Patent Application
20250195727
The present application relates to the technical field of drug balloons, and specifically relates to a drug coating, a drug balloon and a preparation method for drug balloon and use thereof.
The drug balloon catheter is an interventional medical device consisting of a catheter and a drug balloon. The drug balloon consists of a balloon and a drug coating coated on its surface. The drug balloon catheter is mainly used to dilate the stenotic part of the blood vessel. While dilating the blood vessel, it releases the drug onto the tunica intima, thereby inhibiting restenosis of the blood vessel.
The formula of a drug coating generally comprises a drug and a carrier. The drug and the carrier are dissolved in a solvent and then coated on the surface of the balloon to obtain a drug balloon. At present, in domestic and international technologies, the carriers used to obtain drug balloons are generally contrast media, ester compounds, heparin, castor oil or hydrophilic dyes, sugars and sugar derivatives, polymers, etc., and the drug is generally taxol, rapamycin, etc. In short, there are many choices for drug coating formulas. However, for most of the drug coatings obtained from current formulas, it is difficult to control their crystallization state, and it is difficult to ensure the retention time of the drug when treating blood vessels or other luminal stenosis diseases.
Therefore, the technical problem to be solved by the present application is to overcome the shortcomings that it is difficult to control the crystallization state of most of drug coatings obtained from formulas in the prior art and to ensure the retention time of drug balloons when treating blood vessels or other luminal stenosis diseases.
To this end, the present application provides a drug coating, comprising a drug and a carrier, wherein the carrier is a phenolic compound or a pyrone compound, and a mass ratio of the drug to the carrier is 1:(0.01-10).
Further, the phenolic compound is at least one selected from the group consisting of eugenol, thymol, grape polyphenol, tea polyphenol and thyme camphor; and the pyrone compound is at least one selected from the group consisting of maltol, ethyl maltol, coumarin, tartaric acid, flavone and flavonoid compounds;
Further, the drug is at least one selected from the group consisting of taxol, rapamycin, taxol derivative and rapamycin derivative.
The present application provides a drug balloon, which is obtained by coating the aforementioned drug coating on the surface of a balloon.
The present application provides a method for preparing a drug balloon, wherein the drug balloon is the aforementioned drug balloon, and the method comprises the following steps:
Further, the solvent is at least one selected from the group consisting of water, an alcohol compound, an aliphatic hydrocarbon compound, an ether compound, a halogenated hydrocarbon compound, a ketone compound, tetrahydrofuran and acetonitrile; optionally, the aliphatic hydrocarbon compound comprises n-hexane and/or n-butane; the ether compound comprises diethyl ether and/or propylene oxide; the halogenated hydrocarbon compound comprises trichloromethane; and the ketone compound comprises acetone and/or methylbutanone.
Further, a mass ratio of the drug to the solvent is 1:(0.002-50).
Further, the alcohol compound is a compound with a carbon number of 15 or less; and the alcohol compound is at least one selected from the group consisting of ethanol, methanol, isopropanol, propanol, n-butanol, isobutanol and sec-butanol.
Further, in the dissolving step, after adding the drug and the carrier into the solvent, stirring, ultrasonic vibration and standing are performed.
Further, the standing is performed for a time ranging from 0.5 h to 1.5 h.
Further, the method for coating comprises spray coating, dip coating or drop coating.
The present application also provides use of a drug balloon prepared by the aforementioned method for preparing a drug balloon in dilating stenosis of blood vessels, urethra or ureteral lumen and inhibiting restenosis, the blood vessels comprise coronary blood vessels, peripheral blood vessels, intracranial blood vessels, and arteriovenous fistula blood vessels, and the urethra comprises prostatic urethra, bulbous urethra, membranous urethra, and penile urethra.
The technical solution of the present application has the following advantages.
In order to illustrate the technical solutions in the specific embodiments of the present application or in the prior art more clearly, the drawings need to be used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings in the following description show some of the embodiments of the present application, and those of ordinary skill in the art may still obtain other drawings from these drawings without creative efforts.
The following examples are provided for a better understanding of the present application, are not limited to the best embodiments, and do not constitute a limitation on the content or scope of protection of the present application. Any product identical or similar to the present application, derived by anyone under the inspiration of the present application or by combining the present application with other features of the prior art, falls within the scope of protection of the present application.
Where specific experimental steps or conditions are not indicated in the examples, the operations or conditions of conventional experimental steps described in the literatures in the present art can be followed. The reagents or instruments used without the manufacturer indicated are conventional reagent and products that are commercially available.
The balloon material used in the examples of the present application is a self-made balloon made of nylon material. The specific preparation method is as follows.
Preforming: The two ends of the balloon material tube were stretched thin, and a certain proportion of the bubble length is reserved in the middle to obtain a preformed balloon;
Mold molding: The preformed balloon was put into the balloon mold for blow molding, and then nitrogen gas was injected into the preformed balloon. The temperature of the balloon mold was controlled to be in a range from 110° C. to 120° C., and the pressure of nitrogen gas in the preformed balloon is in a range from 300 psi to 400 psi.
The product number of tea polyphenol used in the examples of the present application is T821916, purchased from Macklin.
The product number of maltol used in the examples of the present application is M813318, purchased from Macklin.
The product number of eugenol used in the examples of the present application is E809010, purchased from Macklin.
The product number of ethyl maltol used in the examples of the present application is E824420, purchased from Macklin.
This example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was tea polyphenol, and the solvent was acetone. The mass ratio of the drug to the carrier was 25:1, and the mass ratio of the drug to the solvent was 30:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was maltol, and the solvent was acetone. The mass ratio of the drug to the carrier was 20:1, and the mass ratio of the drug to the solvent was 30:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was eugenol, and the solvent was acetonitrile. The mass ratio of the drug to the carrier was 1:10, and the mass ratio of the drug to the solvent was 500:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was ethyl maltol, and the solvent was isopropanol. The mass ratio of the drug to the carrier was 100:1, and the mass ratio of the drug to the solvent was 1:50.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was a taxol derivative, the taxol derivative was docetaxel (specific product number was D807092, purchased from Macklin), the carrier was maltol, and the solvent was acetone. The mass ratio of the drug to the carrier was 20:1, and the mass ratio of the drug to the solvent was 30:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was rapamycin, the carrier was maltol, and the solvent was acetone. The mass ratio of the drug to the carrier was 20:1, and the mass ratio of the drug to the solvent was 30:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
This example provides a drug coating, which comprises a drug and a carrier. The drug was a rapamycin derivative, the rapamycin derivative was zotarolimus (product number: Z872686, purchased from Macklin), and the carrier was maltol, and the solvent was acetone. The mass ratio of the drug to the carrier was 20:1, and the mass ratio of the drug to the solvent was 30:1.
This example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
This comparative example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was sorbitol (the product number of sorbitol was D817607, purchased from Macklin), and the solvent was acetone. The mass ratio of the drug to the carrier was 25:1, and the mass ratio of the drug to the solvent was 30:1.
This comparative example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
This comparative example provides a drug coating, which comprises a drug and a carrier. The drug was taxol, the carrier was ethyl maltol, and the solvent was propanol. The mass ratio of the drug to the carrier was 110:1, and the mass ratio of drug to the solvent was 1:50.
This comparative example provides a drug balloon, which was obtained by coating the balloon surface with the aforementioned drug coating. The specific preparation method of the drug coating comprises the following steps:
A scanning electron microscope (SEM) was used to observe the morphology of the drug coating obtained in Example 1 and Comparative Example 1 respectively. The morphology diagrams thereof were shown in
Balloons with a size of 2.75×12 mm were selected to obtain a drug balloon according to the methods of Examples 1-7 and Comparative Examples 1-2, respectively, and the retention time of the drug balloons in the blood vessels was tested. The specific test method was as follows. The drug balloons were tested in vivo in animals. The selected animals were white pigs with a weight of about 30 kg. The test blood vessel sites were the coronary artery vessels. The drug-coated balloons were delivered to the coronary artery site of the animal. After dilating for 30 seconds, the drug balloons were taken out and then the drug content of the dilated segment vascular tissue was tested on the 30th day, and the ratio of remaining drug content was calculated. The ratio of remaining drug content=tissue drug content/nominal drug content on the balloon surface×100%. The test results were shown in Table 1.
The method for testing the drug content of the dilated segment vascular tissue was as follows. The vascular tissue was obtained, a tissue masher was used to grind the tissue homogenate at 1000 r/min, and the tissue homogenate was added into 5 mL of mixed solution of methanol and acetonitrile (in which the volume ratio of methanol to acetonitrile was 1:1), then 200 μg of internal standard drug (the internal standard drug was the drug used in the corresponding examples or comparative examples) was added therein, vortex was formed for 1 min, and the materials were centrifuged for 15 min at a condition of 4000 r/min to obtain a supernatant. The supernatant was diluted with asolvent of methanol and water (volume ratio of 1:1). After the supernatant was diluted to twice its volume, the tissue drug concentration data was obtained by testing using liquid chromatography-mass spectrometry.
As shown in Table 1, for Examples 1-7, the 30th-day retention content of the drugs in coronary artery blood vessels was 10.45±3.55 μg/g, and the ratio of remaining drug content was 10.1‰±3.4‰. For Comparative Examples 1-2, the 30th-day retention content of the drugs in coronary artery blood vessels was 0.45±0.15 μg/g, and the ratio of remaining drug content was 0.45‰±0.15‰. It can be seen that the retention time of the drug in the tissue in the present application was longer than that in the comparative examples.
Balloons with a size of 8.0×40 mm were selected to obtain drug balloons according to the methods of Examples 1-7 and Comparative Examples 1-2 respectively, and the retention time of the drug balloons in the urethra was tested. The specific test method was as follows. The drug balloon was used to dilate the urethra of a dog (beagle dog of about 15 kg). After 3 minutes of dilation, the drug balloon was taken out. Then, the drug content in the dilated segment urethra was tested on the 30th day, and the ratio of remaining drug content was calculated; the ratio of remaining drug content=tissue drug content/nominal drug content on the balloon surface×100%. The test results were shown in Table 2;
The method for testing the drug content in the dilated segment urethra was as follows. The vascular tissue in the urethral tissue was obtained, a tissue masher was used to grind the tissue homogenate at 1000 r/min, and the tissue homogenate was added into 5 mL of mixed solution of methanol and acetonitrile (in which the volume ratio of methanol to acetonitrile was 1:1), then 200 μg of internal standard drug (the internal standard drug was the drug used in the corresponding examples or comparative examples) was added therein, vortex was formed for 1 min, and the materials were centrifuged for 15 min at a condition of 4000 r/min to obtain a supernatant. The supernatant was diluted with a solvent of methanol and water (volume ratio of 1:1). After the supernatant was diluted to twice its volume, the tissue drug concentration data was obtained by testing using liquid chromatography-mass spectrometry.
As shown in Table 2, for Examples 1-7, the 30th-day tissue retention amount of the drugs in the urethra was 17.4±1.8 μg/g, and the ratio of remaining drug content was 8.6%±0.9%; for Comparative Examples 1-2, the 30th-day tissue retention amount of the drugs in the urethra was 0.65±0.15 μg/g, and the ratio of remaining drug content was 0.45%±0.05%. It can be seen that the retention time of the drug in the tissue in the present application was longer than that in the comparative examples.
Balloons with a size of 4.0×20 mm were selected to obtain drug balloons according to the methods of Examples 1-7 and Comparative Examples 1-2 respectively, and the drug release rate of the drug balloons were tested. The specific test method was as follows. The simulated blood vessels of appropriate size were immersed in the bovine serum protein PBS simulated solution, and then the above-mentioned drug balloons were inserted into the simulated blood vessels respectively and dilated to burst pressure (12 atm) and kept at this pressure for 60 s, and then the pressure was relieved, and the dilated drug balloons were removed from the solution and put into a 5 mL brown volumetric flask. 5 mL of methanol was added therein and stood for half an hour to obtain the eluted solution of the drug. Then high performance liquid chromatography was used to measure the drug content of the eluted solution, and the residual drug rate was calculated. The test results were shown in Table 3.
The method for preparing the bovine serum protein PBS simulated solution was as follows. 10 g of bovine serum protein was weighted and added into 100 mL of PBS buffer solution to prepare a 0.1 g/mL of bovine serum protein solution. The method for preparing PBS buffer solution was as follows. 8 g of NaCl, 0.2 g of KCl, 1.44 g of Na2HPO4 and 0.24 g of KH2PO4 were weighed and dissolved in 800 ml of distilled water, the pH value of the solution was adjusted to 7.4 with HCl, and finally distilled water was added therein to adjust the volume to 1 L.
Using the same method, the drug content was measured in the simulated blood vessel after the drug balloon was dilated, and the drug release rate was obtained. The specific calculation formulas were:
As shown in Table 3, for Examples 1-7, the in vitro drug release rate was 98.35%±0.85%, the residual drug rate was 1.15%±0.85%, and the drug loss was 0.85%±0.45%; for Comparative Examples 1-2, the in vitro drug release rate was 79.65%±1.45%, the residual drug rate was 10%±0.4%, and the drug loss was 10.35%±1.05%. It can be seen that the drug release rate of the present application was higher than that of the comparative examples, and both the residual drug rate and drug loss were lower than that of the comparative examples.
Obviously, the above examples are merely examples made for clear description, rather limiting the implementations. For those of ordinary skill in the art, other different forms of variations or modifications can also be made on the basis of the above-mentioned description. All embodiments are not necessary to be and cannot be exhaustively listed herein. In addition, obvious variations or modifications derived therefrom all fall within the scope of protection of the present application.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/082303 | 3/22/2022 | WO |
