Drug coating composition, drug coating, drug balloon, and preparation method and application thereof

Abstract

The present invention relates to the technical field of drug balloons, and discloses a drug coating composition, a drug coating, a drug balloon, and a preparation method and application thereof. The drug coating composition comprises the following components in percentage by mass: 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent. The present invention also relates to a drug coating prepared from the drug coating composition, a drug balloon comprising the drug coating, and a preparation method and application of the drug balloon. The drug coating composition provided by the present invention uses a specific poloxamer as a carrier component, and after compounding with an active ingredient and a solvent in a specific amount, the prepared drug coating can be distributed more evenly. The drug balloon provided by the present invention not only has a drug coating with uniform distribution, good firmness, and a reasonable release rate, but also has been proven by animal experiments to have a very good therapeutic effect on the disease.

Description

Technical Field

[0001] The present invention relates to the technical field of drug balloons, and in particular to a drug coating composition, a drug coating, a drug balloon, and a preparation method and application thereof. Background Art

[0002] The emergence of coronary intervention has ushered in a new era of revascularization treatment for coronary heart disease, and postoperative restenosis is one of the main challenges it faces. The occurrence of restenosis not only leads to the recurrence of angina symptoms, requiring revascularization to relieve symptoms, but also may cause acute coronary syndrome in some patients. The use of drug-eluting stents (DES) has reduced the restenosis rate, but drug-eluting stents themselves have some insurmountable limitations. On the one hand, this limitation comes from the metal structure of the stent, which can cause difficulty in passing or continue to stimulate neointimal hyperplasia as a foreign body, leading to restenosis; on the other hand, it comes from the polymer carrier, which can delay endothelial repair, increase the incidence of stent thrombosis, and repeatedly prolong the dual antiplatelet therapy. In-stent restenosis (ISR) is a pathophysiological evolution process, which is different from restenosis in histological manifestations and is characterized by neointimal formation. In the era of drug-eluting stents, ISR still occurs, and once it occurs, there is a lack of effective treatment methods. Superimposing another drug-eluting stent in a restenosis drug-eluting stent will increase the subsequent restenosis rate as high as 43%. In recent years, new devices and treatment strategies have emerged to overcome this problem, and drug-eluting balloon (DEB) is one of the most promising technologies.

[0003] In addition, in the era of drug-eluting stents, there are still great risks in using stents for complex lesions such as bifurcation lesions, small vessel lesions, and patients with diabetes and coronary heart disease. This provides an entry point for drug-eluting balloons. The results of previous studies have shown that drug-eluting balloons have obvious advantages over drug-eluting stents in treating small vessel lesions and bifurcation lesions.

[0004] Therefore, the unique structure of the drug eluting balloon (DEB), a combination of traditional balloon angioplasty and advanced drug elution technology, avoids the side effects caused by metal frames and polymer carriers, and releases drugs in a targeted manner to the blood vessel wall in a specific area, thereby enriching the drugs there without causing systemic side effects.

[0005] At present, similar products of many companies have been launched on the market. However, the drug layer of the existing drug balloon is unevenly distributed at the front, middle and back ends, and the drug layer is prone to form accumulation in a certain part and cannot be evenly adsorbed on the surface of the balloon.

[0006] These products all use paclitaxel as the active ingredient, with contrast agents, urea, shellac, and magnesium stearate as carriers for the composite drug layer. The balloon and balloon material are also not significantly different from the balloon used for expansion stents. Since contrast agents have certain toxic side effects, they will cause a certain degree of damage to the human body after entering the human body, and the drug layer of this formula will be lost in large quantities before reaching the lesion after entering the blood vessel. The drug coating of shellac and magnesium stearate is not firm, and large pieces of the drug layer fall off, and shellac contains certain impurities. After the formula of the current marketed products is sprayed on the surface of the balloon, there will be different degrees of drug shedding before the product is used, resulting in drug loss and affecting the treatment effect.

[0007] In addition, some existing drug balloons either fall off in large pieces once they enter the blood vessels, with most of them being washed away by the blood flow; or the release rate is too slow, resulting in the drug being unable to be released to the lesion during the balloon inflating process, and a large amount of drug remains on the balloon after the balloon is withdrawn.

[0008] Therefore, there is an urgent need to develop a drug balloon with uniform drug coating distribution, good drug coating firmness and reasonable drug release rate. Summary of the invention

[0009] One of the purposes of the present invention is to overcome the problem of uneven distribution of drug coating of drug balloons in the prior art, and to provide a drug coating composition, a drug coating, a drug balloon and a preparation method and application thereof. The second purpose of the present invention is to further overcome the problem of easy detachment of drug coating and unreasonable drug release rate of drug balloons in the prior art.

[0010] In order to achieve the above-mentioned object, the first aspect of the present invention provides a drug coating composition, wherein the composition comprises the following components in percentage by mass: 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent;

[0011] Wherein, the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.

[0012] The second aspect of the present invention provides a drug coating prepared from the composition described in the first aspect.

[0013] The third aspect of the present invention provides a drug balloon comprising the drug coating according to the second aspect.

[0014] A fourth aspect of the present invention provides a method for preparing a drug balloon, wherein the method comprises the following steps:

[0015] (1) mixing 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent in percentage by mass to obtain a mixed solution; wherein the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407;

[0016] (2) coating the mixed solution obtained in step (1) onto a bare balloon to obtain the drug balloon.

[0017] The fifth aspect of the present invention provides the use of the drug balloon described in the third aspect or the drug balloon prepared by the preparation method described in the fourth aspect in the stenosis and dilation of the lumen of a blood vessel and the inhibition of restenosis.

[0018] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0019] (1) The drug coating composition provided by the present invention uses a specific poloxamer as a carrier component, which, after being compounded with an active component and a solvent in a specific amount, can make the prepared drug coating more evenly distributed.

[0020] (2) The present invention further optimizes the carrier component. When poloxamer 124 is selected as the carrier component, the firmness of the drug coating can be further improved and the release rate can be made more reasonable on the basis of good uniformity of the drug coating.

[0021] (3) The drug balloon provided by the present invention not only has a drug coating with uniform distribution, good firmness and reasonable release rate, but also has been proven to have a very good therapeutic effect on diseases through animal experiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 are photos of the drug balloons prepared in Examples 1 to 7 of the present invention, wherein (a)

[0023] -(g) correspond to drug balloons S-1 to S-7 respectively;

[0024] Figure 2 are photos of drug balloons prepared in Comparative Examples 1 to 4 of the present invention, wherein (a) to (d) correspond to drug balloons D-1 to D-4, respectively;

[0025] Figure 3 are electron microscopic images of the distribution of active ingredients of the drug balloons prepared in Examples 1 to 7 of the present invention, wherein (a) to (g) correspond to drug balloons S-1 to S-7, respectively;

[0026] Figure 4 The electron micrographs of the active ingredient distribution of the drug balloons prepared in Comparative Examples 1 to 4 of the present invention, wherein (a) to (d) correspond to drug balloons D-1 to D-4, respectively;

[0027] Figure 5 1 is a graph showing the content of active ingredients in the drug balloon prepared in Example 1 of the present invention after drug release testing, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0028] Figure 6 1 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Example 2 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0029] Figure 7 3 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Example 3 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0030] Figure 8 This is a graph showing the content of the active ingredient (paclitaxel) after the drug release test of the drug balloon prepared in Example 4 of the present invention;

[0031] Fig. 9 This is a graph showing the content of the active ingredient (paclitaxel) after the drug release test of the drug balloon prepared in Example 5 of the present invention;

[0032] Fig.10 1 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Example 6 of the present invention, wherein (a) and (b) correspond to rapamycin and bivalirudin, respectively;

[0033] Fig.11 This is a graph showing the content of the active ingredient (rapamycin) after the drug release test of the drug balloon prepared in Example 7 of the present invention;

[0034] Fig.12 1 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Comparative Example 1 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0035] Fig.13 1 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Comparative Example 2 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0036] Fig.14 1 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Comparative Example 3 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively;

[0037] Fig.151 is a graph showing the content of active ingredients after drug release testing of the drug balloon prepared in Comparative Example 4 of the present invention, wherein (a) and (b) correspond to paclitaxel and bivalirudin, respectively. DETAILED DESCRIPTION

[0038] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0039] The first aspect of the present invention provides a drug coating composition, wherein the composition comprises the following components in percentage by mass: 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent;

[0040] Wherein, the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.

[0041] In the present invention, the drug coating composition uses at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407 as a carrier component, and after being compounded with an active component and a solvent in a specific amount, the prepared drug coating can be distributed more evenly, and it can be ensured that after the balloon reaches the lesion, the lesions in the developing part can all receive sufficient drug treatment. If the distribution is uneven, the lesions in the developing part may not receive enough drugs.

[0042] The carrier component selected in the present invention is a traditional drug component, which has been used clinically for many years and has been proven to be safe and effective.

[0043] The mass percentage of the carrier component can be selected from 0.3%, 0.5%, 0.8%, 1.2%, 1.5%, 1.8%, 2.3%, 2.6%, 3%, 3.5%, 3.8%, 4%, and any value within the range of any two of the above values.

[0044] In the present invention, the amount of the carrier component is very important. If the amount of the carrier component is too much, the drug will form agglomeration during the spraying process, resulting in uneven spraying, and the drug is not easy to dry after spraying, and is always wet, which affects the firmness of the drug layer; if the amount of the carrier component is too little, the adhesion between the drug layer and the balloon surface is reduced, and the drug layer is easy to crack and fall off.

[0045] The mass percentage of the active ingredient can be selected from 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 5%, and any value within the range of any two of the above values.

[0046] The mass percentage of the solvent can be selected from 92%, 93%, 94%, 95%, 96%, 97%, 98%, and any value within the range of any two of the above values.

[0047] In some embodiments of the present invention, the composition includes the following components in mass percentage: 0.5-1.5% of carrier component, 1.5-3.5% of active ingredient and 95-98% of solvent. When each component is within the above range, the carrier component and the active ingredient can be more fully combined, and within this range, the active ingredient can be better and more evenly dissolved in the solvent, avoiding the drug from being deposited in the sprayer container, resulting in insufficient or excessive drug loading in the sprayed drug layer. The prepared drug coating is more evenly distributed, and the drug solution has better adhesion and flexibility after drying, avoiding drug shedding and loss.

[0048] In some preferred embodiments of the present invention, the carrier component is poloxamer 124. The use of poloxamer 124 as a carrier component can make the drug molecules in the formula evenly dispersed and firmly attached to the surface of the balloon body, so that there is almost no drug loss during the folding and inflation of the balloon, and the obtained drug coating has good firmness. In addition, poloxamer 124 has good hydrophilic properties, and can quickly release the drug after entering the blood vessel and reaching the lesion without the phenomenon of the whole drug falling off.

[0049] In the present invention, firmness refers to the degree of bonding between the drug coating and the balloon surface.

[0050] The drug release rate refers to the speed at which the drug is released after the drug balloon reaches the lesion and is deployed. If the release rate is too fast, the balloon wall will be washed away by the blood flow before it is completely attached to the tissue, resulting in insufficient drug absorption by the lesion tissue; if the release rate is too slow, active drugs will still remain on the balloon body after the drug balloon is withdrawn, resulting in insufficient drug absorption by the tissue.

[0051] During clinical operations, the deployment time of a drug-eluting balloon in a blood vessel is generally less than 60 seconds, and the deployment is usually completed in about 40 seconds.

[0052] In some embodiments of the present invention, the active ingredient is selected from at least one of paclitaxel, rapamycin, a paclitaxel derivative and a rapamycin derivative.

[0053] In some preferred embodiments of the present invention, the active ingredient further comprises bivalirudin.

[0054] In some preferred embodiments of the present invention, the active ingredients include paclitaxel and bivalirudin.

[0055] In some preferred embodiments of the present invention, the solvent is selected from at least one of ethanol, chloroform, acetonitrile, methanol and purified water. Those skilled in the art can select a suitable solvent according to the specific active ingredients. For example, when paclitaxel and bivalirudin are two-component active ingredients, a combination of organic solvents such as ethanol and acetonitrile and purified water is selected as the solvent; when paclitaxel or rapamycin is a single-component active ingredient, an organic solvent such as ethanol and acetonitrile is selected as the solvent.

[0056] In the present invention, the definition of purified water is as known in the art, which refers to water with a resistivity greater than 0.1×10 6 Ω*cm of water.

[0057] In some embodiments of the present invention, the composition comprises the following components in percentage by mass: 0.5-1.5% poloxamer 124, 1-2% paclitaxel, 0.5-1.5% bivalirudin and 95-98% solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water.

[0058] In some preferred embodiments of the present invention, the mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 3-5:1-3:1-2.

[0059] When the components of the present invention are combined within the above specific range, the prepared drug coating is not only evenly distributed on the balloon, but also has good firmness and reasonable release rate. After the balloon reaches the lesion and is unfolded, the active drug release rate is more than 90% within the normal clinical operation time.

[0060] The second aspect of the present invention provides a drug coating prepared from the composition described in the first aspect.

[0061] The third aspect of the present invention provides a drug balloon comprising the drug coating according to the second aspect.

[0062] A fourth aspect of the present invention provides a method for preparing a drug balloon, wherein the method comprises the following steps:

[0063] (1) mixing 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent in percentage by mass to obtain a mixed solution; wherein the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407;

[0064] (2) coating the mixed solution obtained in step (1) onto a bare balloon to obtain the drug balloon.

[0065] The preparation method of the drug balloon of the present invention uses a specific poloxamer as a carrier component, which is compounded with an active component and a solvent in a specific amount as a raw material, and a simple and easy-to-operate method is used to make the prepared drug balloon contain a uniformly distributed drug coating.

[0066] In some embodiments of the present invention, in step (1), the mixing is performed under ultrasonic conditions. Ultrasonic conditions can make the components mix more uniformly.

[0067] In some preferred embodiments of the present invention, the frequency of the ultrasound is 5-10 kHz.

[0068] In some preferred embodiments of the present invention, in step (2), the coating method is selected from one of spraying, dipping and dripping.

[0069] In some preferred embodiments of the present invention, in step (2), the coating is followed by natural drying to obtain the drug balloon.

[0070] In some embodiments of the present invention, in step (1), the carrier component is 0.5-1.5%, the active ingredient is 1.5-3.5%, and the solvent is 95-98%, by mass percentage.

[0071] In some preferred embodiments of the present invention, the active ingredient is selected from at least one of paclitaxel, rapamycin, paclitaxel derivatives and rapamycin derivatives.

[0072] In some preferred embodiments of the present invention, the active ingredients include paclitaxel and bivalirudin.

[0073] In some preferred embodiments of the present invention, the solvent is selected from at least one of ethanol, chloroform, acetonitrile, methanol and purified water.

[0074] In some preferred embodiments of the present invention, the raw materials in step (1) include, by mass percentage, 0.5-1.5% of poloxamer 124, 1-2% of paclitaxel, 0.5-1.5% of bivalirudin and 95-98% of a solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water.

[0075] The fifth aspect of the present invention provides the use of the drug balloon described in the third aspect or the drug balloon prepared by the preparation method described in the fourth aspect in the stenosis and dilation of the lumen of a blood vessel and the inhibition of restenosis.

[0076] The present invention can avoid the shortcomings of the traditional drug balloon from processing to use, can be used in combination with the existing drug balloon assembly, and is safe and simple to operate. The special drug coating formula in the present invention ensures the release, firmness and uniformity of the drug.

[0077] The present invention will be described in detail below through examples.

[0078] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if no manufacturer is specified, are all conventional products that can be obtained through commercial channels.

[0079] Example 1

[0080] The drug coating composition includes the following components in percentage by mass: 1% of poloxamer 124, 1.5% of paclitaxel, 1% of bivalirudin, and 96.5% of a solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water. The mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 4:2:1.

[0081] The above components are mixed under ultrasonic conditions with a frequency of 5 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-1.

[0082] Example 2

[0083] The drug coating composition includes the following components in percentage by mass: 1.5% of poloxamer 124, 1% of paclitaxel, 0.5% of bivalirudin, and 97% of a solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water. The mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 4:1:2.

[0084] The above components are mixed under ultrasonic conditions with a frequency of 10 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-2.

[0085] Example 3

[0086] The drug coating composition comprises the following components in percentage by mass: 0.5% of poloxamer 124, 2% of paclitaxel, 1.5% of bivalirudin, and 96% of a solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water. The mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 3:3:1.

[0087] The above components are mixed under ultrasonic conditions with a frequency of 6 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-3.

[0088] Example 4

[0089] The drug coating composition includes the following components in percentage by mass: 0.3% of poloxamer 188, 5% of paclitaxel, and 94.7% of acetonitrile.

[0090] The above components are mixed under ultrasonic conditions with a frequency of 8 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-4.

[0091] Example 5

[0092] The drug coating composition comprises the following components in percentage by mass: 4% of poloxamer 237, 3% of paclitaxel, and 93% of a solvent; the solvent is a mixed solvent of ethanol and acetonitrile, wherein the mass ratio of ethanol to acetonitrile in the mixed solvent is 1:1.

[0093] The above components are mixed under ultrasonic conditions with a frequency of 9 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-5.

[0094] Example 6

[0095] The drug coating composition includes the following components in percentage by mass: 1% of poloxamer 338, 3% of rapamycin, 1% of bivalirudin, and 95% of a solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water. The mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 5:1:1.

[0096] The above components are mixed under ultrasonic conditions with a frequency of 5-10 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-6.

[0097] Example 7

[0098] The drug coating composition includes the following components in percentage by mass: 2% of poloxamer 407, 1% of rapamycin, and 97% of ethanol.

[0099] The above components are mixed under ultrasonic conditions with a frequency of 5-10 kHz to obtain a mixed solution; the mixed solution is added into a balloon sprayer and sprayed onto a bare balloon; the sprayed balloon is removed and naturally dried to obtain the drug balloon S-7.

[0100] Comparative Example 1

[0101] The drug balloon D-1 was prepared according to the method of Example 1, except that poloxamer 124 was replaced by an equal amount of mannitol.

[0102] Comparative Example 2

[0103] The drug balloon D-2 was prepared according to the method of Example 1, except that poloxamer 124 was replaced by an equal amount of sodium alginate.

[0104] Comparative Example 3

[0105] The drug balloon D-3 was prepared according to the method of Example 1, except that the dosage of poloxamer 124 was adjusted to 5%, paclitaxel to 1.5%, bivalirudin to 1%, and solvent to 92.5%.

[0106] Comparative Example 4

[0107] The drug balloon D-4 was prepared according to the method of Example 1, except that the dosage of poloxamer 124 was adjusted to 0.2%, paclitaxel to 1.5%, bivalirudin to 1%, and solvent to 97.3%.

[0108] Test Example 1 Drug coating firmness test

[0109] After a series of operations including packaging, sterilization, simulated transportation, accelerated aging, drop test, and stacking test, drug balloons S-1 to S-7 and drug balloons D-1 to D-4 were subjected to the balloon tube holder connected to a pressure pump for pressurization and expansion, and the shedding of the drug coating was observed.

[0110] The results are shown in Table 1.

[0111] Test Example 2 Drug Release Test

[0112] The drug balloons S-1 to S-7 and drug balloons D-1 to D-4 were tested as follows:

[0113] The test balloon is inserted into an elastic rubber tube with an inner diameter slightly larger than the nominal diameter of the test balloon, and placed in a brown glass bottle containing a certain amount of sustained-release liquid (0.01M PBS solution containing 85% anhydrous ethanol, 37°C). The liquid level should cover the entire balloon. Let it stand for 1 minute, then expand the balloon to the nominal pressure, maintain it for 45±2s, and take out the balloon immediately after decompression. At this time, the active ingredient content in the sustained-release liquid is determined by high-performance liquid chromatography. The method is as follows:

[0114] First, a linear regression is performed using a liquid chromatograph with the concentration of the active ingredient standard as the ordinate and the corresponding peak area as the abscissa, the regression equation is calculated, the correlation coefficient is determined, and a standard curve is drawn. Then, the corresponding concentration is found based on the peak area of ​​the sustained-release solution and compared with the standard curve, or the concentration C of the sustained-release solution is calculated based on the regression equation, and then the total amount M of the active ingredient in the sustained-release solution can be calculated based on the volume V of the sustained-release solution, M=C×V.

[0115] Drug release rate, % = total amount of active ingredient M / initial total amount of active ingredient.

[0116] The results are shown in Table 1 (if there is more than one active ingredient, the drug release rate in the table is the average of the release rates of the multiple active ingredients).

[0117] Test Example 3 Drug coating uniformity test

[0118] The drug-loaded parts of drug balloons S-1 to S-7 and drug balloons D-1 to D-4 were divided into three parts of approximately the same length, each part was weighed, and the content of the active ingredient in each part was detected by liquid chromatography.

[0119] Take paclitaxel as an example:

[0120] Calculation: Paclitaxel loading per unit weight of the entire balloon = Σ drug loading per portion / Σ weight per portion

[0121] The proportion of each drug amount = (drug loading per unit weight - drug loading per unit weight of the entire balloon) / drug loading per unit weight of the entire balloon, and the obtained value should be taken as an absolute value.

[0122] The average of the three dosage ratios was taken, and the difference between each dosage and the average was calculated.

[0123] The testing methods for bivalirudin and rapamycin are the same.

[0124] The results are shown in Table 1.

[0125] Table 1

[0126]

[0127]

[0128] It can be seen from the results in Table 1 that the drug balloons S-1 to S-3 prepared in Examples 1-3 all performed well in terms of firmness, drug release rate and uniformity. In Examples 4-7, different active ingredients and carrier components were used, and the drug balloons S-4 to S-7 prepared by the content of each component was not within the most preferred range were slightly inferior to the drug balloons S-1 to S-3 in terms of firmness, drug release rate and uniformity. The drug balloons D-1 to D-2 prepared in Comparative Examples 1-2 using mannitol and sodium alginate as carrier components were inferior to all the embodiments in terms of firmness, drug release rate and uniformity. In Comparative Example 3, too much poloxamer 124 was used as a carrier component, and the firmness and uniformity of the drug coating of the prepared drug balloon D-3 deteriorated. In Comparative Example 4, too little poloxamer 124 was used as a carrier component, and the drug coating was slightly cracked and fell off. Therefore, after a series of operations, the drug layer of the drug balloon provided by the present application falls off well, and the drug can be released quickly without the entire drug falling off. The coating has good uniformity, indicating that the drug balloon of the present application has excellent firmness, drug release rate and uniformity.

[0129] Photos of drug-eluting balloons S-1 to S-7 are shown in Figure 1 As shown, the photos of drug balloons D-1 to D-4 are as follows Figure 2 As shown. Figure 1 and Figure 2 It can be seen that the drug balloon prepared in the present application has good uniformity and is firmly bonded to the balloon surface.

[0130] Electron microscopic images of the active ingredient distribution of drug balloons S-1 to S-7 are shown in Figure 3 As shown, the electron microscopy images of the active ingredient distribution of drug balloons D-1 to D-4 are as follows Figure 4 shown.

[0131] The content of active ingredients in drug balloons S-1 to S-7 after drug release test is shown in the figure below. Figures 5 to 11 As shown, the content of active ingredients in drug balloons D-1 to D-4 after drug release test is shown in FIG. Figures 12 to 15 shown.

[0132] Test Example 4 Biological Performance Test

[0133] The drug balloons S-1 to S-3 were subjected to biological performance tests.

[0134] The test method is as follows:

[0135] Equipment and consumables:

[0136] Digital Subtraction Angiography System DSA:GE Optima IGS 330

[0137] Respiratory anesthesia machine: Aeon 7200

[0138] ECG monitor: Mindray iPM7

[0139] Single-lumen endotracheal tube, electrode patch, sterile surgical sheet, normal saline, iodine tincture, conventional interventional instruments, etc.

[0140] Experimental drugs:

[0141] Induction anesthetics, isoflurane, ceftiofur sodium, aspirin, clopidogrel, etc.

[0142] Experimental design:

[0143] In the experiment, each experimental pig is expected to have 2 to 3 coronary arteries (depending on the actual situation), and each blood vessel is intervened with a drug balloon. The balloon diameter is determined according to the blood vessel size, and the balloon diameter / animal blood vessel diameter = 1.10:1 to 1.20:1 is used to intervene in the coronary artery of a healthy ordinary white pig. The drug balloon is placed in the selected blood vessel site and pressed to a certain pressure to fully expand the balloon, and the pressure is maintained for 60 seconds.

[0144] All the above experiments used pigs, and they were given aspirin 100 mg and oxypidogrel 75 mg three days before surgery; after surgery, they were given aspirin 100 mg and flopidogrel 75 mg every day until the final follow-up.

[0145] Experimental groups:

[0146] 1 Experimental Group:

[0147] -Test product specifications: 2.5x15mm, 2.75x15mm, 3.0x15mm;

[0148] - Set 6 experimental observation time points (5 minutes, 2 hours, 24 hours, 7 days, 14 days, 28 days after surgery)

[0149] - 3 animals per experimental observation time point,

[0150] -At each test endpoint, 6 to 8 coronary vessels and important organs (heart, liver, spleen, lung, kidney, brain) were tested.

[0151] - Before and 5 minutes, 30 minutes, 1 hour, 1.5 hours, 3 hours, 6 hours, 24 hours, 7 days, 14 days, and 28 days after coronary artery vascular treatment, randomly select no less than 6 animals and collect 10 ml blood samples from each animal for blood drug concentration testing.

[0152] 2) Control group

[0153] The pig coronary vessels, whole blood and internal organs of blank experimental animals were selected as blank control substances, and there were 2 animals in the control group.

[0154] The experimental animals were given aspirin (100 mg, PO) and clopidogrel (75 mg, PO) once a day for three days before surgery.

[0155] In order to empty the gastric contents of the animals, the experimental animals were fasted but not allowed to drink for 12 hours during the operation.

[0156] The preoperative anesthesia of the experimental animals and the preparation of the surgical area were carried out in accordance with standard operating procedures. After the animals were anesthetized, they were weighed, antibiotics were given prophylactically, and a cannula was placed in the ear vein for intravenous fluid replacement. After the endotracheal intubation was completed, the surgical area was prepared and disinfected and fixed on the operating table.

[0157] Surgical steps:

[0158] Before the operation, sodium heparin injection (150U / kg) was given intravenously to monitor the coagulation time (ACT) to ensure that the ACT value was greater than 300s at the beginning of the operation. During the operation, the hemodynamics, EKG (electrocardiogram), blood oxygen saturation, etc. of the experimental animals were monitored in real time.

[0159] The balloon catheter treatment surgery was performed in accordance with standard operating procedures. A 5F / 6F guide catheter was selected through a 6F vascular sheath. Under the guidance of a 0.035" guide wire, a femoral artery vascular access was established. The guide catheter was pushed to the opening of the coronary artery under the guidance of the guide wire. Coronary angiography was performed and the target vascular treatment position was selected. The balloon catheter was prepared, the air in the catheter was emptied, and the catheter reached the target vascular treatment position along the 0.014" guide wire through the vascular access established by the guide catheter.

[0160] The pressure pump sucks in a 50 / 50 mixture of contrast agent and heparinized saline, expands the balloon at an expansion ratio of 1.05 to 1.20:1 (balloon expansion diameter / arterial vessel diameter), makes the balloon fully adhere to the wall, releases the pressure after maintaining the pressure for 60 seconds, and then withdraws the balloon catheter from the body. Perform angiography before and during balloon expansion and after the balloon catheter is depressurized and skimmed out, record the angiography data, and evaluate the immediate postoperative efficacy. If vascular spasm occurs during the use of the balloon catheter, 200ug nitroglycerin is administered through the catheter to relieve spasm according to the actual situation, and the administration is recorded. After the operation, all instruments and equipment are removed from the experimental animals. Resuscitate the experimental animals and continue to feed and observe them until the set experimental observation point.

[0161] Aspirin (100 mg, PO) and clopidogrel (75 mg, PO) were given daily during the postoperative observation period until the end point of the trial.

[0162] Blood sample collection:

[0163] At 5 minutes, 30 minutes, 1 hour, 1.5 hours, 3 hours, 6 hours, 24 hours, 7 days, 14 days, and 28 days after coronary artery vascular treatment, no less than 6 animals were randomly selected to collect 10 ml of blood samples from each animal. After the blood samples were collected, they were stored in K2EDTA anticoagulant tubes for blood drug concentration testing. The sample labels included the test number, animal number, blood collection time and date, etc. The blood samples were tested after collection.

[0164] End-point angiography review and sampling:

[0165] At the end of the observation period, the experimental animals were anesthetized again, blood samples were collected, and 12,500 U of sodium heparin injection was given intravenously. Angiography was repeated to observe the situation during the product treatment period. After the review, the experimental animals were euthanized by intravenous injection of an overdose of potassium chloride solution under deep anesthesia.

[0166] Autopsy was performed to examine the chest, abdominal cavity and organs and take samples. The complete heart was carefully removed from the chest cavity. The reference position of the balloon catheter treatment segment in the coronary artery was determined by the intraoperative angiography results. The reference position was the main branch of the coronary artery. A 15 mm long coronary artery was cut along the reference position of the balloon catheter implantation and stored in a 5 ml cryotube. A 10 mm long coronary artery was cut at the proximal and distal ends of the treatment segment along the two ends of the balloon catheter implantation site and stored separately in 5 ml cryotubes. About 5 to 10 g of myocardial tissue was taken around the treatment segment coronary artery and stored in a 5 ml cold tube. The abdominal cavity, chest cavity and skull of the animal were then cut open, and the liver, spleen, lung, kidney, brain and other major organs were carefully removed. 10 g to 20 g of apical myocardial tissue, lung tissue, liver tissue, kidney tissue, spleen tissue, and brain tissue samples were randomly cut and stored in 10 ml cryotubes. All collected samples were immediately placed in a -80 ° C refrigerator for storage. The samples collected from each experimental animal included: coronary vessels of the treatment segment, proximal coronary vessels of the treatment segment, distal coronary vessels of the treatment segment, myocardial tissue around the treatment segment vessels, lungs, liver, kidneys, spleen, brain, etc. In addition, 10 ml of whole blood was collected in a K2EDTA anticoagulant tube at each observation time point before the angiography review and stored in a -80°C refrigerator for the detection of blood drug concentration.

[0167] Test evaluation:

[0168] By analyzing the drug concentration in tissue, whole blood, and important organs collected from blood vessels, tissues, and blood, it was found that the drug balloon of this formula has a good biological effect. The drug concentration in the coronary vascular tissue of the treatment section is significantly higher than that in other tissues. This shows that the drug balloon provided by the present invention has a good clinical effect, and the drug can better reach the diseased tissue and be fully absorbed by the tissue. The blood drug concentration test results show that the drug is relatively less lost by blood flow in the blood vessels, which once again proves that the carrier has a positive effect on the firmness and release rate of the drug.

[0169] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A drug coating composition, characterized in that: The composition comprises the following components in percentage by mass: 0.3-4% of carrier component, 1-5% of active ingredient and 92-98% of solvent; Wherein, the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407.

2. The composition according to claim 1, wherein The composition comprises the following components in percentage by mass: 0.5-1.5% of carrier component, 1.5-3.5% of active ingredient and 95-98% of solvent; And / or, the carrier component is poloxamer 124.

3. The composition according to claim 1 or 2, wherein The active ingredient is selected from at least one of paclitaxel, rapamycin, paclitaxel derivatives and rapamycin derivatives; And / or, the solvent is selected from at least one of ethanol, chloroform, acetonitrile, methanol and purified water.

4. The composition according to claim 3, wherein The active ingredients also include bivalirudin.

5. The composition according to claim 3, wherein The active ingredients include paclitaxel and bivalirudin.

6. The composition according to claim 1 or 2, wherein The composition comprises the following components in percentage by mass: 0.5-1.5% of poloxamer 124, 1-2% of paclitaxel, 0.5-1.5% of bivalirudin and 95-98% of solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water.

7. The composition according to claim 6, wherein The mass ratio of ethanol, acetonitrile and purified water in the mixed solvent is 3-5:1-3:1-2.

8. A drug coating prepared from the composition of any one of claims 1-7.

9. A drug balloon comprising the drug coating according to claim 8.

10. A method for preparing a drug balloon, characterized in that: The method comprises the following steps: (1) mixing 0.3-4% of a carrier component, 1-5% of an active ingredient, and 92-98% of a solvent in percentage by mass to obtain a mixed solution; wherein the carrier component is selected from at least one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407; (2) coating the mixed solution obtained in step (1) onto a bare balloon to obtain the drug balloon.

11. The preparation method according to claim 10, wherein: In step (1), the mixing is performed under ultrasonic conditions; And / or, in step (2), the coating method is selected from one of spraying, dipping and dripping; And / or, in step (2), the coating is followed by natural drying to obtain the drug balloon.

12. The preparation method according to claim 11, wherein The frequency of the ultrasound is 5-10kHz; And / or, in step (2), the coating method is spraying.

13. The preparation method according to claim 10 or 11, wherein: In terms of mass percentage, in step (1), the carrier component is 0.5-1.5%, the active ingredient is 1.5-3.5%, and the solvent is 95-98%; and / or, the active ingredient is at least one selected from paclitaxel, rapamycin, a paclitaxel derivative and a rapamycin derivative; And / or, the solvent is selected from at least one of ethanol, chloroform, acetonitrile, methanol and purified water.

14. The preparation method according to claim 13, wherein: The active ingredients include paclitaxel and bivalirudin.

15. The preparation method according to claim 13, wherein: In terms of mass percentage, the raw materials in step (1) include 0.5-1.5% of poloxamer 124, 1-2% of paclitaxel, 0.5-1.5% of bivalirudin and 95-98% of solvent; the solvent is a mixed solvent of ethanol, acetonitrile and purified water.

16. Use of the drug balloon according to claim 9 or the drug balloon prepared by the preparation method according to any one of claims 10 to 15 in preparing products for stenosis dilation and restenosis inhibition of vascular lumens.

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