CN107998458B

CN107998458B - Balloon drug coating and drug balloon

Info

Publication number: CN107998458B
Application number: CN201711399181.XA
Authority: CN
Inventors: 翁玉麟; 牛冬子; 石全; 刘宝瑞; 谷卓阳
Original assignee: Dingke Medical Technology Suzhou Co ltd
Current assignee: Dingke Medical Technology Suzhou Co ltd
Priority date: 2017-12-22
Filing date: 2017-12-22
Publication date: 2021-02-19
Anticipated expiration: 2037-12-22
Also published as: CN107998458A

Abstract

The invention discloses a balloon drug coating and a drug balloon, which comprises nano-scale and/or micro-scale excipient particles and drug particles. The balloon drug coating formed by the balloon drug coating has a large surface area, so that the surface area of contact between drugs and the balloon can be increased on one hand, the binding force with the balloon is improved, and on the other hand, the contact area between the expanded balloon and the vessel wall can be increased, so that the drug particles can be fully contacted with the vessel wall and quickly and uniformly adhered to the vessel wall, the drugs can be quickly released to the vessel wall, and the release efficiency and the utilization rate of the drugs are improved.

Description

Balloon drug coating and drug balloon

Technical Field

The invention relates to the field of medical supplies, in particular to a balloon drug coating and a drug balloon.

Background

Angioplasty is a vascular interventional technique involving mechanical widening of an occluded blood vessel usually caused by atherosclerosis. A catheter having a tightly folded balloon is typically inserted into the vascular system of a patient and delivered to the site of the lesion where the balloon is inflated with a certain pressure. The balloon may be inflated to a certain diameter and length. Percutaneous Coronary Intervention (PCI) in coronary angioplasty treats stenosis of the coronary arteries of the heart. Percutaneous Transluminal Angioplasty (PTA) of peripheral blood vessels treats blood vessels other than coronary arteries.

Balloon catheters are the most common instruments used in PCI surgery. The sacculus pipe possesses sacculus and pipe body, and sacculus and pipe body link to each other, are located the distal end of body. A user of a balloon catheter places a balloon at a stenotic site in a blood vessel and expands to treat the site.

The drug coating balloon catheter is formed by coating a layer of drug on the surface of a balloon of the balloon catheter, and can be used for treating intravascular stenosis, wherein blood vessels comprise coronary arteries, peripheral blood vessels and the like. It can evenly spray the medicine to the pathological blood vessel without leaving the implants such as stent in the human body, thereby providing a window for the secondary treatment.

While the drug utilization of drug balloons is mainly affected by two aspects: drug delivery and drug release. The existing research shows that more than 80% of the medicine in the medicine balloon is lost in the operation process. In addition to the loss of drug during the procedure, the drug is not completely released during a short period of expansion (about 60 seconds) of the balloon, and about 5% to 10% of the drug remains on the balloon surface after the procedure is completed.

For example, the paccocath drug eluting balloon technology is commercialized in the beram medical science of germany, a paclitaxel release coronary balloon catheter with the trade name of sequent please is used, paclitaxel is used as an active drug, and iopromide contrast agent is used as a carrier, although the product has a certain effect in clinical application, the balloon drug coating of the beram commercial product is in a solid form and does not have viscosity, so that the performance of the drug coating is influenced; and, observe the condition of its surface under electron microscope, as shown in figure 1, its surperficial medicine coating presents the graininess of size inequality, and it is inhomogeneous to distribute on the sacculus surface, these all lead to the roughness increase on sacculus surface, and then increased the shearing force of sacculus surface medicine coating and blood, lead to that the medicine on sacculus surface is washed away by blood more easily in the process that the sacculus pipe was carried, simultaneously, coarse surface and the uneven medicine coating granule of size lead to the area of contact to reduce, when making sacculus medicine coating and pathological change position contact, produce certain clearance, and only partly convex medicine coating granule can laminate with the vascular wall, thereby release the medicine and cause adverse effect on the vascular wall.

For another example, chinese patent application CN 201610808118.6 discloses a solution in which a protective film with a plurality of sealing gaps is added outside a drug coating to prevent loss during drug delivery, and the drug is released to expand the sealing gaps of the protective film during balloon expansion, so that the drug is released from the gaps to improve the drug utilization rate, but because most of the drug coating is still enclosed in the protective film during balloon expansion, the drug coating is isolated and cannot directly contact with the blood vessel wall, and too small a contact area also has an adverse effect on the drug release.

The general inflation time of medicine coating sacculus in the use does not exceed 1 minute, and the medicine must be effectual transferring to the vascular wall from the sacculus surface in a minute, and in such short time, still can have a large amount of medicines to remain in the sacculus surface and can't release and lead to the problem that the medicine utilization ratio is low in current scheme.

On the other hand, during the process of delivering the drug balloon to the blood vessel, the drug content on the surface of the balloon is lost due to the scouring of blood or the dissolution of the drug into blood, and the amount of the drug which can be transferred from the surface of the balloon to the lesion site is affected.

Chinese patent application CN201010121627.4 has designed that the outer surface of the balloon is a non-planar structure with concavities and convexities, so that the amount of adsorbed drugs is increased, and the drugs adsorbed on the outer wall of the balloon can be kept as far as possible without being washed away by blood in the blood vessel, but will damage the balloon and affect the rated burst pressure thereof.

In the chinese patent application 201410289533.6, a plasma etching method is used to form a nano-scale microporous structure on the surface of the balloon, so as to improve the bonding force between the surface of the balloon and the drug coating, increase the drug loading rate and avoid the loss of the drug during the drug delivery process, but the plasma etching has an influence on the performance of the balloon and can reduce the burst pressure of the balloon.

Chinese patent application CN201110176942.1 describes a method for preparing a drug balloon by electrostatic self-assembly, which covers the drug coating with balloons made of different materials by self-assembly method. The number of the medicines can be overlapped layer by layer due to more circulation times of the electrostatic self-assembly, but the surface charge is gradually reduced after three times, and the medicine amount and the binding force assembled on the outer layer are in a descending trend.

Disclosure of Invention

The invention aims to solve the problems in the prior art, and surprisingly discovers that a balloon medicine coating formed by nano-scale and/or micron-scale coating particles can increase the contact area of a medicine and target positions such as a lesion position and a blood vessel wall, so that the medicine transfer rate is improved, and the balloon medicine coating is provided.

The purpose of the invention is realized by the following technical scheme:

a balloon drug coating that is a mixture comprising nanoscale and/or microscale excipient particles and drug particles.

Preferably, the size of the nanometer excipient particles and the size of the drug particles are between 1 and 100 nanometers, and the size of the micron excipient particles and the size of the drug particles are between 1 and 100 micrometers.

Preferably, the balloon drug coating is a liquefied hydrophobic mixture. Because the medicine coating has the characteristic of liquefaction, and the medicine coating particle is tiny, consequently receive the erodeing of blood more easily, consequently make sacculus medicine coating have hydrophobicity to it is difficult for being dissolved by blood and erodeing away and take away.

Also, in order to uniformly diffuse and distribute the drug while avoiding the drug being dissolved and washed away by blood during delivery, it is preferable that the excipient is a triglyceride, triacetyl triglyceride, capric triglyceride or caprylic triglyceride, and more preferably a triglyceride, having hydrophobicity and biocompatibility, so that the balloon drug coating is rendered hydrophobic as a whole.

And the drug is preferably a macrolide immunosuppressant, macrolide antibiotic, rapamycin, structural derivatives and functional analogs of rapamycin, everolimus, structural derivatives and functional analogs of everolimus, paclitaxel, taxanes, temsirolimus compounds, oxazololimus, everolimus, sirolimus, bisomolimus, myolimus, deforolimus, tacrolimus or temsirolimus or compounds of temsirolimus, oxazololimus, everolimus, sirolimus, bisomolimus, myolimus, deforolimus, tacrolimus or compounds of temsirolimus.

Preferably, the balloon drug coating comprises 1-10 uniform particle layers stacked layer by layer, and the total thickness of the balloon drug coating is 2-100 microns.

Preferably, the balloon drug coating layer has a ratio of the excipient to the drug by mass of 1: 9-9: 1.

Another aspect of the present invention provides a drug balloon, including a balloon and any one of the balloon drug coatings described above, wherein the balloon drug coating uniformly coats an outer surface of the balloon through a spraying process.

Preferably, the balloon is folded into a 3-6 wing structure.

The preferable drug content on the surface of the balloon is 1-100 ug/mm²In the meantime.

The technical scheme of the invention has the advantages that:

the balloon drug coating formed by the balloon drug coating has a very large surface area, so that the contact surface area of the drug and the balloon can be increased, the binding force with the balloon is improved, the contact area with the vessel wall after the balloon is inflated and expanded can be increased, the drug particles can be fully contacted with the vessel wall and quickly and uniformly adhered to the vessel surface, and the release efficiency and the utilization rate of the drug are improved.

Meanwhile, the balloon drug coating has hydrophobicity, the drug amount which is easily dissolved in blood or washed away by blood in the conveying process due to the fact that the coating particles are reduced can be effectively reduced, the drug amount reaching the pathological change position can be increased, and the biocompatibility of the excipient is also convenient for rapid and sufficient drug release after the balloon drug coating is in contact with the pathological change position.

The characteristic of further liquefaction changes the conventional thinking mode that the existing drug coating in the field is a solid coating, so that the balloon drug coating has certain viscosity, the balloon drug coating and the balloon have better adhesive force and better binding force between drug coating particles, the loss of the drug in the conveying process is reduced, and the drug coating is adhered to the surface of a blood vessel wall when being contacted with a lesion position.

The liquefied balloon medicine coating is convenient for folding the balloon, and folds the balloon, is favorable for shielding the balloon medicine coating on the surface of the balloon to realize protection, and is favorable for further reducing the loss of the balloon medicine coating in the conveying process.

The multi-layered structure is beneficial to uniformly distributing micron-sized and/or nano-sized drug coating particles and reducing the roughness of the surface of the balloon, and meanwhile, the multi-layered structure can fully utilize the bonding force between layers and a multi-layer structure to solve the problem that the whole or part of the drug coating of the balloon can be separated from the balloon when the bonding force between the drug coating of the single layered balloon and the surface of the balloon is not good under the condition of the same thickness in the conveying process.

Due to the improvement of the bonding force between the balloon medicine coating and the balloon and the medicine transfer rate, a thicker balloon medicine coating can be formed on the surface of the balloon, so that the medicine amount carried by the balloon is increased, and the balloon medicine transfer system is beneficial to providing more medicines in one treatment process.

Drawings

Fig. 1 is an electron micrograph of the surface of a drug balloon available in baylang;

FIG. 2 is a cross-sectional view of the drug balloon of the present invention in a folded state;

fig. 3 is an electron microscope picture of the surface condition of the drug balloon of example 5 of the present invention;

fig. 4 is a partial electron micrograph of the surface condition of the drug balloon of example 3 of the present invention.

Detailed Description

Objects, advantages and features of the present invention will be illustrated and explained by the following non-limiting description of preferred embodiments. The embodiments are merely exemplary for applying the technical solutions of the present invention, and any technical solution formed by replacing or converting the equivalent thereof falls within the scope of the present invention claimed.

The invention discloses a drug balloon, which comprises a balloon and a balloon drug coating uniformly coating the outer surface of the balloon.

As shown in fig. 2, the balloon is folded into an evenly-divided structure with 3 wings to 6 wings, and the formed wings have certain curling, so that the outer diameter of the balloon is reduced, the balloon is convenient to transport, and the balloon medicine coating on the outer surface of the balloon is covered and protected by the wings.

The balloon drug coating is a hydrophobic liquefied mixture which comprises nanoscale and micron-sized excipient particles and drug particles, wherein the nanoscale excipient particles and the drug particles are 1-100 nanometers in size, and the micron-sized excipient particles and the drug particles are 1-100 micrometers in size.

Because the sacculus medicine coating that micron order and/or nanometer medicine coating granule (excipient granule and medicine granule) formed has very big surface area, can increase the contact surface area of medicine and sacculus on the one hand, thereby improve the cohesion with the sacculus, on the other hand, can increase the sacculus aerify expand the area of contact with the vascular wall after opening, and then make the medicine granule can endure more abundant, more even with vascular surface contact and adhesion on it, make the medicine can release to the vascular wall fast on, thereby improve the release efficiency and the utilization ratio of medicine.

In addition, micron-scale and/or nanometer-scale drug coating particles are also beneficial to enabling the drug particles to be uniformly distributed in the whole balloon drug coating, so that when the balloon drug coating is in contact with the vessel wall, the drug particles are uniformly distributed to the pathological change position, the drug particles are beneficial to uniformly releasing the drug, the drug releasing area is increased, the drug utilization rate is improved, and the treatment effect is improved.

Furthermore, the nano-scale and/or micron-scale drug coating particles are beneficial to realizing the uniform distribution of the drug coating particles and reducing the gaps among the drug coating particles, avoiding the occurrence of hollow structures and being beneficial to reducing the surface roughness of the coating, so that the drug balloon has lower surface roughness when the coating coats the surface of the balloon, and the reduction of the surface roughness can reduce the shearing force between the balloon and blood in the conveying process on one hand, thereby being convenient for conveying and reducing the loss amount of the drug coating of the balloon due to blood scouring in the conveying process; on the other hand, smooth surface and even medicine coating granule also are favorable to sacculus medicine coating and pathological change position more fully to be contacted, avoid producing the clearance or only have the medicine coating granule of bulge and vessel wall contact to the release of medicine of further being convenient for.

And compared with the balloon medicine coating formed by micron-sized medicine coating particles, the balloon medicine coating of the nano-sized medicine coating particles has a better effect, in addition, when the micron-sized particles and the nano-sized particles are not doped with each other in the medicine coating particles, the particle size difference is small, the particle uniformity of the obtained coating is better, and therefore the surface roughness of the coating can be further reduced and the contact area with the blood vessel wall is increased.

Preferably, the excipient is triglyceride, triacetin, capric acid triglyceride or caprylic acid triglyceride, exemplified by triglyceride, having hydrophobicity and biocompatibility.

The medicine is a macrolide immunosuppressant, a macrolide antibiotic, rapamycin, structural derivatives and functional analogs of rapamycin, everolimus, structural derivatives and functional analogs of everolimus, paclitaxel, taxanes, temsirolimus compounds, azolsirolimus, everolimus, sirolimus, bisiollimus, myolimus, deforolimus, tacrolimus or temsirolimus compounds, oxazololimus, everolimus, sirolimus, bisiollimus, myolimus, deforolimus, tacrolimus or temsirolimus compounds, in the embodiment, paclitaxel is taken as an example.

And the mass ratio of the excipient to the drug is 1: 9-9: 1, the specific proportion is set according to actual needs.

Furthermore, the balloon drug coating comprises 1-10 uniform particle layers which are overlapped layer by layer, the total thickness of the balloon drug coating is 2-100 microns, and the drug content on the surface of the balloon is 1-100 ug/mm²In the meantime.

Specifically, when a balloon drug coating is formed on the balloon, the method is realized by the following steps:

1) mixing excipient, medicine and solvent in certain proportion, and heating and stirring for certain time to form medicine liquid;

2) pre-folding the balloon to form a crease on the balloon;

3) spraying the formed liquid medicine on the surface of the balloon by an ultrasonic spraying machine;

4) after the solvent in the liquid medicine is volatilized, a balloon medicine coating is formed on the surface of the balloon;

5) and folding and molding the balloon sprayed with the balloon medicine coating according to the preformed crease.

In the above 1), the solvent is preferably ethanol, acetone, methanol, etc., more preferably acetone, and the solution is heated to 20-70 ℃ during the preparation of the drug solution, and the stirring time is 5-60 minutes.

In the above 2), the balloon is folded through the folding machine, the balloon is heated by the inflation pressure inside the balloon in the folding process, the folding machine is used for compressing for a period of time, so that folding traces are formed on the surface of the balloon, the inflation pressure inside the balloon is controlled to be 0.5-5 atm, the folding time is 10-300 s, and the balloon is heated to 30-70 ℃ in the folding process.

In the step 3), the prepared liquid medicine is placed at a solution storage part of spraying equipment, the liquid medicine is sprayed out from a nozzle by using a certain pressure, the liquid medicine is atomized by an ultrasonic device at the nozzle, the speed of the liquid medicine discharged from a needle cylinder is adjusted to be 15-25ul/min according to different requirements, and the power of the ultrasonic device is adjusted to be 10-1000 watts.

When spraying, the pressure of 1-10 atm is provided in the saccule, so that the saccule is inflated to form a shape with a protruding outer surface, the saccule performs autorotation and/or linear motion along an axis, the autorotation speed of the saccule is controlled to be between 1-100 revolutions per second, preferably between 160-260rpm, the linear motion speed of the saccule is controlled to be between 0.1-100 mm/s, preferably between 0.1-20 mm/s, and once or several times of spraying is performed as above, so when multiple times of spraying are performed, a plurality of uniform particle layers which surround the periphery of the saccule and are sequentially overlapped are formed.

Through effective setting and mutual cooperation of the medicine discharging speed of the needle cylinder, the ultrasonic power, the rotating speed of the balloon and the linear moving speed, the size of formed spraying particles is uniform, the spraying particles can be uniformly distributed and fully covered on the surface of the balloon in the spraying process, and the finally formed medicine coating is guaranteed to have the optimal performance.

In the above 5), the balloon is formed into a 3-6-flap structure by folding the balloon at the time of the fold formation.

Example 1

1) Mixing paclitaxel, triglyceride and acetone according to the mass ratio of 1:5:44, heating and stirring at constant temperature until paclitaxel and triglyceride are completely dissolved to form a liquid medicine.

2) And pre-folding the balloon to form a crease.

3) Injecting the prepared liquid medicine into spraying equipment, adjusting the medicine discharging speed of a needle cylinder to be 20ul/min, adjusting the power of an ultrasonic device to be 30 watts, controlling the pressure inside the saccule to be 2atm, controlling the self-rotation speed of the saccule to be 3 r/s, performing linear reciprocating motion at 0.3mm/s, and spraying from one end of the saccule to the other end for a spraying period, wherein the spraying period is 10 periods in total.

4) And obtaining the saccule coated with the saccule medicine coating after the acetone is volatilized.

5) And folding and shaping the saccule coated with the saccule medicine coating.

Example 2

Paclitaxel, triglyceride and acetone are mixed according to the mass ratio of 1:4: 20.

Other procedures and conditions are the same as those in embodiment 1, and are not described herein again.

Example 3

Paclitaxel, triglyceride and acetone are mixed according to the mass ratio of 2:8: 5.

Example 4

Paclitaxel, triglyceride and acetone are mixed according to the mass ratio of 3:10: 7.

Example 5

Paclitaxel, triglyceride and acetone are mixed according to the mass ratio of 1:2: 47.

Example 6

Paclitaxel, triglyceride and acetone are mixed according to the mass ratio of 32:3: 15.

The surface uniformity of the drug balloon of examples 1-6 was observed by an electron microscope (leica DM4000M metallographic microscope), wherein fig. 3 shows the surface condition of the drug balloon of example 5 of the present invention, and fig. 4 shows the enlarged view of the surface area of the drug balloon of example 3 of the present invention, and it can be seen from the drawings: compared with products sold in the Brown market, the balloon drug coating effectively covers the whole balloon surface, the size and the distribution of particles of the balloon drug coating are more uniform, the drug balloon has a smoother surface, the surface roughness is greatly reduced, so that the drug balloon is beneficial to conveying, the shearing force between the drug coating and blood in the conveying process is reduced, the drug loss in the conveying process is reduced, meanwhile, the drug coating is beneficial to fully contacting with the vessel wall, and the problem that the drug transfer is not fully influenced due to insufficient contact caused by gaps generated between drug coating particles with different sizes and the vessel wall is avoided.

On the other hand, the research of the invention finds that: for the drug coating, the balloon drug coating with proper viscosity is favorable for being attached to the balloon, the balloon is prevented from being washed away by blood when passing through a blood vessel, the balloon is easier to be adhered to and transferred with a blood vessel wall and the like, the preferable viscosity range is about 500-5000 cp, more preferably 500-1000 cp, and most preferably 800-1000 cp, and the results of the viscosity measurement of the drug balloon in the embodiments 1-6 of the invention are as follows:

the balloon drug coating is liquefied, has certain viscosity, and the viscosity of the balloon drug coating is about 500-3000 cp according to different component proportions, and can be adhered to the surface of the balloon.

Further, the percentage of the medicine flushed by blood in the conveying process of the medicine balloon in the weight of the medicine on the balloon is determined through a medicine falling rate experiment, the falling rate of the medicine in the conveying process indicates the firmness of the medicine coating on the balloon, the lower the falling rate, the less the medicine lost in the conveying process, the more the medicine reaching the target position, and the more the medicine capable of exerting the treatment effect.

The following simulation test is specifically adopted:

a) inserting a guide wire into a guide wire lumen of the balloon catheter;

b) pushing the drug balloon catheter along the guide wire to simulate surgical application;

c) pushing the balloon to a target simulated lesion position;

d) the balloon is not expanded, and is directly withdrawn;

e) eluting the residual drug on the withdrawn drug balloon;

f) drug residual amount M1 on the withdrawn balloon was determined using high performance liquid chromatography.

The falling rate = (Mn-M1)/Mn 100%. Wherein Mn is the nominal content of the drug.

According to the processes, the dropping rates of the medicines of the medicine balloons in the embodiments 1 to 6 and the Beilang market are obtained through one-by-one analysis, the medicine balloon has the medicine dropping rate not higher than 20%, and the medicine dropping rate of the medicine balloon in the Beilang market is about 33%, so that the medicine dropping rate of the medicine balloon is far lower than that of the medicine balloon in the Beilang market, compared with the medicine balloon in the Beilang market, the medicine coating of the balloon is firmer on the balloon, the medicine loss in the conveying process is less, and more medicine reaches the target position.

The invention has various embodiments, and all technical solutions formed by adopting equivalent transformation or equivalent transformation are within the protection scope of the invention.

Claims

1. The balloon medicine coating is characterized in that: the balloon drug coating is a mixture comprising nano-scale and/or micro-scale drug particles and nano-scale excipient particles; the balloon drug coating is a hydrophobic liquefied mixture, and the viscosity of the balloon drug coating is 500-5000 cp; the excipient is triglyceride, triacetic acid triglyceride, capric acid triglyceride or caprylic acid triglyceride with hydrophobicity and biocompatibility.

2. A balloon drug coating according to claim 1, characterized in that: the sizes of the nanoscale excipient particles and the nanoscale drug particles are 1-100 nanometers; the size of the micron-sized drug particles is 1-100 microns.

3. A balloon drug coating according to claim 1, characterized in that: the drug is a macrolide immunosuppressant, a macrolide antibiotic, rapamycin, structural derivatives and functional analogs of everolimus, paclitaxel, taxanes, oxazololimus, everolimus, sirolimus, bisolimus, myolimus, deforolimus, tacrolimus or temsirolimus.

4. A balloon drug coating according to claim 1, characterized in that: the balloon drug coating comprises 1-10 uniform particle layers stacked layer by layer, and the total thickness of the balloon drug coating is 2-100 microns.

5. A balloon drug coating according to any one of claims 1 to 4, characterized in that: the mass ratio of the excipient to the medicine is 1: 9-9: 1.

6. A drug balloon, characterized in that: the balloon drug coating comprises a balloon and the balloon drug coating as claimed in any one of claims 1 to 5, wherein the balloon drug coating uniformly coats the outer surface of the balloon.

7. The drug balloon of claim 6, wherein: the balloon is folded into a structure with 3 wings to 6 wings.

8. The drug balloon of claim 6, wherein: the drug content on the surface of the balloon is 1-100 mu g/mm²In the meantime.