WO2016206078A1

WO2016206078A1 - Method for preparing drug balloon

Info

Publication number: WO2016206078A1
Application number: PCT/CN2015/082452
Authority: WO
Inventors: 张芝芳
Original assignee: 浙江巴泰医疗科技有限公司
Priority date: 2015-06-24
Filing date: 2015-06-26
Publication date: 2016-12-29
Also published as: CN104922735A; CN104922735B

Abstract

A method for preparing a drug balloon comprises the following steps: (1) preparing a particle coating at a surface of a balloon, wherein the particle coating is made of sodium chloride, calcium chloride or urea; (2) placing the balloon having the particle coating in a drug solution to crystallize the drug on a surface of the particle coating and to form a drug coating; removing the balloon from the drug solution and drying the balloon to obtain the drug balloon.

Description

Method for preparing drug balloon

Technical field

The invention relates to the technical field of medical device preparation, and in particular to a method for preparing a drug balloon.

Background technique

The emergence of drug-eluting stents is a milestone in the history of coronary intervention because it reduces in-stent restenosis, but drug-eluting stents still have a stenosis rate of 5% to 10%, and for special lesions, this stenosis rate is even more high. Moreover, in recent years, drug stents have been found to have late stent thrombosis, which has led to the clinical demand for new medical devices. The drug-coated balloon belongs to an interventional medical device. After the drug is delivered intravascularly, the blood vessel is withdrawn, the drug stays in the lesion, and the drug is continuously released to inhibit the narrowing of the blood vessel. This is an ideal new medical device. It has become a new research hotspot in the field of vascular intervention.

At present, for the treatment of vascular stenosis, a method of placing a drug stent is generally used clinically. However, sometimes it is not always possible to implant a stent or to implant a stent. The drug balloon is a catheter-based drug delivery device used to prevent restenosis after balloon balloon dilatation. Initial animal and human studies have found that the arterial wall has a variability in drug specificity, and The drug carried by the balloon is quickly eluted, which has caused a lot of clinical controversy. In recent years, with the advancement of technology, the research on drug balloon has made great progress. In 2004, Bruno Scheller of Germany published his animal research results on drug balloon prevention and restenosis in Ciculation magazine. Drug balloon can prevent it. Restenosis after angioplasty. In clinical trials, 52 patients with in-stent restenosis were treated with paclitaxel-coated balloon catheter, and satisfactory results were obtained.

At present, the technical difficulties of drug balloons are:

(1) The drug coating needs to be able to remain in the blood vessel wall for a long time after a brief expansion in the body, and is slowly released;

(2) The drug coating needs to have a good bonding strength with the balloon surface to avoid a large loss of the drug during the folding process of the balloon;

(3) The drug coating needs to be able to rapidly transfer the drug to the vessel wall after a brief contact with the vessel wall.

Summary of the invention

In order to overcome the difficulties of the prior art described above, the present invention provides a method for preparing a drug balloon, including The following steps:

(1) preparing a particulate coating on the surface of the balloon, the particulate coating being made of sodium chloride, calcium chloride or urea;

(2) placing the balloon with the particle coating in the drug solution to crystallize the drug on the surface of the particle coating to form a drug coating; removing the balloon from the drug solution and drying to obtain the drug balloon .

Further, the present invention can be used to prepare a drug balloon containing paclitaxel, rapamycin or everolimus. When used to prepare such a drug balloon, the drug solution is a mixture of a drug, an additive, and a solvent selected from the group consisting of paclitaxel, rapamycin or everolimus, the additive being selected from the group consisting of PVP (poly Vinyl pyrrolidone), PEG (polyethylene glycol), PVA (polyvinyl alcohol) or stearic acid, the solvent being selected from the group consisting of methanol, ethanol or acetonitrile. The thickness of the particulate coating layer is preferably from 1 to 50 μm, and the thickness of the drug coating layer is preferably from 10 to 30 μm.

Further, in the above drug solution, the concentration of the drug is preferably 13 to 60 mg/mL, and the mass ratio of the drug to the additive is preferably 3:7 to 7:3.

Further, the process of the step (1) is: coating an aqueous solution of a particulate coating material (ie, sodium chloride, calcium chloride or urea) on the surface of the balloon, and drying to obtain a particle coating having a concentration of 0.5. ~40mg/mL. The amount of coating is such that the particle coating thickness is preferably from 1 to 50 μm.

Further, an aqueous solution of the particulate coating material is applied by ultrasonic spraying or solution immersion.

Further, in the step (2), the medicine is crystallized on the surface of the particle coating by a cooling method or an anti-solvent method.

The cooling method can adopt the following operation method: immersing the balloon with the particle coating in the drug solution, cooling the drug solution to the crystallization temperature of the drug, and keeping the drug crystallized on the particle coating for a certain period of time.

The anti-solvent method can be carried out by adding an anti-solvent (for example, water) of the drug to the drug solution, and then immersing the balloon with the particle coating in the drug solution, and keeping the drug in the particle coating at room temperature for a certain period of time. Crystallization.

Further, in the above preparation method, the following steps can be adopted:

(a) Preparation of drug solution: 0.15 g of paclitaxel and 0.3 g of PVP were added to 10 mL of ethanol and mixed uniformly, and heated at 40 ° C until paclitaxel and PVP were completely dissolved.

(b) Preparation of microparticle coating: Take a balloon of 4.0mm*60mm size, spray the sodium chloride solution with a concentration of 0.5mg/mL on the surface of the balloon by ultrasonic spraying, and obtain a microparticle coating after drying. The amount is preferably 1 to 50 μm in thickness.

(c) Balloon application: The balloon with the particle coating was immersed in the drug solution of the step (a), and the temperature of the drug solution was lowered to -20 ° C for 1 hour.

(d) The balloon was slowly taken out, and the balloon was left to stand at 40 ° C for 30 minutes to obtain a drug balloon (drug coating thickness: 10 μm).

Further, another method for preparing a drug balloon can adopt the following steps:

(a) Preparation of drug solution: 0.5 g of paclitaxel and 0.3 g of PEG were added to 10 mL of methanol and uniformly mixed, and heated at 60 ° C until paclitaxel and PEG were completely dissolved.

(b) Preparation of microparticle coating: Take a 3.0mm*20mm balloon and apply a calcium chloride solution with a concentration of 10mg/mL on the surface of the balloon by ultrasonic spraying. After drying, a particle coating is obtained. It is preferable to obtain a thickness of 1 to 50 μm.

(c) To the solution of the step (a), 1 ml of water for injection was added, and the mixture was stirred and allowed to stand for 1 minute.

(d) The balloon with the particle coating was immersed in the solution of step (c) and kept at room temperature for 1 hour.

(e) The balloon was slowly taken out, and the balloon was allowed to stand at room temperature for 1 hour to obtain a drug balloon (drug coating thickness: 20 μm).

The principle of the present invention is that a microparticle coating is prepared on the surface of the balloon, and the microparticles on the microparticle layer can serve as a crystal nucleus of the drug crystal. The balloon is then placed in the drug solution and measures are taken to reduce the solubility of the drug solution. As the solubility of the drug decreases, the drug crystallizes at the microparticles on the surface of the balloon. As the solubility decreases and the crystallization time prolongs, the drug crystallizes more and more. When it reaches a certain level, the balloon is taken out from the drug solution and dried. , you can get the drug balloon you need.

The advantages of the present invention over the prior art are:

(1) The affinity of the drug to the surface of the balloon is good, and the coating is detached when the folding press is small; the method of improving the affinity is to coat the particle coating without physically or chemically modifying the balloon itself, effectively maintaining The mechanical properties and service life of the balloon itself are simple to operate and do not require special processing equipment. Compared with other similar technologies, the production cost is greatly reduced.

(2) Using small molecular substances such as calcium chloride, sodium chloride and urea as the material of the microparticle coating, the surface of the microparticle coating formed has a particulate structure, which can be used as a crystal nucleus for drug crystallization, which is beneficial for inducing drug in the microparticle coating. The surface of the layer is slowly crystallized to form a drug coating with a uniform drug distribution. Simultaneous crystallization process To compensate for the defects of the particle coating and improve the overall bonding strength of the coating.

(3) Due to the use of the microparticle coating to improve the affinity of the drug and the balloon, the composition of the drug coating is simple, and the drug content in the coating is high, which effectively increases the contact area between the drug and the blood vessel wall.

(4) The drug can be quickly transferred to the vessel wall with a brief contact, and the drug can remain in the vessel wall for a longer period of time.

DRAWINGS

1 is a SEM photograph of the surface of the drug balloon obtained in Example 1.

Fig. 2 is a photograph showing the peeling off of the coating during the expansion of the drug balloon obtained in Example 1.

Figure 3 is a photograph of the peeling off of the coating of the commercially available B. Bruan drug balloon during balloon dilation.

Figure 4 is a photograph of the peeling off of the coating of the marketed Invatec drug balloon during balloon expansion.

detailed description

The technical solution of the present invention will be further specifically described below through specific embodiments. It is to be understood that the invention is not limited to the embodiments described below, and that any form of modifications and/or changes made to the invention are intended to fall within the scope of the invention. In the present invention, unless otherwise specified, all parts and percentages are by weight, and equipment and raw materials used are commercially available or commonly used in the art. The methods in the following examples, unless otherwise stated, are all conventional methods in the art.

Example 1:

(1) Preparation of drug solution: 0.15 g of paclitaxel and 0.3 g of PVP were added to 10 mL of ethanol and mixed uniformly, and heated at 40 ° C until paclitaxel and PVP were completely dissolved.

(2) Preparation of particle coating: A balloon of 4.0 mm*60 mm size was taken, and a sodium chloride solution having a concentration of 0.5 mg/mL was sprayed on the surface of the balloon by ultrasonic spraying, and dried to obtain a particle coating of 1 μm thick.

(3) Balloon application: The balloon with the particle coating was immersed in the drug solution of the step (1), and the temperature of the drug solution was lowered to -20 ° C for 1 hour.

(4) The balloon was slowly taken out, and the balloon was allowed to stand at 40 ° C for 30 minutes to obtain a drug balloon having a drug coating thickness of 10 μm.

1 is a SEM picture of the surface of a drug balloon prepared in Example 1. As can be seen from the picture, the surface of the drug balloon is needle-like, and the crystal length is mainly concentrated at 20 μm. Most of the diameter is concentrated at 3 μm. This crystal form can prolong the release time of the drug in the body and make the drug last longer.

Example 2:

(1) Preparation of drug solution: 0.5 g of paclitaxel and 0.3 g of PEG were added to 10 mL of methanol and uniformly mixed, and heated at 60 ° C until paclitaxel and PEG were completely dissolved.

(2) Preparation of balloon particle coating: Take a balloon of 3.0mm*20mm size, spray the calcium chloride solution with a concentration of 10mg/mL on the surface of the balloon by ultrasonic spraying, and obtain a particle coating of 5μm thick after drying. .

(3) To the solution of the step (1), 1 ml of water for injection was added, and the mixture was stirred and allowed to stand for 1 minute.

(4) The balloon having the particle coating layer was immersed in the solution of the step (3) and kept at room temperature for 1 hour.

(5) The balloon was slowly taken out, and the balloon was left to stand at room temperature for 1 hour to obtain a drug balloon having a drug coating thickness of 20 μm.

Example 3:

(1) Preparation of drug solution: 0.13 g of rapamycin and 0.3 g of PVA were added to 10 ml of acetonitrile, and the mixture was stirred to completely dissolve the drug.

(2) Preparation of balloon particle coating: The balloon of 4.0 mm*30 mm size was immersed in a urea solution of 20 mg/mL, and the balloon was slowly taken out after 10 minutes, placed at 40 ° C, and dried to obtain a particle coating of 30 μm thick. ;

(3) Balloon application: A balloon having a particle coating was immersed in the drug solution of the step (1), and the drug solution was cooled to -60 ° C for 30 minutes.

(4) The balloon was slowly taken out, and the balloon was allowed to stand to dry at room temperature for 30 minutes to obtain a drug balloon having a drug coating thickness of 15 μm.

Example 4:

(1) Preparation of drug solution: 0.6 g of everolimus and 0.3 g of magnesium stearate were added to 10 ml of Stir well in ethanol and heat at 70 ° C until paclitaxel and magnesium stearate are completely dissolved.

(2) Preparation of balloon particle coating: Take a 3.0mm*20mm balloon, spray the sodium chloride solution with a concentration of 40mg/mL on the surface of the balloon, and obtain a 50μm thick particle coating after drying. .

(3) The balloon having the particle coating layer was immersed in the drug solution of the step (1), and the drug solution was cooled to -60 ° C for 10 minutes.

(4) The balloon was slowly taken out, and the balloon was left to stand at room temperature for 1 hour to obtain a balloon having a drug coating thickness of 30 μm.

The procedures of Examples 5 to 20 refer to Example 1, and each of the solutions of the ultrasonically sprayed particulate coating material is used. The drug crystallization is carried out by a cooling method, and the concentration of the drug solution is adjusted according to the desired thickness. The specific results are shown in Table 1. In Table 1, numbers 1 to 20 correspond to examples 1 to 20, and numbers 21 to 30 are comparative examples, and the steps are also referred to in the first embodiment.

Table 1 Product parameters of different examples and comparative examples

Folding pressure grip drug loss test:

For each of the drug balloons obtained in the examples and the comparative examples, the drug loading amount before and after folding was measured, and the drug loss rate of the folded crimp was calculated.

Take the determination of the drug loading of paclitaxel as an example: take 10 paclitaxel drug capsules prepared according to the above method, cut the drug-loading part of the balloon, take a stoppered glass test tube, add 10mL of acetonitrile to it, pay attention to the ball The capsule is completely immersed in acetonitrile, and the ultrasound completely dissolves the drug and shakes it to obtain a sample solution to be tested. According to the chromatographic conditions of the Chinese Pharmacopoeia 2010 paclitaxel content detection method, 10uL was accurately injected into the liquid chromatograph. Standard curve drawing: accurately weigh the appropriate amount of paclitaxel reference substance, put it into a 50mL volumetric flask, dissolve it with acetonitrile and dilute to the mark, and shake it. The above stock solution was gradually diluted into five reference solutions having a concentration ranging from 1 μg/mL to 2000 μg/mL. According to the chromatographic conditions of the Chinese Pharmacopoeia 2010 paclitaxel content detection method, 10 μL of precision was injected into the liquid chromatograph to record the chromatogram. The concentration of the paclitaxel reference substance was plotted on the abscissa, and the corresponding peak area was linearly regressed to obtain a standard curve. The paclitaxel concentration in the sample solution was calculated according to the standard curve, and the paclitaxel content was further calculated. In addition, 10 paclitaxel drug balloons obtained by the same method were taken, and after folding and crimping, the drug-loaded portion of the balloon was cut out, and the paclitaxel content was tested and calculated according to the same method as above. The drug loss rate was obtained by comparing the drug content before and after folding the crimping. The principle of measuring the drug loading of other drugs is the same. The results are shown in Table 2.

Simulated drug release test:

For each of the drug pockets obtained in each of the examples and the comparative examples, simulated drug release was performed, and the drug release rate was measured. The specific steps are as follows: take 10 drug balloons, remove the protective sleeve, and insert into a 3.0mm silicone tube. The silicone tube was immersed in a beaker containing water for injection, and the balloon was pressurized to 6 atm using a filling device, and the balloon was removed from the silicone tube after pressing for 30 s. The drug loading on the surface of the balloon was measured according to the method for detecting the loss of the folded drug, and at the same time, 10 drug balloons prepared in the same manner were taken to test the drug content. The release rate was obtained by comparing the drug content before and after the simulated release. The results are shown in Table 2.

In vivo dose test:

In vivo dose tests were performed on the drug balloons obtained in each of the examples and comparative examples, respectively. The specific method is as follows: a pig with a weight of about 30 kg is punctured by a right iliac artery through a standard angiography, and after transporting the drug balloon to the deep femoral artery, the balloon is filled for 1 minute, then contracted and withdrawn, respectively, at 10 minutes, 1 After days, 3 days, and 7 days and 28 days, the pigs were sampled after sacrifice, and the drug in the tissues was extracted with methanol, and the concentration of the drug in the tissues was determined by HPLC-MS. The results are shown in Table 2.

Table 2 Test results

*: "-" means not detected.

2 to 4 are photographs showing the peeling off of the coating of Example 1, B. Bruan drug balloon, and Invatec drug balloon, respectively. As can be seen from the figure, compared with the products on the two markets, the coating material has substantially no shedding phenomenon during the expansion process.

It can be seen from Table 2 that the drug balloon of the present invention has a lower average drug loss before and after folding and crimping, and the most The high is only 7.7%, far lower than other products. It shows that the bond strength of the coating and the balloon is very high. It can be seen from the data that as the thickness of the particle coating decreases, the bonding strength between the coating and the balloon gradually decreases. When the thickness of the particle coating is 0.2 μm, the drug loss is too high to meet the requirements. In addition, if other substances (such as starch, hydroxymethylcellulose, etc.) are used as the material of the fine particle coating, the bonding strength cannot be compared with sodium chloride, calcium chloride or urea.

In addition, the release rate of the drug balloon of the present invention has reached a standard, and rapid release and transfer to the blood vessel wall can be achieved.

It can also be seen from Table 2 that the drug of the drug balloon of the present invention still maintains a certain concentration within 28 days, that is, the drug can last for more than 28 days; and the film prepared by other techniques or the thickness and material do not match. On the 28th day of the required drug balloon, the concentration of the drug could not be detected.

The above-mentioned embodiments are only a preferred embodiment of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

A method for preparing a drug balloon, comprising the steps of:

(1) preparing a particulate coating on the surface of the balloon, the particulate coating being made of sodium chloride, calcium chloride or urea;

(2) placing the balloon with the particle coating in the drug solution to crystallize the drug on the surface of the particle coating to form a drug coating; removing the balloon from the drug solution and drying to obtain the drug balloon .
The method according to claim 1, wherein the particle coating layer has a thickness of from 1 to 50 μm and the drug coating layer has a thickness of from 10 to 30 μm.
The preparation method according to claim 1, wherein the drug solution is a mixture of a drug, an additive and a solvent, and the drug is selected from the group consisting of paclitaxel, rapamycin or everolimus, and the additive is selected from the group consisting of paclitaxel, rapamycin or everolimus. PVP, PEG, PVA or stearic acid, the solvent being selected from the group consisting of methanol, ethanol or acetonitrile.
The preparation method according to claim 3, wherein the concentration of the drug in the drug solution is 13 to 60 mg/mL, and the mass ratio of the drug to the additive is 3:7 to 7:3.
The preparation method according to any one of claims 1 to 4, wherein the step (1) is: coating an aqueous solution of the particulate coating material on the surface of the balloon, and drying to obtain a particle coating, the solution being The concentration is 0.5 to 40 mg/mL.
The preparation method according to claim 5, wherein the aqueous solution of the particulate coating material is applied by ultrasonic spraying or solution immersion.
The process according to any one of claims 1 to 4, wherein the drug is crystallized on the surface of the particle coating by a cooling method or an anti-solvent method.
The preparation method according to any one of claims 1 to 4, comprising the steps of:

(a) Preparation of the drug solution: 0.15 g of paclitaxel and 0.3 g of PVP were added to 10 mL of ethanol and mixed uniformly, and heated at 40 ° C until the paclitaxel and PVP were completely dissolved;

(b) preparation of the microparticle coating: a balloon of 4.0 mm*60 mm size was taken, and a sodium chloride solution having a concentration of 0.5 mg/mL was sprayed on the surface of the balloon by ultrasonic spraying, and dried to obtain a microparticle coating;

(c) balloon application: immersing the balloon with the particle coating in the drug solution of step (a), reducing the temperature of the drug solution to -20 ° C for 1 hour;

(d) Slowly remove the balloon and leave the balloon to dry at 40 ° C for 30 minutes to obtain the drug. Balloon.
The preparation method according to any one of claims 1 to 4, comprising the steps of:

(a) Preparation of the drug solution: 0.5 g of paclitaxel and 0.3 g of PEG were added to 10 mL of methanol and uniformly mixed, and heated at 60 ° C until the paclitaxel and PEG were completely dissolved;

(b) preparation of microparticle coating: take a 3.0mm*20mm balloon, spray a calcium chloride solution with a concentration of 10mg/mL on the surface of the balloon by ultrasonic spraying, and obtain a microparticle coating after drying;

(c) adding 1 ml of water for injection to the solution of step (a), stirring uniformly and allowing to stand for 1 minute;

(d) immersing the balloon with the particle coating in the solution of step (c), maintaining at room temperature for 1 hour;

(e) The balloon was slowly taken out, and the balloon was allowed to stand at room temperature for 1 hour to obtain a drug balloon.