WO2022048270A1

WO2022048270A1 - Drug balloon and preparation method therefor

Info

Publication number: WO2022048270A1
Application number: PCT/CN2021/102911
Authority: WO
Inventors: 朱熠门; 郭芳; 朱清; 南文斌
Original assignee: 上海鸿脉医疗科技有限公司
Priority date: 2020-09-07
Filing date: 2021-06-29
Publication date: 2022-03-10
Also published as: CN114146231A; AR123438A1

Abstract

The present invention relates to a drug balloon and a preparation method therefor. The drug balloon comprises a balloon body and a coating provided on the surface of the balloon body; the coating sequentially comprises a bottom layer, a drug-carrying layer, and a functional layer from inside to outside; the bottom layer comprises a hydrophilic material and/or a lipophilic material; the drug-carrying layer comprises a drug and a carrier; the functional layer comprises a drug and a functional material; and the functional material comprises at least one of a drug receptor protein inhibitor, a drug metabolism isoenzyme inducer, and a drug metabolism isoenzyme inhibitor. Thus, by means of the bottom layer, the adhesion of the drug to the surface of the balloon can be reduced, and residues of the drug on the surface of the balloon can be reduced; moreover, by means of the functional layer, the loss of the drug during a delivery process can be reduced, and the speed of drug metabolism can be adjusted.

Description

Drug balloon and preparation method thereof

technical field

The invention relates to the technical field of medical devices, in particular to a drug balloon and a preparation method thereof.

Background technique

Drug balloon catheter is an interventional treatment method combining traditional balloon angioplasty and advanced drug-eluting technology. During interventional treatment, the drug on the drug balloon catheter can be quickly released when the balloon reaches the lesion location, avoiding the side effects caused by the long-term retention of the metal stent and the polymer carrier, and is an effective method for metal stent angioplasty. In addition, it has a good application in the process of vascular restenosis after drug stent implantation, and gradually shows its superiority. However, the drug balloon catheter also has the problem that the drug on the surface of the balloon is lost in the delivery process, and most of the drug remains on the surface of the balloon after interventional therapy (about 10-20%), which reduces the use of drugs. Rate. Not only that, the existing drug balloon catheter needs to release the drug after the balloon is inflated to a larger diameter, and there is a waiting period caused by the dissolution of the sustained-release layer. As a result, the action period of the drug is shortened, and the therapeutic effect of the drug is affected. In addition, the existing drug balloon catheter also has the problems of uncontrollable drug metabolism rate, unable to achieve the effect of sustained release and long-term treatment, and low drug load.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a drug balloon and a preparation method thereof, which are used to solve the problems of large drug delivery loss, high drug residues on the surface of the balloon, and uncontrollable drug metabolism rate.

In order to achieve the above purpose, the present invention provides a drug balloon, comprising a balloon body and a coating provided on the surface of the balloon body, the coating sequentially including a bottom layer, a drug-carrying layer and a functional layer from the inside to the outside. ; The bottom layer includes hydrophilic material and/or lipophilic material; The drug-loading layer includes drugs and carriers; The functional layer includes drugs and functional materials, and the functional materials include drug receptor protein inhibitors, drug metabolism At least one of an isoenzyme inducer and a drug metabolism isoenzyme inhibitor.

Optionally, the thickness of the bottom layer is 0.1 μm˜1.0 μm, and the thickness of the drug-loading layer is 1.0 μm˜20 μm.

Optionally, the material of the bottom layer is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, polyglycerol ester, chitosan, chitin, dextran , a combination of any one or more of polystearate, phospholipid and polycitrate.

Optionally, the carrier material of the drug-loading layer is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, polyglycerol ester, chitosan, chitin, A combination of any one or more of dextran, polystearate, phospholipid and polycitrate.

Optionally, the drug receptor protein inhibitor is an inhibitor of immunoaffinity protein FKBP12, and the inhibitor of immunoaffinity protein FKBP12 is selected from any one or a combination of the following materials:

3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate; (3R)-4-(p-toluene Sulfonyl)-1,4-thiazole-3-carboxylic acid-L-leucine ethyl ester; (3R)-4-(p-toluenesulfonyl)-1,4-thiazole-3-carboxylic acid-l- Phenyllanin benzyl ester.

Optionally, the drug metabolism isoenzyme inhibitor is an inhibitor of CYP3A4 isoenzyme, and the inhibitor of CYP3A4 isoenzyme is selected from any one or a combination of the following materials:

Posaconazole, erythromycin, telithromycin, HIV protease inhibitor, boceprevir, telaprevir, amiodarone, amprenavir, atonavir, cimetidine, ciproflox Star, clarithromycin, diltiazem, doxycycline, enoxacin, fluconazole, fluvoxamine, imatinib, indinavir, itraconazole, ketoconazole, micon azole, nefazodone, ritonavir, saquinavir, telithromycin, verapamil, voriconazole.

Optionally, the drug metabolism isozyme inducer is an inducer of CYP3A4 isozyme, and the inducer of CYP3A4 isozyme is selected from any one or a combination of the following materials:

Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenytoin, phenobarbital, Primidone, etravirine, rifampicin, St. John's wort, pioglitazone, topiramate.

Optionally, the drug is selected from any one or a combination of the following drugs: paclitaxel, rapamycin and abciximab.

Optionally, the drug loading amount of the drug-loading layer is 0.5 μg/mm ² to 5 μg/mm ² .

Optionally, the mass ratio of the carrier to the drug in the drug-loading layer is (0.1-10):1.

To achieve the above object, the present invention also provides a preparation method of a drug balloon, comprising:

provide a balloon;

A bottom layer is arranged on the surface of the balloon, and the bottom layer includes a hydrophilic material and/or a lipophilic material;

A drug-carrying layer is provided on the surface of the bottom layer, and the drug-carrying layer includes a drug and a carrier;

A functional layer is disposed on the surface of the drug-loading layer, the functional layer includes a drug and a functional material, and the functional material includes a drug receptor protein inhibitor, a drug metabolism isoenzyme inducer, and a drug metabolism isoenzyme inhibitor at least one of them.

Optionally, the preparation process of the functional layer includes:

Preparation of functional layer solution;

The functional layer solution is loaded into the ultrasonic spraying equipment, and the process conditions of the ultrasonic spraying equipment are set;

Use the ultrasonic spraying equipment to spray the functional layer solution back and forth along the axial direction of the balloon;

Wherein, the process conditions of the ultrasonic spraying equipment include:

The flow rate is 0.01mL/min～0.1mL/min;

The distance between the nozzle and the balloon is 10mm to 30mm;

The spraying speed is 0.05mL/min～0.3mL/min;

The moving speed of the nozzle is 2mm/s～5mm/s.

Optionally, the mass ratio of the drug receptor protein inhibitor to the drug in the functional layer is (0.25-4.0): 1; the mass ratio of the drug metabolism isoenzyme inhibitor to the drug in the functional layer is ( 0.25-4.0): 1; the mass ratio of the drug metabolism isoenzyme inducer to the drug in the functional layer is (0.25-4.0): 1.

Compared with the prior art, the pharmaceutical balloon of the present invention has the following advantages:

First, the present invention can reduce the direct contact between the drug and the surface of the balloon through the bottom layer, and reduce the residue of the drug on the surface of the balloon after interventional therapy. At the same time, the present invention can play the role of protecting the drug-carrying layer through the functional layer, thereby reducing the loss of the drug during the delivery process, and also increasing the drug-carrying capacity of the balloon through the functional layer. These aspects maximize the release of the drug when the drug balloon reaches the lesion site, improving the therapeutic effect of the drug;

Second, when the present invention realizes the functional layer by adding the drug receptor protein inhibitor, the added drug receptor protein inhibitor can realize the slow metabolism of the drug and avoid drug metabolism during the delivery process. In addition, the functional layer enables the drug to be released only when the drug balloon begins to expand after reaching the lesion location, thereby increasing the action period of the drug, reducing the waiting period for drug release, and being conducive to fully exerting the therapeutic effect of the drug. It should be understood that, in the traditional drug balloon, there is only one drug-loading layer, and the drug will have metabolic problems early during the delivery process, which reduces the action period of the drug. Moreover, in the traditional drug balloon, the drug can be released only when the balloon is in full contact with the blood vessel wall, so that the waiting period for drug release is long. However, the drug balloon of the present invention can inhibit the metabolism of the drug through the drug receptor protein inhibitor during the delivery process, and the drug can be released when the balloon begins to expand after reaching the lesion location, thereby reducing the waiting period for drug release;

Third, the present invention can also adjust the drug release cycle by adjusting the dosage of drug receptor protein inhibitor, drug metabolism isoenzyme inducer and drug metabolism isozyme inhibitor to adjust the speed of drug metabolism to achieve sustained release and The effect of long-term treatment, or to achieve the purpose of accelerating drug metabolism.

Description of drawings

Fig. 1 is the end face structure diagram of the medicine balloon in the preferred embodiment of the present invention;

FIG. 2 is a flow chart of preparing a medical balloon in a preferred embodiment of the present invention.

detailed description

The embodiments of the present invention are described below through specific specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied in other different specific embodiments. Various details in this specification can also be modified or changed in various ways without departing from the spirit of the present invention based on different viewpoints and applications. It should be noted that the drawings provided in this embodiment are only used to illustrate the basic concept of the present invention in a schematic way, so the drawings only show the components related to the present invention rather than the number, shape and the number of components in actual implementation. Dimensions are drawn. In actual implementation, the type, quantity and proportion of each component can be changed at will, and the layout type of each component may also be more complicated.

In addition, each embodiment in the following description has one or more technical features, but this does not mean that the person using the present invention must implement all the technical features in any embodiment at the same time, or can only implement different embodiments separately. one or all of the technical features. In other words, under the premise of possible implementation, those skilled in the art can selectively implement some or all of the technical features in any embodiment according to the disclosure of the present invention and depending on design specifications or actual needs, or A combination of some or all of the technical features in the multiple embodiments is selectively implemented, thereby increasing the flexibility of the implementation of the present invention.

In order to make the objects, advantages and features of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings. It should be noted that the accompanying drawings are all in a very simplified form and in an inaccurate scale, and are only used to facilitate and clearly assist the purpose of explaining the embodiments of the present invention. As used in this specification, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. As used in this specification, the meaning of "plurality" generally includes at least two, unless the content clearly dictates otherwise. As used in this specification, the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. It will also be understood that the present invention repeats reference numerals and/or letters in various embodiments. This repetition is for simplicity and clarity, and does not in itself indicate a relationship between the various embodiments and/or configurations discussed. It will also be understood that when an element is referred to as being "connected" to another element, it can be directly connected to the other element or one or more intervening elements may be present.

The equipment and materials used in the specific implementation are described as follows:

Special ultrasonic spraying equipment, produced by Hangzhou Jiazhen Ultrasonic Technology Co., Ltd., model: HC-LA5001GL.

Dextran, Aladdin reagent, pharmaceutical grade, M _W 40000, Mw is the unit of weight average molecular weight;

Rapamycin, Fujian Kerui Pharmaceutical Company, medical grade;

Paclitaxel, Yunnan Hande Biotechnology Co., Ltd., medical grade;

Abciximab, manufactured by Wuhan Ruilisheng Technology Development Co., Ltd., medical grade;

The inhibitor of FKBP12, produced by Shanghai Magnesium Cheng Chemical Co., Ltd., has a purity of 98%;

The inhibitor of CYP3A4, produced by Shanghai Magnesium Cheng Chemical Co., Ltd., has a purity of 98%;

The inducer of CYP3A4, produced by Shanghai Meicheng Chemical Co., Ltd., with a purity of 98%;

Polyethylene glycol, Aladdin reagent, Mn4000, Mn is the unit of number average molecular weight.

Other organic solvents are Sinopharm reagents, analytical grade.

Referring to FIG. 1, an embodiment of the present invention provides a drug balloon, including a balloon body 1, and the outer surface of the balloon body 1 is provided with a coating, and the coating sequentially includes a bottom layer 2, Drug-loading layer 3 and functional layer 4. That is, the bottom layer 2 is disposed on the outer surface of the balloon body 1 , the drug-carrying layer 3 is disposed on the bottom layer 1 , and the functional layer 4 is disposed on the drug-carrying coating 3 . Wherein, the bottom layer 2 includes hydrophilic material and/or lipophilic material. Preferably, the bottom layer 2 includes both hydrophilic and lipophilic materials. The drug-loading layer 3 includes a carrier and a drug; the functional layer 4 includes a drug and a functional material, and the functional material includes a drug receptor protein inhibitor, a drug metabolism isoenzyme inhibitor, and a drug metabolism isozyme inducer. at least one of. It should be understood that the drugs in the drug-loading layer 3 are of the same type as the drugs in the functional layer 4 .

It should also be understood that the use of a drug receptor protein inhibitor (since the content of the receptor protein inhibitor can determine when the drug begins to metabolize) avoids the drug being metabolized during delivery and only occurs when the drug balloon reaches the lesion. Metabolism of the drug does not begin until the initial stage of inflation of the drug balloon. Such a structure is beneficial to increase the action period of the drug and reduce the waiting period of the drug release, so as to give full play to the therapeutic effect of the drug. The use of drug metabolism isoenzyme inhibitors can realize the slow metabolism of drugs and achieve the therapeutic effect of slow and long-term metabolism of drugs. The use of drug metabolism isoenzyme inducers can realize the accelerated metabolism of drugs and achieve the therapeutic effect of rapid drug metabolism.

Therefore, in the present invention, by adding functional materials, the drug metabolism rate can be adjusted to better meet various therapeutic needs. In particular, compared with the traditional balloon with only one drug-carrying layer, the present invention increases the drug-carrying capacity of the balloon through the functional layer, and further exerts the therapeutic effect of the drug. In addition, the drug balloon of the present invention can reduce the direct contact between the drug and the surface of the balloon through the bottom layer 2, and reduce the residue of the drug on the surface of the balloon after interventional treatment, and at the same time, the functional layer 4 of the present invention can protect the drug-carrying The role of layer 3 reduces the loss of the drug during the delivery process, so that the release of the drug is maximized when the drug balloon reaches the lesion location, and the therapeutic effect of the drug is improved. In addition, the drug balloon of the present invention has the advantages of simple structure, convenient processing, high qualification rate, suitable for large-scale production and the like.

Further, the material of the bottom layer 2 is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, polyglycerol ester, chitosan, chitin, dextran , a combination of any one or more of polystearate, phospholipid and polycitrate.

Optionally, the preparation process of the bottom layer 2 is as follows: weighing a certain quality of the bottom layer material, and dissolving the bottom layer material in an organic solvent, after the bottom layer material is fully dissolved, the bottom layer solution is obtained; then dip coating or spraying or coating is used. A coating process is used to form a layer of bottom material coating on the outer surface of the balloon; after frequent drying in a warm vacuum, a drug balloon with a bottom layer 2 is obtained. Further, the organic solvent for preparing the bottom layer solution may include methanol, ethanol, acetone, dichloromethane, acetonitrile or tetrahydrofuran.

Further, the carrier material of the drug-loading layer 3 is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, polyglycerol ester, chitosan, chitin, A combination of any one or more of dextran, polystearate, phospholipid, and polycitrate.

Optionally, the preparation process of the drug-carrying layer 3 is as follows: weighing a certain mass of carrier material and drug, and dissolving them in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile or tetrahydrofuran to obtain a drug-carrying layer solution; Then, a layer of drug-loading layer 3 is formed on the bottom layer of the balloon by dipping or spraying or coating process; after vacuum drying at room temperature, the drug balloon with the drug-loading layer 3 is obtained.

Further, the drug receptor protein inhibitor is an inhibitor of the immunoaffinity protein FKBP12, and the inhibitor of the immunoaffinity protein FKBP12 is selected from any one or a combination of the following materials:

3-Pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate, (3R)-4-(p-toluene Sulfonyl)-1,4-thiazole-3-carboxylic acid-L-leucine ethyl ester, and (3R)-4-(p-toluenesulfonyl)-1,4-thiazole-3-carboxylic acid-l - Phenyllanin benzyl ester.

Preferably, the mass ratio of the drug receptor protein inhibitor to the drug in the functional layer 4 is (0.25-4.0): 1, for example, (0.25-3.5): 1, (0.25-3.0): 1, (0.25 ~2.0): 1, (1.0 ~ 4.0): 1, (2.0 ~ 4.0): 1, (3.0 ~ 4.0): 1. Within this range, metabolism of the drug during delivery can be effectively prevented. And it should be known that the drug metabolism cycle in the functional layer 4 increases with the increase of the added amount of the drug receptor protein inhibitor. Therefore, by adjusting the content of the drug receptor protein inhibitor, the drug metabolism rate can be adjusted. Achieve slow metabolism of drugs.

Further, the drug metabolism isoenzyme inhibitor is an inhibitor of CYP3A4 isoenzyme, and the inhibitor of CYP3A4 isoenzyme is selected from any one or a combination of the following materials:

Posaconazole, erythromycin, telithromycin, HIV protease inhibitor, boceprevir, telaprevir, amiodarone, amprenavir, aprepitant, atonavir, cimetidine Butin, ciprofloxacin, clarithromycin, diltiazem, doxycycline, enoxacin, fluconazole, fluvoxamine, imatinib, indinavir, itraconazole, ketone Conazole, miconazole, nefazodone, ritonavir, saquinavir, telithromycin, verapamil, and voriconazole.

Preferably, the mass ratio of the drug metabolism isoenzyme inhibitor to the drug in the functional layer 4 is (0.25-4.0): 1, for example, (0.25-3.5): 1, (0.25-3.0): 1, ( 0.25 to 2.0): 1, (1.0 to 4.0): 1, (2.0 to 4.0): 1, (3.0 to 4.0): 1. Within this range, the metabolism rate of the drug can be effectively adjusted, neither too slow nor too fast, so as to realize the controllable metabolism of the drug and give full play to the therapeutic effect of the drug. It should be known that the drug metabolism cycle in the functional layer 4 is lengthened with the increase of the added amount of the drug metabolism isoenzyme inhibitor. Therefore, by adjusting the content of the drug metabolism isoenzyme inhibitor, the drug metabolism rate can be adjusted. .

Further, the drug metabolism isozyme inducer is an inducer of CYP3A4 isozyme, and the inducer of CYP3A4 isozyme is selected from any one or a combination of the following materials:

Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenytoin, phenobarbital, Primidone, etravirine, rifampicin, St. John's wort, pioglitazone, and topiramate.

Preferably, the mass ratio of the drug metabolism isoenzyme inducer to the drug in the functional layer 4 is (0.25-4.0): 1, for example, (0.25-3.5): 1, (0.25-3.0): 1, ( 0.25 to 2.0): 1, (1.0 to 4.0): 1, (2.0 to 4.0): 1, (3.0 to 4.0): 1. Within this range, the metabolic rate of the drug can be effectively adjusted, the controllable metabolism of the drug can be realized, and the therapeutic effect of the drug can be fully exerted. Similarly, the drug metabolism cycle in the functional layer 4 increases with the increase of the added amount of the drug metabolism isoenzyme inducer.

Optionally, the preparation process of the functional layer 4 is as follows: weighing a certain quality of functional materials and drugs, and dissolving them in an organic solvent such as ethanol to obtain a functional layer medicinal solution; then, loading the functional layer solution into a special ultrasonic spraying equipment; Set flow parameters and balloon rotation speed (for example, 5.0 rev/s), adjust the distance between the ultrasonic nozzle of the ultrasonic spraying equipment and the balloon, and control the ambient temperature; use the ultrasonic spraying equipment to spray the functional layer solution along the drug-loaded layer. The balloon shaft of the balloon is sprayed back and forth; after spraying, vacuum drying is performed to obtain a drug balloon with a functional layer 4 .

In this embodiment, the flow parameter of the ultrasonic spraying equipment is preferably 0.01mL/min～0.1mL/min. More preferably, the spraying speed of the ultrasonic spray head is 0.05mL/min～0.3mL/min, so as to ensure the uniformity of spraying. Further, the distance between the ultrasonic nozzle of the ultrasonic spraying equipment and the balloon is 10mm˜30mm. Further, the temperature of the spraying environment is controlled at 18°C-28°C. Further, the moving speed of the spray head is 2 mm/s˜5 mm/s.

Further, the thickness of the bottom layer 2 is preferably 0.1 μm-1.0 μm, for example, 0.2 μm-0.9 μm, 0.3 μm-0.8 μm, 0.4 μm-0.7 μm. The bottom layer 2 within this range is neither too thick nor too thin, so as to ensure that the bottom layer 2 is effectively adhered to the surface of the balloon and prevented from falling off. Further, the thickness of the drug-loading layer 3 is preferably 1.0 μm-20 μm, for example, 5.0 μm-20 μm, 1.0 μm-15 μm, 1.0 μm-10 μm, 10 μm-20 μm. The drug-carrying layer 3 within this range will not be too thick to avoid the generation of thrombus, and will not be too thin, so as to ensure enough drugs to be carried.

Further, the drug is selected from any one or a combination of the following drugs: paclitaxel, rapamycin and abciximab.

Further, the drug loading amount of the drug-loading layer 3 may be 0.5 μg/mm ² to 5.0 μg/mm ² . The setting of the drug loading here is only for illustration and does not constitute a limitation of the present invention. In actual use, a reasonable drug loading should be set according to the balloon specification to ensure the therapeutic effect. Further, the mass ratio of the polymer material of the drug-loading layer 3 to the drug may be (0.1-10):1.

Further, as shown in FIG. 2 , an embodiment of the present invention also provides a method for preparing a drug balloon, comprising the following steps:

Step S11: providing a balloon body 1; the present invention does not limit the structure of the balloon body 1;

Step S12: disposing a bottom layer 2 on the outer surface of the balloon body;

Step S13: disposing a drug-loading layer 3 on the surface of the bottom layer 2;

Step S14 : disposing the functional layer 4 on the surface of the drug-carrying layer 3 .

In order to explain the present invention, the preparation process of the inventive drug balloon is further described below with reference to specific examples, but the following manners do not constitute a limitation of the present invention.

Example 1

First, take five 3.0mm*20mm (diameter*length) balloon catheters, the material of each balloon catheter is Pebax (block polyetheramide), and each balloon catheter is treated as follows:

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 2: Use the plasma cleaning technology to clean the sundries on the surface of the balloon, and the plasma cleaning time is 15 minutes; the inert gas used in the plasma cleaning technology is argon, the power is 100KHz, and the pressure in the working chamber during cleaning is 0.3atm.

Step 3: Using dextran as the bottom layer material, spray a layer of dextran bottom layer with molecular weight Mw of 150,000 Da on the surface of the balloon, and the thickness of the bottom layer is 0.1 μm.

Step 4: Dissolve 500 mg of rapamycin and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL. The drug-loading layer solution was sprayed on the surface of the balloon to form a drug-loading layer with a drug-loading amount of 5 μg/mm ² , and the thickness of the drug-loading layer was 5 μm.

Step 5: By weight ratio, 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate: 3%, rapamycin: 1%, water: 5-10%, ethanol: 82-93%, mix to obtain a functional layer solution with a rapamycin concentration of 52 mg/mL; put the functional layer solution into a special Ultrasonic spraying equipment, set the flow rate to 0.1mL/min, set the balloon speed to 5.0rev/s, and use ethanol to wet the balloon surface (ie, the surface of the drug-loading layer) before spraying; adjust the ultrasonic The ultrasonic spray head of the spraying equipment is 10-30mm away from the balloon, and the ambient temperature is controlled to 28°C; the ultrasonic spraying equipment is turned on, and spraying back and forth 10 times along the axial direction of the balloon to form a functional layer, and finally control the functional layer of the balloon. The drug-loaded content of 4.0 μg/mm 2 was 4.0 μg/mm ² ; after spraying, the balloon was placed in a 28° C. environment to dry for 120 min.

Example 2

Same as Example 1, get 5 balloon catheters of 3.0mm*20mm (diameter*length), the material of the balloon of each balloon catheter is Pebax, and each balloon catheter is done as follows:

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 4: Dissolve 500 mg of paclitaxel and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL. The drug-loading layer solution was sprayed on the surface of the balloon to form a drug-loading layer with a drug-loading amount of 5 μg/mm ² , and the thickness of the drug-loading layer was 5 μm.

Step 5: By weight ratio, 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate: 3%, paclitaxel: 1%, water: 5-10%, ethanol: 82-93%, mix to obtain a functional layer solution with a paclitaxel concentration of 52 mg/mL; put the functional layer solution into a special ultrasonic spraying equipment, set The flow rate is 0.1mL/min, the speed of the balloon is set to 5.0rev/s, and ethanol is used to wet the surface of the balloon (ie, the surface of the drug-loading layer) before spraying; adjust the distance of the ultrasonic nozzle of the ultrasonic spraying equipment The balloon is 10-30mm, and the ambient temperature is controlled at 28°C; the ultrasonic spraying equipment is turned on, and the functional layer is formed by spraying back and forth 10 times along the axial direction of the balloon, and finally the drug loading content on the functional layer of the balloon is controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in a 28° C. environment to dry for 120 min.

Example 3

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 4: Dissolve 500 mg of abciximab and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL. The drug-loading layer solution was sprayed on the surface of the balloon to form a drug-loading layer with a drug-loading amount of 5 μg/mm ² , and the thickness of the drug-loading layer was 5 μm.

Step 5: By weight ratio, 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate: 3%, abciximab: 1%, water: 5-10%, ethanol: 82-93%, mix to obtain a functional layer solution with abciximab concentration of 52 mg/mL; put the functional layer solution into a special Ultrasonic spraying equipment, set the flow rate to 0.1mL/min, set the balloon speed to 5.0rev/s, and use ethanol to wet the balloon surface (ie, the surface of the drug-loading layer) before spraying; adjust the ultrasonic The ultrasonic spray head of the spraying equipment is 10-30 mm away from the balloon, and the ambient temperature is controlled at 28°C; the ultrasonic spraying equipment is turned on, and spraying back and forth 10 times along the axial direction of the balloon to form a functional layer, and finally control the functional layer of the balloon. The drug-loaded content of 4.0 μg/mm 2 was 4.0 μg/mm ² ; after spraying, the balloon was placed in a 28° C. environment to dry for 120 min.

Example 4

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 4: Dissolve 500 mg of rapamycin and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL. The drug-loaded layer solution was sprayed on the surface of the balloon to form a drug-loaded layer with a drug-loaded amount of 5 μg/mm ² and a thickness of 5 μm of the drug-loaded layer.

Step 5: By weight ratio, mix posaconazole: 3%, rapamycin: 1%, water: 5-10%, ethanol: 82-93% to obtain a rapamycin concentration of 52 mg/mL Put the functional layer solution into the special ultrasonic spraying equipment, set the flow rate to 0.1mL/min, set the balloon speed to 5.0rev/s, and use ethanol to wet the balloon before spraying Surface (that is, the surface of the drug-loading layer); adjust the ultrasonic spray head of the ultrasonic spraying equipment to be 10-30 mm away from the balloon, and control the ambient temperature to 28 ° C; open the ultrasonic spraying equipment, and spray back and forth along the axial direction of the balloon for more than 10 times. A functional layer was formed, and the drug loading content on the functional layer of the balloon was finally controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 5

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: by weight ratio, mix posaconazole: 3%, paclitaxel: 1%, water: 5-10%, ethanol: 82-93% to obtain a functional layer solution with a paclitaxel concentration of 52 mg/mL; The functional layer solution was loaded into a special ultrasonic spraying equipment, the flow rate was set to 0.1 mL/min, the speed of the balloon was set to 5.0 rev/s, and ethanol was used to wet the surface of the balloon before spraying (i.e., drug-loaded). Adjust the ultrasonic spray head of the ultrasonic spraying equipment to be 10-30 mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying equipment, spray back and forth 10 times along the axial direction of the balloon to form a functional layer, and finally control the The drug loading content on the functional layer of the balloon was 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 6

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 4: Dissolve 500 mg of abciximab and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL, and spray the drug-loaded layer solution on the surface of the balloon to form a drug-loaded layer solution. The drug-loaded layer with the drug dose of 5 μg/mm ² and the thickness of the drug-loaded layer was 5 μm.

Step 5: By weight ratio, mix posaconazole: 3%, abciximab: 1%, water: 5-10%, ethanol: 82-93%, and mix to obtain abciximab concentration of 52 mg/mL Put the functional layer solution into the special ultrasonic spraying equipment, set the flow rate to 0.1mL/min, set the balloon speed to 5.0rev/s, and use ethanol to wet the balloon before spraying surface; adjust the ultrasonic spray head of the ultrasonic spraying equipment to be 10-30mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying equipment, spray back and forth 10 times along the axial direction of the balloon to form a functional layer, and finally control the The drug loading content on the functional layer of the balloon was 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 7

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: by weight ratio, mix the drug metabolism isoenzyme inducer aprepitant: 3%, rapamycin: 1%, water: 5-10%, ethanol: 82-93%, and obtain rapa A functional layer solution with a concentration of 52 mg/mL of mycin; put the functional layer solution into a special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use it before spraying Wet the surface of the balloon with ethanol; adjust the ultrasonic spray head of the ultrasonic spraying device to be 10-30 mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying device, and spray back and forth along the axial direction of the balloon 10 times to form For the functional layer, the drug loading content on the functional layer of the balloon was finally controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in a 28° C. environment to dry for 120 minutes.

Example 8

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: Then according to the weight ratio, mix the drug metabolism isoenzyme inducer aprepitant: 3%, paclitaxel: 1%, water: 5-10%, ethanol: 82-93%, and mix to obtain the paclitaxel concentration of 52 mg /mL of functional layer solution; put the functional layer solution into the special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use ethanol to wet the described functional layer before spraying The surface of the balloon; adjust the ultrasonic spray head of the ultrasonic spraying equipment to be 10-30mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying equipment, spray back and forth along the axial direction of the balloon 10 times to form a functional layer, and finally control The drug loading content on the functional layer of the balloon was 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 9

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 2: Use the plasma cleaning technology to clean the debris on the surface of the balloon, and the plasma cleaning time is 15 minutes; the plasma cleaning technology adopts the inert gas as argon, the power is 100KHz, and the pressure in the working chamber is 0.3atm during cleaning.

Step 5: Based on the weight ratio, mix the drug metabolism isozyme inducer aprepitant: 3%, abciximab: 1%, water: 5-10%, ethanol: 82-93% to obtain axi A functional layer solution with a monoclonal antibody concentration of 52 mg/mL; put the functional layer solution into a special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use it before spraying Wet the surface of the balloon with ethanol; adjust the distance between the ultrasonic spray head of the ultrasonic spraying device to 10-30 mm from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying device, and spray back and forth 10 times along the axial direction of the balloon to form For the functional layer, the drug loading content on the functional layer of the balloon was finally controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 10

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: In a weight ratio, the drug receptor protein inhibitor 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine- 2-carboxylate: 2%, drug metabolism isoenzyme inducer aprepitant: 1%, rapamycin: 1%, water: 5-10%, ethanol: 82-93%, mixed to obtain axi A functional layer solution with a monoclonal antibody concentration of 52 mg/mL; put the functional layer solution into a special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use it before spraying Wet the surface of the balloon with ethanol; adjust the ultrasonic spray head of the ultrasonic spraying device to be 10-30 mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying device, and spray back and forth along the axial direction of the balloon 10 times to form For the functional layer, the drug loading content on the functional layer of the balloon was finally controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 11

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: In a weight ratio, the drug receptor protein inhibitor 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine- 2-carboxylate: 2%, drug metabolism isoenzyme inhibitor posaconazole: 1%, rapamycin: 1%, water: 5-10%, ethanol: 82-93%, mixed to obtain axi A functional layer solution with a monoclonal antibody concentration of 52 mg/mL; put the functional layer solution into a special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use it before spraying Wet the surface of the balloon with ethanol; adjust the distance between the ultrasonic spray head of the ultrasonic spraying device to 10-30 mm from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying device, and spray back and forth 10 times along the axial direction of the balloon to form For the functional layer, the drug loading content on the functional layer of the balloon was finally controlled to be 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Example 12

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: By weight ratio, the drug metabolism isozyme inhibitor posaconazole: 1.5%, the drug metabolism isozyme inducer aprepitant: 1.5%, rapamycin: 1%, water: 5 -10%, ethanol: 82-93%, mix to obtain a functional layer solution with abciximab concentration of 52 mg/mL; put the functional layer solution into a special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the Set the speed of the balloon to 5.0 rev/s, and use ethanol to wet the surface of the balloon before spraying; adjust the distance between the ultrasonic nozzle of the ultrasonic spraying equipment to 10-30 mm from the balloon, and control the ambient temperature to 28 °C; turn on the ultrasonic spraying equipment , spray back and forth 10 times along the axial direction of the balloon to form a functional layer, and finally control the drug loading content on the functional layer of the balloon to be 4.0 μg/mm ² ; after spraying, place the balloon on the Dry at 28°C for 120min.

Example 13

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 5: By weight ratio, 3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate: 1%, posaconazole: 1%, aprepitant: 1%, rapamycin: 1%, water: 5-10%, ethanol: 82-93%, mixed to obtain abciximab concentration of 52 mg /mL of functional layer solution; put the functional layer solution into the special ultrasonic spraying equipment, set the flow rate to 0.1 mL/min, set the balloon speed to 5.0 rev/s, and use ethanol to wet the described functional layer before spraying The surface of the balloon; adjust the ultrasonic spray head of the ultrasonic spraying equipment to be 10-30mm away from the balloon, and control the ambient temperature to 28°C; turn on the ultrasonic spraying equipment, spray back and forth along the axial direction of the balloon 10 times to form a functional layer, and finally control The drug loading content on the functional layer of the balloon was 4.0 μg/mm ² ; after spraying, the balloon was placed in an environment of 28° C. to dry for 120 minutes.

Comparative Example

Step 1: Wipe the balloon surface with 75% ethanol and set aside.

Step 3: Dissolve 500 mg of rapamycin and 5 g of polyethylene glycol in ethanol to prepare a drug-loaded layer solution with a drug concentration of 50 mg/mL. The drug-loading layer solution was sprayed on the surface of the balloon to form a drug-loading layer with a drug-loading amount of 5 μg/mm ² , and the thickness of the drug-loading layer was 5 μm.

Further, in order to verify the drug loss in the delivery process of the balloon catheter (ie, the drug balloon) of the above-mentioned embodiment, the above-mentioned balloon catheter that was folded and crimped was transported into the abdominal aorta of New Zealand white rabbits of about 2.0 ± 0.5 kg. at the specified location in . After adequate wetting, the balloon catheter was inflated to open and held at the lesion site for 1 minute. Then, the balloon was removed, the residual rate of the drug remaining on the balloon was measured, and the content of the drug transported in the abdominal aorta of New Zealand rabbits was measured within a specified time. The loss rate of the drug during the delivery was calculated according to the drug residue rate and the transferred drug content.

In addition, in order to verify that the drug is absorbed by the tissue, the above-mentioned balloon catheter was implanted into the iliac artery of New Zealand white rabbits, and the balloon catheter was inflated at 16 atm to dilate, and the pressure was maintained for 1 minute. Then, the balloon catheter was removed under reduced pressure, and the rabbit died suddenly after 1 hour of blood flushing. Then, the drug concentration in the tissue and the drug residual rate on the balloon catheter were measured. In addition, the test of tissue drug absorption rate is as follows: dissect and obtain the dilated blood vessel of the balloon catheter, and dilute the volume to 2 mL after grinding; then, use a liquid chromatograph to measure the drug content in the solution, and calculate the tissue drug absorption rate. Wherein, the calculation formula of the tissue drug absorption rate is: (total drug dose-delivery loss drug dose-residual drug dose on the balloon)/total drug dose. Furthermore, the test for the drug residue rate on the balloon surface is as follows: take out the used balloon catheter, cut and grind it, and then dilute to 2mL; then, use a liquid chromatograph to measure the drug content in the solution, and calculate the drug residue. Rate.

In the above tests, the operating conditions of the liquid chromatograph are:

Detector: UV detector;

Chromatographic column: SB-Aq C185μm 250×4.6mm;

Mobile phase: methanol: acetonitrile: water = 23:41:36;

Column temperature: 30℃;

Detection wavelength: 227nm;

Flow rate: 1.5 ml/min;

Injection volume: 10 μL.

Finally, the test results are shown in Table 1 below:

Table 1 Test results of drug balloon performance

It can be seen from the above table that in the absence of the bottom layer and the functional layer, the balloon catheter provided by the comparative example has a large drug loss during the delivery process, and the drug residue rate on the balloon surface is also high, while the tissue drug absorption rate. but very low. Compared with the comparative example, the drug loss of the drug balloons provided in Examples 1 to 9 of the present invention during the delivery process is significantly reduced, and the drug residue on the surface of the balloon is also significantly reduced, thereby significantly improving the transfer rate of the drug. The utilization rate of the drug is high, and the therapeutic effect of the drug is better.

It should be noted that drug receptor protein inhibitors, drug metabolism isoenzyme inhibitors and drug metabolism isozyme inducers can be used alone, or in combination of two or three to achieve regulation of drug metabolism. purpose of speed. No matter what kind of functional material the functional layer 4 adopts, the drug-loading layer 3 can be protected to avoid drug loss during the delivery process. Moreover, by adjusting the ratio of the drug receptor protein inhibitor, the drug metabolism isoenzyme inhibitor and the drug metabolism isozyme inducer, the time of drug metabolism can be precisely controlled, and the therapeutic effect of the drug can be effectively improved.

The above description is only a description of the preferred embodiments of the present invention, and is not intended to limit the scope of the present invention. Any changes and modifications made by those of ordinary skill in the field of the present invention based on the above disclosure all belong to the protection scope of the present invention.

Claims

A drug balloon, characterized in that it comprises a balloon body and a coating provided on the surface of the balloon body, the coating sequentially comprises a bottom layer, a drug-loading layer and a functional layer from the inside to the outside; the bottom layer Including hydrophilic materials and/or lipophilic materials; the drug-loading layer includes drugs and carriers; the functional layer includes drugs and functional materials, and the functional materials include drug receptor protein inhibitors, drug metabolism isozyme inducers at least one of a drug and a drug metabolism isoenzyme inhibitor.
The drug balloon according to claim 1, wherein the bottom layer has a thickness of 0.1 μm to 1.0 μm, and the drug-loaded layer has a thickness of 1.0 μm to 20 μm.
The drug balloon according to claim 1, wherein the material of the bottom layer is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, polyglycerol ester , a combination of any one or more of chitosan, chitin, dextran, polystearate, phospholipid and polycitrate.
The drug balloon according to claim 1, wherein the carrier material of the drug-loading layer is selected from polyethylene glycol, polyethylene glycol-polycaprolactone, polysorbate, polyxylitol, A combination of any one or more of polyglycerol ester, chitosan, chitin, dextran, polystearate, phospholipid and polycitrate.
The drug balloon according to claim 1, wherein the drug receptor protein inhibitor is an inhibitor of immunoaffinity protein FKBP12, and the inhibitor of immunoaffinity protein FKBP12 is selected from any of the following materials A combination of one or more:

3-pyridine-3-propyl-(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-pyrrolidine-2-carboxylate; (3R)-4-(p-toluene Sulfonyl)-1,4-thiazole-3-carboxylic acid-L-leucine ethyl ester; and (3R)-4-(p-toluenesulfonyl)-1,4-thiazole-3-carboxylic acid-1 - Phenyllanin benzyl ester.
The drug balloon according to claim 1, wherein the drug metabolism isozyme inhibitor is an inhibitor of CYP3A4 isozyme, and the inhibitor of CYP3A4 isozyme is selected from any one of the following materials one or a combination of:

Posaconazole, erythromycin, telithromycin, HIV protease inhibitor, boceprevir, telaprevir, amiodarone, amprenavir, atonavir, cimetidine, ciproflox Star, clarithromycin, diltiazem, doxycycline, enoxacin, fluconazole, fluvoxamine, imatinib, indinavir, itraconazole, ketoconazole, micon azole, nefazodone, ritonavir, saquinavir, telithromycin, verapamil, voriconazole.
The drug balloon according to claim 1, wherein the drug metabolism isozyme inducer is an inducer of CYP3A4 isozyme, and the inducer of CYP3A4 isozyme is selected from any one of the following materials one or a combination of:

Aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenytoin, phenobarbital, Primidone, etravirine, rifampicin, St. John's wort, pioglitazone, topiramate.
The drug balloon according to claim 1, wherein the drug is selected from any one or a combination of the following drugs: paclitaxel, rapamycin and abciximab.
The drug balloon according to claim 1, wherein the drug-loading amount of the drug-loading layer is 0.5 μg/mm 2 to 5 μg/mm 2 .
The drug balloon according to claim 1, wherein the mass ratio of the carrier of the drug-loading layer to the drug is (0.1-10):1.
A method for preparing a drug balloon, comprising:

provide a balloon;

A bottom layer is arranged on the surface of the balloon, and the bottom layer includes a hydrophilic material and/or a lipophilic material;

A drug-carrying layer is provided on the surface of the bottom layer, and the drug-carrying layer includes a drug and a carrier;

A functional layer is disposed on the surface of the drug-loading layer, the functional layer includes a drug and a functional material, and the functional material includes a drug receptor protein inhibitor, a drug metabolism isoenzyme inducer, and a drug metabolism isoenzyme inhibitor at least one of them.
The method for preparing a drug balloon according to claim 11, wherein the preparation process of the functional layer comprises:

Preparation of functional layer solution;

The functional layer solution is loaded into the ultrasonic spraying equipment, and the process conditions of the ultrasonic spraying equipment are set;

Use the ultrasonic spraying equipment to spray the functional layer solution back and forth along the axial direction of the balloon;

Wherein, the process conditions of the ultrasonic spraying equipment include:

The flow rate is 0.01mL/min～0.1mL/min;

The distance between the nozzle and the balloon is 10mm to 30mm;

The spraying speed is 0.05mL/min～0.3mL/min;

The moving speed of the nozzle is 2mm/s～5mm/s.
The method for preparing a drug balloon according to claim 11 or 12, wherein the mass ratio of the drug receptor protein inhibitor to the drug in the functional layer is (0.25-4.0): 1; the functional layer The mass ratio of the drug metabolism isoenzyme inhibitor to the drug in the functional layer is (0.25-4.0):1; the mass ratio of the drug metabolism isoenzyme inducer to the drug in the functional layer is (0.25-4.0):1.