CN107865982B

CN107865982B - Drug-coated balloon

Info

Publication number: CN107865982B
Application number: CN201610865184.7A
Authority: CN
Inventors: 宋精忠; 谢琦宗
Original assignee: Lifetech Scientific Shenzhen Co Ltd
Current assignee: Lifetech Scientific Shenzhen Co Ltd
Priority date: 2016-09-28
Filing date: 2016-09-28
Publication date: 2020-09-25
Anticipated expiration: 2036-09-28
Also published as: WO2018059167A1; CN107865982A

Abstract

The invention discloses a drug coating balloon, which comprises a balloon body and a drug coating covering the surface of the balloon body, wherein the drug coating contains active drugs and carriers, the active drugs comprise antiproliferative drugs, and the carriers comprise a transdermal enhancer. The invention uses the penetration enhancer which can promote the rapid penetration and absorption of the drug as a carrier, so that the drug can rapidly penetrate into the tissues of the diseased part after being released, and the absorption rate of the drug in the vascular system or the diseased tissues of other body lumens is improved. The defect that after the drug coating saccule is placed into a human body in clinical use, the drug permeates to a target lesion part too slowly and is washed away by high-speed blood flow without being absorbed by blood vessels and lost can be solved, and a large amount of drug can be retained in the tunica media of the blood vessels due to the increase of the drug amount absorbed by tissues, so that the drug effect can be continuously exerted to inhibit long-term restenosis.

Description

Drug-coated balloon

Technical Field

The invention relates to an interventional medical device, in particular to a drug-coated balloon.

Background

A medicine coating balloon belongs to an interventional instrument, and the principle of the balloon is that active medicines are loaded on the surface of a common balloon and are conveyed to a target pathological change part of a blood vessel, and then the medicines are fully contacted with the blood vessel wall through inflation and expansion of the balloon, so that long-term stenosis of the target pathological change part is eliminated.

Except for capillaries and lymphatic capillaries, the walls of blood vessels are generally divided into intima, media and adventitia in that order from the luminal surface. The intima is the innermost layer of the vessel wall, consisting of the endothelium and the subendothelial layer. Endothelial cells and substrates constitute a permeable dense barrier through which liquids, gases and macromolecular substances can selectively penetrate into the media. The thickness and composition of the tunica media vary depending on the type of blood vessel. The aorta is mainly elastic membrane, and a little of smooth muscle is arranged between the aorta and the aorta; the middle artery is composed primarily of smooth muscle.

Therefore, in the drug-coated balloon interventional procedure, the drug coating on the balloon surface is eluted from the balloon surface and released into the blood vessel of the lesion site after reaching the target lesion site, and the drug effect cannot be fully exerted. Wherein only the drugs absorbed by the intima of the blood vessel and entering the intima-media smooth muscle cell layer of the blood vessel can exert the curative effect, inhibit the malignant hyperplasia of the smooth muscle cells and reduce the restenosis rate. Because the restenosis of the blood vessel is a chronic process, the more the drug amount absorbed by the intima of the blood vessel and entering the media of the blood vessel is, the longer the drug stays in the vascular tissue of the target lesion part correspondingly, and the better the effect of inhibiting the restenosis of the blood vessel is. When the medicine coating is released from the surface of the saccule to the inner wall of the blood vessel within a few minutes after the saccule is contacted with the target lesion blood vessel, because the speed of the medicine absorbed by the endothelium of the blood vessel is very slow, a large amount of medicine is not absorbed and is washed away by high-speed blood flow, and enough medicine can not be ensured to penetrate through the intima and enter the tunica media of the blood vessel to inhibit the malignant hyperplasia of smooth muscle cells, and the long-term inhibition of the restenosis of the blood vessel can not be ensured.

The existing drug coating saccule adds a carrier and an additive into a drug coating to increase the solubility of the drug and improve the immediate drug release rate (i.e. the load transfer rate) of the drug. The carriers and the additives can only ensure that the active medicine is quickly released to the vascular wall of a diseased part as much as possible in a short time when the saccule is contacted with a diseased target blood vessel, and the medicine released to the inner wall of the blood vessel can not be ensured to be quickly absorbed by the vascular tissue and not to be washed away and lost by blood; in addition, because insufficient active drug penetrates the intima to enter the tunica media of the blood vessel, insufficient drug can be remained in the tunica media of the blood vessel for a long time to continuously exert the drug effect, and long-term restenosis of the blood vessel is inhibited.

Disclosure of Invention

Based on this, it is necessary to provide a drug-coated balloon, which can satisfy the premise that a large amount of drugs are rapidly transferred from the balloon surface to the vascular wall of a local target lesion site in a very short interventional operation process, and more importantly, can accelerate the absorption rate of the drugs by the vascular endothelium, so that the drugs are not easily washed away and lost by continuous blood flow, thereby increasing the total amount of the drugs entering the tunica media of the blood vessel through the tunica intima of the blood vessel, ensuring that the tunica media of the blood vessel can continuously exert drug effect after the interventional operation, and inhibiting long-term restenosis.

The absorption process of the anti-restenosis drug or the anti-proliferative drug from the endothelial surface to the media is mainly because the drug concentration difference exists between the drug concentration on the endothelial surface and the media of the blood vessel, and the drug permeates the intima and enters the media smooth muscle cell layer to reach the target site to play a role in passive diffusion and permeation. We have found that the use of a permeation enhancer as a drug carrier can reduce the resistance of the drug to passage through the endothelium, assisting the rapid passage of the drug through the endothelium, diffusion, and through the substrate to the media. Therefore, the penetration enhancer can be added into the drug coating of a drug-carrying device such as a drug eluting balloon or a drug eluting stent, so that the drug can more rapidly penetrate into endothelium and a substrate to reach a blood vessel tunica media and play a role in inhibiting smooth muscle cell proliferation.

The invention provides a drug coating balloon, which comprises a balloon body and a drug coating covering the surface of the balloon body. The drug coating contains an active drug and a carrier. The active drug comprises an anti-restenosis drug or an anti-proliferative drug. The carrier includes a penetration enhancer. When the drug coating saccule is placed into a human body, the active drug is released at the placement target site and transferred to the inner wall of the blood vessel after the drug coating is pressed with the blood vessel wall. The penetration enhancer carrier in the drug coating acts on vascular endothelial cells, changes the structure of the endothelial cells, influences the permeability of the endothelial cells, and accelerates the penetration of the drug to the vascular intima of a lesion part and the penetration and diffusion to the media, so that the drug is more quickly absorbed by tissues, the total drug amount absorbed by the tissues is increased, and the drug can be kept in the vascular media for a long time to continuously exert the drug effect.

In one embodiment, the mass ratio of the active drug to the carrier is (0.5-49): 1.

in one embodiment, the carrier further comprises a dispersant. Because the lipophilic anti-restenosis drugs or anti-proliferative drugs are easy to aggregate mutually, and the hydrophilic and lipophilic dispersing agents can be rapidly combined with the lipophilic drugs to separate drug particles, the probability of agglomeration among drug molecules is reduced, and the coating uniformity is improved. Secondly, after the dispersing agent is added, the fineness of the drug coating particles can be improved, the size of the drug particles is reduced, and the small-sized drug is easier to absorb. In addition, the specific surface area of the drug molecules combined with the dispersing agent is increased, the solubility is improved, the adsorption capacity after the drug molecules are contacted with a lipophilic structure of a blood vessel is improved, and the transfer of a drug coating from the surface of the balloon to the blood vessel wall is facilitated. In addition, after the dispersing agent is combined with the lipophilic medicament, the lipophilic medicament is protected in the balloon conveying process, so that the adhesion of the medicament coating and the surface of the balloon body is facilitated, the loss of the medicament coating in the conveying process is reduced, and the balloon is ensured to have sufficient medicament to transfer to tissues before the wall is expanded and attached. Therefore, when the dispersing agent and the penetration enhancer act synergistically, the release process of the medicine can be accelerated, the penetration and absorption of the medicine on the endothelial surface can be promoted, and the particle shedding and the process loss of the medicine coating on the surface of the balloon in the conveying process can be reduced, so that a better treatment effect can be obtained.

In one embodiment, the mass ratio of the dispersing agent to the penetration enhancer is (0.01-50) to 1.

In one embodiment, the antiproliferative drug is selected from at least one of paclitaxel, paclitaxel derivatives, rapamycin, or rapamycin derivatives.

In one embodiment, the penetration enhancer is at least one selected from the group consisting of alcohol compounds and derivatives thereof, fatty acids and derivatives thereof, and aromatic acids and derivatives thereof. Unlike transdermal patches or other transdermal agents, the vascular wall composition is different from that of the skin, and the physiological environment in the blood vessel is also different from that of transdermal administration, so that the transdermal agent suitable for being used as the drug coating of the vascular implantation or intervention medical equipment should overcome the influence of the pH value of blood and the hemodynamic environment of continuous blood flow scouring, and cannot interact with other substances in blood.

In one embodiment, the alcohol compound is selected from a fatty alcohol selected from octanol, decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, arachidyl alcohol, or behenyl alcohol, or a polyol. The polyhydric alcohol is selected from propylene glycol, glycerol or polyethylene glycol.

In one embodiment, the fatty acid is selected from caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, or arachidonic acid.

In one embodiment, the aromatic acid is selected from benzoic acid, phenylacetic acid, syringic acid, cinnamic acid, o-hydroxybenzoic acid, p-aminobenzoic acid, p-aminomethylbenzoic acid, p-aminosalicylic acid, or phthalic acid.

In one embodiment, the derivative includes esters, amides, anhydrides, or salts; the salts include magnesium, sodium, zinc, calcium, barium or copper salts.

In one embodiment, the penetration enhancer is selected from at least one of lauryl alcohol, myristyl alcohol, stearyl alcohol, lauric acid, palmitic acid, stearic acid, magnesium stearate, sodium stearate, zinc stearate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, glycerol monooleate, polyoxyethylene stearate, sodium benzoate, cinnamic acid, o-hydroxybenzoic acid, p-aminosalicylic acid, or phthalic anhydride.

In one embodiment, the dispersant is selected from at least one of acetate, maleate, polyvinylpyrrolidone, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinate, gluconate, polyethylene glycol 1000, polyethylene glycol 2000, acetamide, poloxamer, pentaerythritol, glutamate, vanillic acid salt, hydroxypropylmethylcellulose, or lactobionic acid salt.

In one embodiment, the content of the active drug on the surface of the balloon body is in a range of 0.5-20 [ mu ] g/mm²。

In one embodiment, the drug-coated balloon is used to deliver the active drug into a blood vessel or lumen. The blood vessel includes a coronary artery blood vessel, a peripheral artery blood vessel, or a cerebral artery blood vessel. The lumen includes the esophagus, airway, intestinal tract, biliary tract, cervix, urinary tract, prostate, or brain passageway. The peripheral arterial vessels include the leg arteries, further, the iliac, external iliac, femoral or popliteal arteries.

Compared with the prior art, the invention at least has the following advantages and beneficial effects:

(1) the drug coating of the drug coating balloon contains the penetration enhancer, and the drug can be quickly absorbed by vascular tissues after being released from the surface of the balloon to the vascular wall, so that the defect that a large amount of drug is washed and lost by high-speed flowing blood before being absorbed by the vascular tissues is overcome;

(2) the medicine can more quickly penetrate the intima to reach the media under the action of the penetration enhancer, so that the medicine quantity absorbed by tissues is higher, enough medicine is reserved in the media layer of the blood vessel for a long time, the continuous action time of the medicine can be prolonged, and the medicine can be ensured to continuously exert the maximum curative effect to inhibit long-term restenosis.

Drawings

FIG. 1 is the release curve of the tunica media drug of the target blood vessel of the balloon dilatation segment after the drug-coated balloons of examples 1 to 7 and comparative example 1 of the invention are placed in a healthy piglet for dilatation;

fig. 2 is an H & E staining diagram of pathological sections of tissues around the drug-coated balloon 28 days after the drug-coated balloon provided in embodiment 1 of the present invention is placed in a healthy piglet for expansion;

fig. 3 is a staining chart of pathological section α -actin of the tissue around the drug-coated balloon 28 days after the drug-coated balloon provided in example 1 of the present invention is placed in a healthy piglet for expansion;

fig. 4 is a Masso trichrome staining graph of pathological sections of tissues around the drug-coated balloon 28 days after the drug-coated balloon provided in example 1 of the present invention is placed in a healthy piglet for expansion;

fig. 5 is a Movat staining diagram of pathological sections of tissues around the drug-coated balloon 28 days after the drug-coated balloon provided in example 1 of the present invention is placed in a healthy piglet and expanded;

fig. 6 is a microphotograph of particle shedding of the drug-coated balloon provided in example 1 of the present invention after an in vitro simulation test;

fig. 7 is a photomicrograph of particle shedding of the drug-coated balloon provided in example 2 of the present invention after in vitro simulation testing;

fig. 8 is a photomicrograph of particle shedding after in vitro simulation testing of the drug-coated balloon provided in example 3 of the present invention;

fig. 9 is a photomicrograph of particle shedding after in vitro simulation testing of the drug-coated balloon provided in example 4 of the present invention;

fig. 10 is a photomicrograph of particle shedding from a drug-coated balloon provided in accordance with example 5 of the present invention after in vitro simulation testing;

fig. 11 is a photomicrograph of particle shedding from a drug-coated balloon provided in accordance with example 6 of the present invention after in vitro simulation testing;

fig. 12 is a photomicrograph of particle shedding from a drug-coated balloon provided in accordance with example 7 of the present invention after in vitro simulation testing;

figure 13 is a photomicrograph of the particle shedding of the drug-coated balloon of comparative example 1 after in vitro simulation testing.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Example 1

11mg of paclitaxel as an active drug, 17mg of lauric acid as a penetration enhancer, 5mg of hydroxypropylmethylcellulose as a dispersant were mixed with 7mL of ethanol and 4mL of purified water to prepare a drug solution. The balloon of the PTA balloon catheter (the size is 4mm in diameter and 40mm in length) is folded into three flaps in ten thousand-grade clean environment, then the medicine solution is dripped on the surface of the balloon with the flaps by a precise injector in hundred-grade clean environment and dried, and the dripping is repeated until the medicine concentration on the surface of the balloon reaches 3 mug/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the vehicle was 22mg, the mass ratio of the active drug to the vehicle was 0.5, and the mass ratio of the dispersing agent to the permeation enhancer in the vehicle was 0.29.

Example 2

495mg of paclitaxel is taken as an active drug, 10mg of isooctyl palmitate is taken as a penetration enhancer, 0.1mg of sodium citrate is taken as a dispersing agent, and the mixture is mixed with 20mL of isopropanol to prepare the drugAnd (3) solution. The balloon of the PTA balloon catheter (the diameter is 4mm, the length is 40mm) is folded into three flaps in ten thousand-level clean environment, then the medicine solution is dripped on the surface of the balloon with the folded flaps in hundred-level clean environment and dried, and the dripping is repeated until the medicine concentration on the surface of the balloon reaches 0.5 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 10.1mg, the mass ratio of the active drug to the carrier is 49, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 0.01.

Example 3

120mg of paclitaxel is taken as an active drug, 36mg of sodium benzoate is taken as a penetration enhancer, and the paclitaxel, the sodium benzoate and 10mL of ethanol and 4mL of purified water are mixed to prepare a drug solution. After a balloon of a PTA balloon catheter (with the diameter of 4mm and the length of 40mm) is folded into three flaps in a ten thousand-level clean environment, a medicine solution is sprayed on the surface of the balloon with the folded flaps by using a spraying device in a hundred-level clean environment, so that the medicine concentration on the surface of the balloon reaches 2 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. The mass ratio of active drug to carrier in this example was 3.33.

Example 4

100mg of paclitaxel as an active drug, 50mg of magnesium stearate as a penetration enhancer, 5mg of polyethylene glycol 1000 as a dispersant, 10mL of ethanol and 4mL of purified water were mixed to prepare a drug solution. After a balloon of a PTA balloon catheter (with the diameter of 4mm and the length of 40mm) is folded into three flaps in a ten-thousand-level clean environment, a medicine solution is sprayed on the surface of the balloon with the folded flaps by using a spraying device in a hundred-level clean environment, so that the medicine concentration on the surface of the balloon reaches 3 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 55mg, the mass ratio of the active drug to the carrier is 1.82, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 0.1.

Example 5

120mg of paclitaxel as active drug, 3mg of lauryl alcohol as penetration enhancer, 9mg of acetamide as dispersant, 2mL of ethanol and 0.4mL of purified waterMixing to prepare a medicine solution. After a balloon of a PTA balloon catheter (with the diameter of 4mm and the length of 40mm) is folded into three flaps in a ten thousand-level clean environment, a medicine solution is sprayed on the surface of the balloon with the folded flaps by a spraying device in a hundred-level clean environment, so that the medicine concentration on the surface of the balloon reaches 2.5 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the vehicle was 12mg, the mass ratio of the active drug to the vehicle was 10, and the mass ratio of the dispersing agent to the permeation enhancer in the vehicle was 3.

Example 6

12mg of paclitaxel as an active drug, 1mg of stearyl alcohol as a penetration enhancer and 5mg of polyvinylpyrrolidone as a dispersant were mixed with 100mL of isopropyl alcohol and 20mL of purified water to prepare a drug solution. After a ball sac of a PTCA ball sac catheter (the diameter is 3mm and the length is 20mm) is folded into three flaps in ten thousand-level clean environment, a medicine solution is sprayed on the surface of the ball sac behind the flaps by a spraying device in hundred-level clean environment, so that the medicine concentration on the surface of the ball sac reaches 1.5 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 6mg, the mass ratio of the active drug to the carrier is 2, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 5.

Example 7

20mg of paclitaxel as an active drug, 0.5mg of stearamide as a penetration enhancer and 25mg of polyethylene glycol 2000 as a dispersant are mixed with 10mL of ethanol and 5mL of purified water to prepare a drug solution. After a balloon of a PTA balloon catheter (with the diameter of 4mm and the length of 40mm) is folded into three flaps in a ten thousand-level clean environment, a medicine solution is sprayed on the surface of the balloon with the folded flaps by using a spraying device in a hundred-level clean environment, so that the medicine concentration on the surface of the balloon reaches 5 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 25.5mg, the mass ratio of the active drug to the carrier is 0.78, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 50.

Example 8

120mg thunderThe patulin is used as an active drug, 4mg of glycerol monooleate is used as a transdermal enhancer, 24mg of poloxamer is used as a dispersing agent, and the dispersing agent, 2mL of ethanol and 10mL of purified water are mixed to prepare a drug solution. The balloon of the PTA balloon catheter (diameter 5mm, length 80mm) is folded into five folds in ten thousand grade clean environment, and then the medicine solution is sprayed on the surface of the balloon with the folded flap by using a spraying device in hundred grade clean environment, so that the medicine concentration on the surface of the balloon reaches 10 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 28mg, the mass ratio of the active drug to the carrier is 4.29, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 6.

Example 9

Rapamycin 210mg as an active drug, polyoxyethylene stearate 2mg as a permeation enhancer, pentaerythritol 40mg as a dispersant, and 45mL of ethanol and 5mL of purified water were mixed to prepare a drug solution. The balloon of the PTA balloon catheter (diameter 7mm, length 120mm) is folded into five folds in ten thousand grade clean environment, and then the medicine solution is sprayed on the surface of the balloon with the folded flap by using a spraying device in hundred grade clean environment, so that the medicine concentration on the surface of the balloon reaches 20 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier is 42mg, the mass ratio of the active drug to the carrier is 5, and the mass ratio of the dispersing agent to the penetration enhancer in the carrier is 20.

Example 10

Rapamycin 10mg as the active drug and magnesium stearate 2mg as the transdermal enhancer were mixed with 20mL of ethanol to prepare a drug solution. After a sacculus of a PTCA sacculus catheter (the diameter is 2.5mm and the length is 18mm) has three folded flaps in a ten thousand-level clean environment, a medicine solution is sprayed on the surface of the sacculus with the folded flaps by a spraying device in a hundred-level clean environment, so that the medicine concentration on the surface of the sacculus reaches 3.5 mu g/mm²After drying at room temperature for 24 hours, packaging and ethylene oxide sterilization, the drug-coated balloon of the present example was obtained. In this example, the total weight of the carrier was 2mg, and the mass ratio of the active drug to the carrier was 5.

Comparative example 1

50mg of paclitaxel is used as an active drug, 20mg of iopromide is used as a carrier, and the paclitaxel and the carrier are mixed with 5mL of ethanol to prepare a drug solution. The balloon of the PTA balloon catheter (diameter is 4mm, length is 40mm) is folded into three flaps in ten thousand grade clean environment, then the medicine solution is sprayed on the surface of the balloon with the flaps by using spraying equipment in hundred grade clean environment, so that the medicine concentration on the surface of the balloon is 3 mug/mm²And drying at room temperature for 24 hours, packaging and sterilizing by ethylene oxide to obtain the drug-coated balloon of the comparative example 1. The mass ratio of the paclitaxel active drug and the carrier in comparative example 1 is 2.5.

Drug release test

The drug-coated balloons provided in examples 1 to 7 and comparative example 1 were placed in healthy piglets, respectively, inflated and expanded at the external iliac artery, removed, and subjected to balloon-expansion surgery for 30min, 24h, 7 days, and 28 days, respectively. During follow-up, target blood vessels around the drug-coated balloon during balloon dilatation surgery are dissociated firstly, the target blood vessels are washed for 3 times at a low speed by 0.1mol/L PBS solution containing heparin (each 1000ml of PBS contains 25000 units of heparin), the three-layer structure of the target blood vessels is stripped and separated, and then the inner membrane, the middle membrane and the outer membrane are obtained respectively after collection. And measuring the content of the drug in the tunica media tissue of the target blood vessel of the balloon dilatation section by using a liquid chromatography-mass spectrometer (LC-MS/MS for short). The test conditions of LC-MS/MS are as follows:

liquid chromatography instrument: an Agilent model 1200 liquid chromatography system (Agilent corporation) containing a quaternary infusion pump model G1312A, a vacuum degasser model G1322A;

mass spectrometer: API4000 QTRAP type triple quadrupole tandem mass spectrometer (AB Sciex company) equipped with electrospray ionization source (ESI for short);

and (3) analyzing the column: venusil XBP C8 column (borna aiger technologies), size: 2.1X 50mm, 5 μm;

mobile phase conditions: carrying out gradient elution on a phase A (containing 0.1% formic acid aqueous solution) and a phase B (containing 0.1% formic acid acetonitrile solution);

column temperature: 30 ℃;

mass spectrum conditions: ESI positive ion detection mode.

The drug release curves of the target blood vessel tunica media of examples 1 to 7 and comparative example 1 were respectively plotted with four follow-up time points as abscissa and the measured drug content of the target blood vessel tunica media at each time point as ordinate, as shown in fig. 1. The curve reflects the absorption of the drug by the target vascular tissue and the retention behavior of the drug in the membranous tissue in the target blood vessel.

Referring to fig. 1, the results show that: compared with comparative example 1, the drug coating of the drug-coated balloons of examples 1 to 7 had higher absorption capacity by the target vascular tissue at 30 min. At 24h, the drug content of the membrane tissue in the target blood vessel of examples 1 to 7 rapidly increased, while the drug content of the drug-coated balloon of comparative example 1 did not increase at 24h, indicating that the drug coating of the drug balloon of examples 1 to 7 of the present invention rapidly permeates into the membrane in the target blood vessel under the action of the penetration enhancer. The drug coating of comparative example 1, which is difficult to penetrate the biological barrier of the target vessel intima, is instantaneously dilated and squeezed at the initial moment and can only allow a small amount of drug to penetrate the intima by virtue of the inherent concentration difference; in the later time, the medicine does not enter the tunica media of the target blood vessel any more, and a small amount of the medicine entering the tunica media of the target blood vessel is gradually consumed, so that the content of the medicine in the tunica media of the target blood vessel is in a monotonous decreasing rule. This further demonstrates the significant effect of the invention with the addition of the penetration enhancer. The drug content of the membrane in the target vessel of examples 1 to 7 did not increase at the long follow-up of days 7 and 28, indicating that between 24h and 7 days, the osmotic absorption of the drug to the membrane in the target vessel and the metabolic utilization of the drug by the membrane in the target vessel reached equilibrium, and after 7 days, the total drug content of the membrane in the target vessel gradually decreased. Whereas comparative example 1 had little drug in the target vessel at the 7 day follow-up, the drug was essentially zero at the 28 day follow-up.

As can be seen from fig. 1, regardless of the drug loading amount at the moment of expansion, the drugs of examples 1 to 7 were rapidly absorbed and entered the target vessel wall over time, and began to gradually increase at 24h and remained for a longer period of time. This excellent drug retention capacity allows for higher drug concentrations at a long term even at lower initial loading. The drug-coated balloons of examples 1 to 7 were shown to be able to release active ingredients to the focal site within a predetermined time, fully exert the therapeutic effect of the drug, prolong the drug action time, and improve the bioavailability of the drug.

In addition, in the same expansion time, the drug amount absorbed by the vascular tissue of the drug-coated balloon provided by the embodiments 1 to 7 of the invention is larger than that absorbed by the vascular tissue of the drug-coated balloon provided by the comparative example 1, and the drug amount lost by blood flow scouring is also reduced.

Histopathological study

The drug-coated balloons provided in examples 1 to 6 and comparative example 1 were respectively placed in healthy small pigs, inflated and expanded at the external iliac artery blood vessels, and removed, balloon-expansion surgery was completed, and follow-up was performed for 28 days after the surgery. In follow-up, the target blood vessel around the drug-coated balloon during balloon dilatation surgery was isolated and slowly washed 3 times with 0.1mol/L PBS solution containing heparin (25000 units of heparin per 1000ml of PBS). The branch vessels at the target vessel were ligated with thin wires, 1cm each was retained at the proximal and distal ends of the target vessel, and fixed by ligation after formalin infusion, and a plurality of paraffin-embedded tissue sections were prepared for histopathological analysis.

Taking example 1 as an example, the histopathological analysis method is explained in detail, and specifically comprises the following steps: the multiple tissue sections of the target blood vessel of example 1 were subjected to H & E staining, α -actin staining, Masso trichrome staining, and Movat staining, respectively, to obtain the staining patterns of fig. 2 to 5. Inflammatory cells, blue areas in Masso trichrome staining and wall thickness loss were scored according to the staining graphs of fig. 2 to 5, respectively, to investigate inflammatory responses, collagen fibrin deposition and central smooth muscle loss.

The investigation principle is that when the medicine of the medicine coating saccule acts on tissues, the medicine can inhibit the proliferation of smooth muscle cells, and simultaneously, inflammatory repair reaction is started, and collagen fibrin deposition is generated at the part losing the smooth muscle cells.

The scoring criteria for each of the three survey indices are as follows:

a. criteria for inflammatory response scoring

Inflammation integral calculation reference standards were classified in 4 grades. The mean value was calculated for a number of observations.

0 minute: there were no inflammatory cells (lymphocytes, eosinophils, macrophages, etc.) around the media and intima.

1 minute: there is a small amount of inflammatory cell infiltration around the media and intima.

And 2, dividing: the intima, media and adventitia have moderate inflammatory cell infiltration, and account for 25-50% of the area of the blood vessel.

And 3, dividing: there are a large number of inflammatory cells in the intima, media and adventitia, surrounding the entire blood vessel, occupying more than 50% of the area of the blood vessel.

b. Collagen fibrin deposition scoring criteria

0 minute: without any loss.

1 minute: blue area in trichrome stain < 25%.

And 2, dividing: the blue area in trichromatic dyeing is 25-50%.

And 3, dividing: the area of blue in trichromatic dyeing is 51-75%.

And 4, dividing: the blue area in trichrome staining was > 75%.

c. Score criteria for media smooth muscle loss

0 minute: without any loss.

1 minute: < 25% of the wall thickness is lost.

And 2, dividing: a wall thickness loss of 25-50%.

And 3, dividing: the wall thickness is lost 51-75%.

And 4, dividing: wall thickness loss > 75%.

The same histopathological analysis was performed on the tissue sections of examples 2 to 6 and comparative example 1, which will not be described herein.

The results of histopathological analysis of the drug-coated balloons of examples 1 to 6 and comparative example 1 are shown in table 1 below.

TABLE 1 histopathological integration results 28 days after drug-coated balloon treatment

The results show that: the drug-coated balloons of examples 1 to 6 had a significantly different effect on peripheral vascular tissue than the drug-coated balloon of comparative example 1.

First, the higher inflammatory score of examples 1 to 6, with a moderate amount of inflammatory cell infiltration of the intima, media and adventitia, indicates that the peripheral target vascular tissue responds more quickly to the drug in the drug coating of examples 1 to 6, i.e., the drug is applied to the vascular tissue more quickly. Second, the higher mesodermal smooth muscle loss and fibrin deposition of examples 1 to 6 indicate a faster onset of the inhibitory effect of the drug on smooth muscle cells.

The above differences further prove that, because the coating of the drug-coated balloon provided in examples 1 to 6 contains a penetration enhancer, it can promote the absorption of the drug into the tunica media of the blood vessel, accelerate the action time of the drug, reduce the dosage lost by blood flow erosion, and ensure the long-term drug content in the vascular tissue.

In vitro simulated particle shedding test

The drug-coated balloons provided in examples 1 to 7 and comparative example 1 were tested for particle shedding during delivery by in vitro simulation testing. The test method is as follows: purified water with the temperature of 37 ℃ and the flow rate of 250mL/min is used for simulating blood flow, and a silicone tube with a suitable size and specification is used for simulating blood vessels and simulating an operation process. The drug-coated balloons of examples 1 to 7 and comparative example 1 were delivered to the target site, respectively, the balloons were expanded to press the simulated blood vessel, the drug coating on the balloon surface was eluted, and the microparticles were detached and washed out to the distal end of the simulated blood vessel along with the simulated blood flow.

The particle size and number of the distal end of the simulated vessel were measured by a particle detector and the results are shown in table 2. And measuring the specific size and shape of the large-size particles with the size larger than 100 mu m through a micrograph. The micrographs of example 1 to 7 for particle shedding are shown in fig. 6 to 12, respectively, and the micrographs of comparative example 1 for particle shedding are shown in fig. 13.

TABLE 2 results of in vitro simulated particle shedding test

As can be seen from Table 2: compared with comparative example 1, the drug-coated balloons of examples 1 to 7 shed fewer particles in each size range and shed smaller maximum size of particles after the simulated blood vessel goes through the delivery and expansion process, i.e., the particle shedding level is better than that of comparative example 1.

Therefore, the dispersing agent added in the drug coatings of examples 1 to 7 has good dispersing ability, and can reduce the size and the number of particles falling off in the use process of the drug-coated balloon. The principle is that the dispersing agent has an interval effect, so that the fineness of the drug coating particles can be improved, and the coating is uniformly distributed. Preventing premature release of the drug prior to the drug balloon being placed at the target site.

Loss test for in vitro simulated delivery process

The isolated pig coronary artery blood vessel is used for simulating the target blood vessel of the human coronary artery system, and the loss test of the in-vitro simulation conveying process is carried out in an in-vitro simulation blood vessel model. Drug loss during delivery of the drug coated balloon to the target site via the delivery sheath was examined.

The drug-coated balloons prepared in examples 1 to 7 and comparative example 1 were inserted into an in vitro simulated blood vessel model, respectively. Floating for 90 seconds in an in-vitro simulated blood vessel model, then taking out the drug-coated saccule, analyzing residual drugs on the drug-coated saccule by respectively utilizing High Performance Liquid Chromatography (HPLC), and calculating the drug loss rate in the delivery process according to the following formula:

the drug loss rate during the delivery process is (the initial drug content loaded on the surface of the balloon-the residual drug content)/the initial drug content loaded on the surface of the balloon x 100%.

The HPLC test conditions are as follows:

the instrument comprises the following steps: hippocastane model LC-20A high performance liquid chromatograph;

a chromatographic column: agilent ZORBAX SB-C18 column, size: 4.6X 250mm, 5 μm;

mobile phase: methanol, acetonitrile, water 230:360: 410;

column temperature: 30 ℃;

a detector: an ultraviolet visible detector with the detection wavelength of 227 nm;

flow rate: 1.0 mL/min.

The HPLC measurement results are shown in table 3:

TABLE 3 in vitro simulation of transport Process loss test results

Table 3 the results show that: the drug-coated balloons provided in examples 1 to 7 of the present invention exhibited reduced loss of drug in the simulated vasculature during delivery to the target site, as compared to comparative example 1. The penetration enhancer added in the drug coating not only does not influence the binding force between the drug coating and the balloon, but also can be used as an affinity agent to enhance the binding force between the surface of the balloon and the drug coating. Meanwhile, the dispersant reduces the fineness of the drug coating particles, so that the dispersant and the drug coating act synergistically to further increase the binding force between the surface of the balloon and the drug coating, and improve the capability of the drug coating to resist the influence of a curved path and friction force in the conveying process.

In conclusion, the drug coating balloon provided by the invention comprises the penetration enhancer in the drug coating. When the drug coating saccule is placed into a human body, after the saccule expands to adhere to the wall, the active drug is released at the placement target site and transferred to the inner wall of the blood vessel. At the moment, the penetration enhancer carrier in the drug coating acts on vascular endothelial cells, changes the structure of the endothelial cells, influences the permeability of the endothelial cells, and accelerates the penetration of the drug to the vascular intima of a lesion part and the penetration and diffusion to the media, so that the drug is more quickly absorbed by tissues, the total drug amount absorbed by the tissues is increased, and the drug can be kept in the vascular media for a long time to continuously exert the drug effect. Moreover, when the same quality effect is required to be achieved, the drug coating balloon provided by the invention can reduce the administration dosage of active drugs in the drug coating, reduce the harm of the drugs to diseased regions and other organs, and control the toxic and side effects of the drugs.

By selecting the type of the proper penetration enhancer and the proportion of the penetration enhancer to the active medicament, the invention can not only promote the active medicament to quickly permeate into the tunica media from the tunica media of the blood vessel, but also does not influence other performances of the medicament coating, and reduces the particle shedding and process loss rate in the conveying and expanding process, and the like. In the drug-coated balloon provided by the invention, the mass ratio of the active drug to the carrier is (0.5-49): 1. when the mass ratio of the active drug to the carrier is too large, a large amount of active drug cannot be firmly combined with the surface of the balloon body, the firmness of the drug coating is reduced, and the loss in the conveying process is large; the carrier can not play a role in promoting drug absorption, the drug amount absorbed by the vascular tissue is low, and the effect of inhibiting the long-term restenosis is influenced. When the mass ratio of the active drug to the carrier is too small, the content of the active drug is too low, which may affect the effectiveness of the drug coating.

According to the drug coating balloon provided by the invention, the carrier of the drug coating can also comprise the dispersing agent, and the penetration enhancer and the dispersing agent in the carrier generate a synergistic effect, so that on the premise of ensuring the transfer rate of the drug coating, the drug can be promoted to permeate and absorb on the endothelial surface, the drug amount entering a blood vessel middle membrane can be improved, and meanwhile, the particle shedding and process loss of the drug coating on the balloon surface in the conveying process can be reduced, and a better treatment effect can be obtained.

The mass ratio of the dispersing agent to the penetration enhancer in the carrier of the drug coating saccule is (0.01-50) to 1. This range allows for both the dispersion and absorption promoting properties of the drug coating. When the dosage of the dispersing agent is too large, in order to not influence the mass ratio of the active medicament to the carrier, the dosage of the penetration enhancer in the carrier is correspondingly reduced, and the effect of promoting the penetration and absorption of the active medicament to the blood vessel tunica media cannot be achieved. When the dosage of the dispersing agent is too small, the active medicament is likely to agglomerate to form more large particles, so that thrombus is caused; and in order not to influence the mass ratio of the active drug to the carrier, the dosage of the penetration enhancer is correspondingly increased, so that the firmness of the drug coating is reduced, the loss in the conveying process is increased, and the immediate drug transfer rate is reduced.

The drug-coated balloon provided by the invention can be used for delivering active drugs to target sites of blood vessels or lumens in human bodies, treating stenosis in the blood vessels or lumens and preventing hyperplasia of intima or epithelium. The blood vessel includes a coronary artery blood vessel, a peripheral artery blood vessel, or a cerebral artery blood vessel. The lumen includes an esophagus, airway, intestine, biliary tract, cervix, urinary tract, or prostate. The peripheral arterial vessels include the leg arteries, further, the iliac, external iliac, femoral or popliteal arteries.

It should be noted that, although in examples 1 to 10, only the PTA balloon or the PTCA balloon is used to schematically illustrate a specific embodiment of the present invention, the technical solution provided by the present invention can also be used for other interventional drug-loaded medical devices or implantable drug-loaded medical devices. Such as stents, occluders, orthopedic implants, dental implants, sutures or bolts. The stent comprises a blood vessel stent, a trachea stent, an esophagus stent, a urethra stent, an intestinal tract stent or a biliary tract stent. The orthopedic implant includes a set screw, a set rivet, or a bone plate. The penetration enhancer is added into the drug coating and is in contact with the surface of the interventional drug-loaded medical device or the implantable drug-loaded medical device or filled in the interventional drug-loaded medical device, so that the drug can be promoted to be absorbed by human tissues, the drug loss caused by blood flow scouring is reduced, the drug absorption by the human tissues is improved, and the clinical treatment effect of the interventional drug-loaded medical device or the implantable drug-loaded medical device is improved.

While the present invention has been described with reference to the embodiments shown in the drawings, the present invention is not limited to the embodiments, which are illustrative rather than restrictive, and it will be apparent to those skilled in the art that many more modifications and variations can be made without departing from the spirit of the invention and the scope of the appended claims.

Claims

1. A drug coating balloon comprises a balloon body and a drug coating covering the surface of the balloon body, wherein the drug coating contains an active drug and a carrier, the active drug comprises an antiproliferative drug, and the carrier comprises a vascular endothelial cell penetration enhancer; the vascular endothelial cell penetration enhancer is selected from at least one of alcohol compounds and derivatives thereof, fatty acids and derivatives thereof, and aromatic acids and derivatives thereof; the alcohol compound is fatty alcohol selected from octanol, decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, arachidyl alcohol or behenyl alcohol.

2. The drug-coated balloon of claim 1, wherein the mass ratio of the active drug to the carrier ranges from (0.5-49): 1.

3. the drug-coated balloon of claim 1, wherein the carrier further comprises a dispersant.

4. The drug-coated balloon according to claim 3, wherein the mass ratio of the dispersing agent to the vascular endothelial cell penetration enhancer is in the range of (0.01-50) to 1.

5. The drug-coated balloon of claim 1, wherein the antiproliferative drug is selected from at least one of paclitaxel, rapamycin, paclitaxel derivatives, or rapamycin derivatives.

6. The drug-coated balloon of claim 1, wherein the fatty acid is selected from caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, or arachidonic acid.

7. The drug-coated balloon of claim 1, wherein the aromatic acid is selected from benzoic acid, phenylacetic acid, syringic acid, cinnamic acid, o-hydroxybenzoic acid, p-aminobenzoic acid, p-aminomethylbenzoic acid, p-aminosalicylic acid, or phthalic acid.

8. The drug-coated balloon of claim 1, wherein the derivative comprises an ester, amide, anhydride, or salt; the salts include magnesium, sodium, zinc, calcium, barium or copper salts.

9. The drug-coated balloon of claim 1, wherein the vascular endothelial cell permeation enhancer is selected from at least one of lauryl alcohol, myristyl alcohol, stearyl alcohol, lauric acid, palmitic acid, stearic acid, magnesium stearate, sodium stearate, zinc stearate, stearamide, isooctyl palmitate, linoleic acid, linolenic acid, glyceryl monooleate, polyoxyethylene stearate, sodium benzoate, cinnamic acid, o-hydroxybenzoic acid, p-aminosalicylic acid, or phthalic anhydride.

10. The drug-coated balloon of claim 3, wherein the dispersant is selected from at least one of acetate, maleate, polyvinylpyrrolidone, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinate, gluconate, polyethylene glycol 1000, polyethylene glycol 2000, acetamide, poloxamer, pentaerythritol, glutamate, vanilloid, hydroxypropylmethylcellulose, or lactobionate.

11. The drug-coated balloon of claim 1, wherein the active drug is present on the surface of the balloon body in an amount ranging from 0.5 to 20 μ g/mm²。