm ^2; recesses 0. 08-025 distance from each other.

The controllable release of arsenic trioxide is rapid release of arsenic trioxide in a short period of time during expansion. After the balloon is delivered to the lesion, when the balloon is pressurized at not less than 6 atm, the release of arsenic trioxide is not less than 40% of the total content, when the balloon pressure is not lower than 10 atm, the arsenic trioxide drug release amount is not less than 80% of its total content. When the balloon pressure is not lower than 14 atm, the arsenic trioxide drug release amount is not lower than the total content. 90%

The arsenic trioxide controlled release balloon, the polymer coating coated on the surface of the balloon body can expand together with the balloon body during the pressure expansion process due to certain ductility and elastic properties, the surface of the polymer coating The recessed hole is torn and expanded under this condition, and the arsenic trioxide drug particles encapsulated in the recessed hole are released into the blood vessel and taken up by the blood vessel wall. When the balloon decompression folds are withdrawn, the polymer coating is also removed by wrinkles.

The object of the present invention can also be achieved by a method for preparing a controllable release of arsenic trioxide, the preparation method comprising the following steps: laser spraying a polymer coating on the surface of the balloon body; Forming a plurality of needle-punched recesses on the surface of the layer; spraying arsenic trioxide drug particles on the polymer coating to fill the arsenic trioxide drug particles into the concave holes; laser polishing the surface of the coating to keep the arsenic trioxide drug particles only in the concave holes of the coating ; Vacuum to make the balloon flap.

In a preferred embodiment of the present invention, the surface of the balloon coating has a concave hole distribution of 4-8/dish ² , preferably the number of concave holes is 4-6/mm ² , and the optimal number of concave holes is 5 number / mm ^2; pitch of recesses each other 0. 08-0 25mm, the pitch is preferably 0. 10-0 recesses 20 best pitch of 0. 10-0 recesses 15.

As described above, the arsenic trioxide controlled release balloon of the present invention is coated with a polymer coating on the surface of the balloon body, and the surface of the polymer coating has a concave pore structure, so that the adsorption amount of the arsenic trioxide drug is greatly improved. Moreover, it is ensured that during the balloon delivery process, the loss rate of the drug carried by the balloon is greatly reduced, and the effective reaching of the lesion site has a therapeutic effect. It can be effectively used in PCTA surgery and in combination with bare stents. The following drawings are only intended to illustrate and explain the present invention, and are not intended to limit the scope of the invention. Wherein: Figure 1 is a schematic view of the structure of the arsenic trioxide controlled release balloon of the present invention.

Fig. 2 is an enlarged schematic view showing the balloon body of the arsenic trioxide controlled release balloon of the present invention and a drug coating thereof. Fig. 3 is an enlarged schematic view showing a portion of a balloon body and a drug coating thereof when the arsenic trioxide controlled release balloon of the present invention is pressurized at 200%. DETAILED DESCRIPTION OF THE INVENTION In order to more clearly understand the technical features, objects and effects of the present invention, the embodiments of the present invention will be described with reference to the accompanying drawings.

As shown in FIG. 1, FIG. 2 and FIG. 3, the present invention provides a controllable release of arsenic trioxide, said trioxide The arsenic controlled release balloon comprises a balloon body 1, a catheter 8 and a stem 9; the balloon body 1 is coated with a polymer coating 2 on its surface, and the polymer coating 2 has a plurality of recesses 21 on its surface. The plurality of recessed holes are obtained by needle-punching of a special recessed hole, and the plurality of recessed holes 21 are spaced apart from each other; the surface of the polymer coating layer 2 is sprayed with arsenic trioxide drug particles 3, and the arsenic trioxide drug particles 3 are filled with In the recessed holes 21, the arsenic trioxide drug particles in each of the recessed holes 21 form a separate particle group, so that the drugs are isolated from each other, such as "island", and the drug is controlled to release; in the balloon expansion process, only arsenic trioxide is fast. freed.

In the present embodiment, the polymer coating 2 functions to control the release of arsenic trioxide drug; the polymer coating 2 is made of a degradable material or a non-degradable material; and the polymer coating material may be selected from polyurethane or tape. One or more of biologically active polyurethanes, polyesters, and copolymers thereof.

In this embodiment, the material of the balloon body is nylon or nylon elastomer; for example: Pebax material can be selected. The balloon has a vacuum flap.

00 ug/mm ² , the optimal arsenic trioxide drug content is 0. 05-5. 00 ug / mm ² , preferably arsenic trioxide drug content is 0. 10-2. 00 ug / mm ² , the best arsenic trioxide drug content in the present embodiment, the arsenic trioxide drug content of the capsule is 0. 05-5. 00 ug / mm ² to 0. 50-1 OOug / mm ^2; and the weight ratio of arsenic trioxide medical weight of the polymer coating is 0.1: 9.9 to 9.9: 0.1, wherein the ratio of the weight of both is preferably 0. 01至100. 00 um, preferably particle size is 0. 01. The granule size of the arsenic trioxide granules is 0. 01-100. 00 um, preferably the particle size is 0. 01. 00 um. 00 um. 00 um.

In the embodiment, the arsenic trioxide controlled release capsule has a rapid release of arsenic trioxide drug in a short period of time during the expansion process, and the arsenic trioxide drug release is released after the balloon is delivered to the lesion site and the balloon is pressurized at not less than 6 atm. The amount of not less than 40% of its total content, when the balloon pressure is not lower than 10 atm, the release of arsenic trioxide is not less than 80% of its total content, and when the balloon pressure is not lower than 14 atm, the release of arsenic trioxide is not Less than 90% of its total content.

The polymer coating coated on the surface of the balloon body can expand together with the balloon body during the pressure expansion process due to the certain ductility and the stretchability, and the concave hole on the surface of the polymer coating is torn under this condition. The enlargement, the arsenic trioxide drug particles encapsulated in the recesses are released into the blood vessel and are taken up by the blood vessel wall. When the balloon decompression wrinkles are withdrawn, the polymer coating is also removed by wrinkles.

The controllable release of arsenic trioxide of the invention utilizes the characteristics of rapid water solubility of arsenic trioxide, coating arsenic trioxide and a sustained release layer on the surface of the balloon, and forming a uniform micro-recessed hole for suppressing the release of arsenic trioxide in the sustained-release layer, and adjusting the scale of the concave hole During the expansion of the balloon, the concave hole is expanded into micropores, and the arsenic trioxide is rapidly released in the blood vessel wall and uniformly enriched on the surface of the blood vessel wall, and the rapid phagocytosis of the cells is used to inhibit cell proliferation, thereby inhibiting restenosis. Efficacy, the balloon can be used for the expansion of PTCA surgery and its use in conjunction with bare stents to reduce the impact of drug stent coating materials on restenosis.

The invention also provides a method for preparing a controllable release of arsenic trioxide, the steps of which are: in the balloon body 1 The surface of the polymer coating 2 is formed with a plurality of needle-punched recesses 21 having a diameter of l_50 um, and the depth of the recessed holes is 0. 08-0. 12 mm; 0. 1 : 9. 9至9. 9 : 0. 1 001-0. 05: 0. 001-0. 05: 0. 1 : 9. 9 to 9. 9 : 0. 1 spraying arsenic trioxide drug particles 3 on the polymer coating 2 (according to the weight of arsenic trioxide drug and the weight of the polymer coating is 0. 1 : 9. 9 to 9. 9 : 0. 1 a ratio of arsenic trioxide drug particles, spraying the drug particles onto the surface of the coating), filling the arsenic trioxide drug particles 3 into the recesses 21; laser grinding the surface of the polymer coating so that the arsenic trioxide drug particles remain only in the recesses of the coating; The vacuum causes the balloon to flap.

In the present embodiment, the surface of the balloon coating has a concave hole distribution of 4-8/mm ² , preferably the number of concave holes is 4-6/mm ² , and the optimal number of concave holes is 5 / mm ² ; The distance between the two holes is 0. 08_0. 25mm, preferably the pitch of the recessed holes is 0. 10-0.

The controllable release of arsenic trioxide prepared according to the above method showed that the compressive strength did not change during the balloon pressure detection process, and no balloon rupture occurred during the experiment. The balloon diameter and the pressurization strength were linear. Incremental correlation indicates that the product of the present invention can meet the performance requirements of the balloon catheter in PTCA surgery and stent implantation. Related data as shown in Table 1

Table 1 Φ 2. 25 arsenic trioxide controlled release balloon pressure test data

In the dynamic flow state of PBS solution, the drug release effect of arsenic trioxide controlled release balloon was detected. When the PBS circulation flow rate was 50 cm/s, the balloon was linearly pressurized and pressurized under the dynamic environment of PBS. The speed was 4 atm/30 s, and the pressurization time lasted for 2.5 min. The change of the arsenic trioxide drug content in the PBS solution was monitored in real time, and the arsenic trioxide drug release scale was prepared, as shown in Table 2.

Table 2 In vitro drug release of arsenic trioxide controlled release balloon

As described above, the arsenic trioxide controlled release balloon of the present invention is coated with a polymer coating on the surface of the balloon body, and the surface of the polymer coating has a concave pore structure, so that the adsorption amount of the arsenic trioxide drug is greatly improved. Moreover, it is ensured that during the balloon delivery process, the loss rate of the drug carried by the balloon is greatly reduced, and the effective reaching of the lesion site has a therapeutic effect. It can be effectively used in PCTA surgery and in combination with bare stents.

The above description is only illustrative of the specific embodiments of the invention and is not intended to limit the scope of the invention. Equivalent changes and modifications made by those skilled in the art without departing from the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims

claims

1. A balloon with controlled release of arsenic trioxide, characterized in that: the balloon with controlled release of arsenic trioxide includes: a balloon body, arsenic trioxide drug and a polymer coating that controls the release of arsenic trioxide drug, wherein the surface of the polymer coating With concave holes, only arsenic trioxide is quickly released during the expansion process.

2. The balloon with controlled release of arsenic trioxide according to claim 1, characterized in that: the polymer coating is sprayed on the surface of the balloon body, and the surface of the polymer coating has a plurality of concave holes, and the plurality of concave holes are adjacent to each other. There are gaps in between, and arsenic trioxide drug particles are sprayed on the polymer coating. The arsenic trioxide drug particles are filled in multiple concave holes. The arsenic trioxide drug particles in each concave hole form an independent particle group, so that the drugs are isolated from each other.

3. The arsenic trioxide controllable release balloon according to claim 2, characterized in that: the arsenic trioxide drug content on the balloon is 0.05-5.00 ug/mm ² ; the arsenic trioxide drug weight and the polymer coating The ratio of the layer weight is 0. 1: 9. 9 to 9. 9: 0. 1; the particle size of the arsenic trioxide drug particles or its independent particle group is 0. 01-100. 00 um.

4. The arsenic trioxide controllable release balloon according to claim 1, characterized in that: the polymer coating is made of degradable material or non-degradable material.

5. The arsenic trioxide controllable release balloon according to claim 4, characterized in that: the polymer coating is made of polyurethane and its copolymer.

6. The arsenic trioxide controllable release balloon according to claim 1, characterized in that: the material of the balloon body is nylon or nylon elastomer.

7. The balloon with controlled release of arsenic trioxide according to claim 2, characterized in that: the plurality of concave holes on the surface of the polymer coating are acupuncture concave holes; and the balloon has vacuum flaps.

8. The balloon with controlled release of arsenic trioxide according to claim 7, characterized in that: the distribution of concave holes on the surface of the balloon coating is 4-8/mm ² ; the distance between the concave holes is 0.08- 0.25mm.

9. A method for preparing a balloon with controlled release of arsenic trioxide according to any one of claims 1 to 8, the preparation method comprising the following steps: laser spraying a layer of polymer coating on the surface of the balloon body; Multiple acupuncture concave holes are formed on the surface of the polymer coating; then arsenic trioxide drug particles are sprayed on the polymer coating to fill the arsenic trioxide drug particles into the concave holes; the surface of the coating is laser polished and vacuumed to fold the balloon wings.

10. The method for preparing a balloon with controlled release of arsenic trioxide as claimed in claim 9, characterized in that: the distribution of concave holes on the surface of the balloon coating is 4-8/mm ² ; the distance between the concave holes is 0.08- 0.25mm.