WO2023178519A1 - 一种药物涂层、药物球囊及药物球囊制备方法与应用 - Google Patents

一种药物涂层、药物球囊及药物球囊制备方法与应用 Download PDF

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Publication number
WO2023178519A1
WO2023178519A1 PCT/CN2022/082303 CN2022082303W WO2023178519A1 WO 2023178519 A1 WO2023178519 A1 WO 2023178519A1 CN 2022082303 W CN2022082303 W CN 2022082303W WO 2023178519 A1 WO2023178519 A1 WO 2023178519A1
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Prior art keywords
drug
balloon
coating
carrier
pharmaceutical
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PCT/CN2022/082303
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English (en)
French (fr)
Inventor
马翠杰
赵丽晓
刘扬扬
何智浩
王哲
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Lepu Medical Technology Beijing Co Ltd
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Lepu Medical Technology Beijing Co Ltd
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Priority to US18/848,702 priority Critical patent/US20250195727A1/en
Priority to PCT/CN2022/082303 priority patent/WO2023178519A1/zh
Priority to EP22932588.1A priority patent/EP4491203A4/en
Publication of WO2023178519A1 publication Critical patent/WO2023178519A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • the present invention relates to the technical field of drug balloons, and specifically relates to a drug coating, a drug balloon and a preparation method and application of the drug balloon.
  • 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 vascular intima, thereby inhibiting restenosis of the blood vessel.
  • the formula of a drug coating generally includes a drug and a carrier.
  • the drug and carrier are dissolved in a solvent and then coated on the surface of the balloon to obtain a drug balloon.
  • 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 paclitaxel. , rapamycin, etc.
  • most of the drug coatings obtained with current formulas are 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.
  • the technical problem to be solved by the present invention is to overcome the shortcomings in the prior art that it is difficult to control the crystallization state of drug coatings obtained from formulas and to ensure the retention time of drug balloons when treating blood vessels or other luminal stenosis diseases.
  • the present invention provides a drug coating, including a drug and a carrier, the carrier being a phenolic compound or a pyrone compound, and the mass ratio of the drug to the carrier being 1: (0.01-10).
  • the phenolic compound is selected from at least one of eugenol, thymol, grape polyphenols, tea polyphenols and thymol;
  • the pyrone compound is selected from maltol, ethyl maltol, At least one of coumarin, tartaric acid, flavones and flavonoids;
  • the carrier is preferably one or more of eugenol, tea polyphenols, thymol, maltol, ethyl maltol, and alcoholic acid.
  • the drug is selected from at least one of paclitaxel, rapamycin, paclitaxel derivatives and rapamycin derivatives.
  • the present invention provides a drug balloon, which is obtained by coating the surface of the balloon with the aforementioned drug coating.
  • the present invention provides a method for preparing a pharmaceutical balloon.
  • the pharmaceutical balloon is the aforementioned pharmaceutical balloon.
  • the preparation method includes the following steps:
  • the solution is applied to the balloon surface to form a drug coating.
  • the solvent is selected from at least one of water, alcohol compounds, aliphatic hydrocarbon compounds, ether compounds, halogenated hydrocarbon compounds, ketone compounds, tetrahydrofuran and acetonitrile;
  • the aliphatic hydrocarbon compound includes n-hexane and/or n-butane;
  • the ether compounds include diethyl ether and/or propylene oxide;
  • the halogenated hydrocarbon compounds include chloroform;
  • the ketone compounds include acetone and/or methyl butanone.
  • the mass ratio of the drug and the solvent is 1:(0.002-50).
  • the alcohol compound is a compound with a carbon number ⁇ 15; the alcohol compound is selected from at least one of ethanol, methanol, isopropanol, propanol, n-butanol, isobutanol, and sec-butanol. kind.
  • the resting time is 0.5-1.5h.
  • the coating method includes spray coating, dip coating or drop coating.
  • the pharmaceutical balloon prepared by the aforementioned pharmaceutical balloon preparation method is used to dilate the stenosis and inhibit restenosis of blood vessels, urethra or ureteral lumen;
  • the blood vessels include coronary blood vessels, peripheral blood vessels, intracranial blood vessels and arteriovenous fistula blood vessels;
  • the urethra includes prostatic urethra, bulbar urethra, membranous urethra, and penile urethra.
  • a drug coating provided by the present invention uses phenolic compounds or pyrone compounds as new carriers, which improves the efficiency of carrier selection for the drug coating and can obtain ideal needle-shaped or columnar crystals, significantly It improves the quality of the drug coating and prolongs the retention time of the drug when treating blood vessels or other luminal stenosis diseases, so that the drug balloon catheter can better inhibit the restenosis of blood vessels when treating vascular stenosis.
  • the drug coating provided by the present invention narrows the selection range of drug coating formulas, simplifies the formula selection process, and has a simple coating preparation method, which greatly improves the firmness of the drug coating.
  • the drug balloon provided by the present invention is used to dilate the stenosis and inhibit restenosis of blood vessels, urethra, and ureteral lumen.
  • Figure 1 is a scanning electron microscope image of the drug coating of Example 1 provided by the present invention; the scale bar in the figure is 5 ⁇ m;
  • Figure 2 is a scanning electron microscope image of the drug coating of Comparative Example 1 provided by the present invention; the scale bar in the figure is 10 ⁇ m.
  • the balloon material used in the embodiment of the present invention is a self-made balloon made of nylon material.
  • the specific preparation method is:
  • Preforming The two ends of the balloon material tube are thinned, and a certain proportion of the bubble length is reserved in the middle to obtain a preformed balloon;
  • Mold molding Put the preformed balloon into the balloon mold for blow molding, and then pour nitrogen into the preformed balloon.
  • the temperature of the balloon mold is controlled at 110-120°C, and the nitrogen in the preformed balloon is The pressure is 300-400psi.
  • the tea polyphenols used in the embodiments of the present invention the product number is T821916, purchased from McLean;
  • the product number of maltol used in the embodiment of the present invention is M813318, purchased from McLean;
  • the product number of eugenol used in the examples of the present invention is E809010, purchased from McLean;
  • the product number of ethyl maltol used in the embodiment of the present invention is E824420, purchased from McLean.
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is tea polyphenols
  • the solvent is acetone.
  • the mass ratio of the drug and the carrier is 25:1, and the mass ratio of the drug and the solvent is 30: 1.
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is maltol
  • the solvent is acetone.
  • the mass ratio of the drug and the carrier is 20:1, and the mass ratio of the drug and the solvent is 30:1. .
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is eugenol
  • the solvent is acetonitrile.
  • the mass ratio of the drug and the carrier is 1:10, and the mass ratio of the drug and the solvent is 500:1. .
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is ethyl maltol
  • the solvent is isopropyl alcohol.
  • the mass ratio of the drug to the carrier is 100:1
  • the mass ratio of the drug to the solvent is 100:1. It's 1:50.
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is a paclitaxel derivative
  • the paclitaxel derivative is docetaxel (specific product number is D807092, purchased from McLean)
  • the carrier is maltol
  • the solvent is acetone.
  • the mass ratio of drug and carrier is 20:1
  • the mass ratio of drug and solvent is 30:1.
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is rapamycin
  • the carrier is maltol
  • the solvent is acetone.
  • the mass ratio of the drug to the carrier is 20:1, and the mass ratio of the drug to the solvent is 30:1.
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • This embodiment provides a drug coating, which includes a drug and a carrier.
  • the drug is a rapamycin derivative
  • the rapamycin derivative is zotarolimus (product number: Z872686, purchased from McLean)
  • the carrier is malt. Phenol
  • the solvent is acetone
  • the mass ratio of drug and carrier is 20:1
  • the mass ratio of drug and solvent is 30:1.
  • This embodiment provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • This comparative example provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is sorbitol (the product number of sorbitol is D817607, purchased from McLean)
  • the solvent is acetone
  • the mass ratio of the drug and carrier is 25 :1, the mass ratio of drug and solvent is 30:1.
  • This comparative example provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • This comparative example provides a drug coating, which includes a drug and a carrier.
  • the drug is paclitaxel
  • the carrier is ethyl maltol
  • the solvent is propanol.
  • the mass ratio of the drug to the carrier is 110:1, and the mass ratio of the drug to the solvent is 1:50.
  • This comparative example provides a drug balloon, which is obtained by coating the balloon surface with the aforementioned drug coating.
  • the specific preparation method of the drug coating includes the following steps:
  • Example 1 and Comparative Example 1 Use a scanning electron microscope (SEM) to observe the morphology of the drug coating obtained in Example 1 and Comparative Example 1 respectively.
  • the morphology diagrams are shown in Figures 1 and 2, as shown in Figures 1 and 2.
  • the drug coating forms upright-growing crystals with uniform crystal sizes, mainly distributed around 5 ⁇ m. This allows the drug coating to better adhere to the lumen wall when it expands in blood vessels, urethra or ureter. fit, more crystals will be attached to the lumen wall, and the metabolism time of the crystals in the tissue is longer; in Figure 2, the formed crystals are not ideal, most of them are grains, and the size is less than 1 ⁇ m. Metabolism time in tissues is very short.
  • the balloon was tested in vivo in animals.
  • the selected animal was a white pig weighing about 30kg.
  • the test blood vessel site was the coronary artery.
  • the drug-coated balloon was delivered to the coronary artery of the animal. After expansion for 30 seconds, the drug balloon was taken out and then in At 30 days, the drug content of the dilated vascular tissue was tested, and the proportion of remaining drug content was calculated.
  • the proportion of remaining drug content tissue drug content/nominal drug amount on the balloon surface ⁇ 100%.
  • the test results are shown in Table 1;
  • the method for testing the drug content of the dilated vascular tissue is as follows: obtain the vascular tissue, use a tissue masher to grind the supporting tissue homogenate at 1000r/min, and add the tissue homogenate to 5 mL of a mixed solution of methanol and acetonitrile (wherein methanol and acetonitrile The volume ratio is 1:1), then add 200 ⁇ g of internal standard drug (the internal standard drug is the drug used in the corresponding example or comparative example), vortex for 1 min, centrifuge for 15 min at 4000 r/min, obtain the supernatant, use methanol The supernatant was diluted with a 1:1 solvent (volume ratio) of water. After the supernatant was diluted twice, tissue drug concentration data was obtained by liquid chromatography-mass spectrometry testing.
  • Example 1 10.2 9.8 Example 2 7.8 7.5 Example 3 8.5 8.2 Example 4 14.0 13.5 Example 5 6.9 6.7 Example 6 9.2 8.9 Example 7 7.8 6.9 Comparative example 1 0.6 0.6 Comparative example 2 0.3 0.3 0.3
  • the 30-day retention amount of the drugs in Examples 1-7 in coronary blood vessels is 10.45 ⁇ 3.55 ⁇ g/g, and the remaining drug content ratio is 10.1 ⁇ 3.4 ⁇ .
  • the 30-day retention amount of the drug in Comparative Example 1-2 in coronary blood vessels was 0.45 ⁇ 0.15 ⁇ g/g, and the remaining drug content ratio was 0.45 ⁇ 0.15 ⁇ . It can be seen that the retention time of the drug in the tissue in the present invention is longer than that in the comparative example.
  • the method to test the drug content in the dilated urethra is: obtain the urethral tissue vascular tissue, use a tissue masher to grind the supporting tissue homogenate at 1000r/min, and add the tissue homogenate to 5 mL of a mixed solution of methanol and acetonitrile (in which methanol and acetonitrile (the volume ratio is 1:1), then add 200 ⁇ g of the internal standard drug (the internal standard drug is the drug used in the corresponding examples or comparative examples), vortex for 1 min, and centrifuge at 4000 r/min for 15 min to obtain the supernatant. The supernatant was diluted with a 1:1 solvent (volume ratio) of methanol and water. After diluting the supernatant twice, the tissue drug concentration data was tested by liquid chromatography-mass spectrometry.
  • Example 1 16.2 8.1
  • Example 2 18.3 9.1
  • Example 3 19.2 9.6
  • Example 4 18.1 9.0
  • Example 5 18.6 9.3
  • Example 6 15.6 7.8
  • Example 7 16.1 8.0 Comparative example 1 0.8 0.4 Comparative example 2 0.5 0.5
  • the 30-day tissue retention of the drugs in Examples 1-7 in the urethra was 17.4 ⁇ 1.8 ⁇ g/g, and the remaining drug content was 8.6% ⁇ 0.9%; the drugs in Comparative Examples 1-2 were The 30-day tissue retention in the urethra is 0.65 ⁇ 0.15 ⁇ g/g, and the remaining drug content is 0.45% ⁇ 0.05%. It can be seen that the retention time of the drug in the tissue in the present invention is longer than that in the comparative example.
  • the preparation method of the bovine serum albumin PBS simulation solution is as follows: weigh 10g of bovine serum albumin and add 100 mL of PBS buffer to prepare a 0.1g/mL bovine serum albumin solution.
  • the preparation method of PBS buffer is as follows: weigh 8g NaCl, 0.2g KCl, 1.44g Na 2 HPO 4 and 0.24g KH 2 PO 4 , dissolve them in 800ml distilled water, adjust the pH value of the solution to 7.4 with HCl, and finally add distilled water Adjust the volume to 1L.
  • Residual drug rate 1-detected drug content/nominal drug content of the drug balloon.
  • the drug content is measured in the simulated blood vessel after the drug balloon is expanded, and the drug release rate is obtained.
  • the specific calculation formula is:
  • Drug release rate detected drug content/nominal drug content of the drug balloon
  • Drug loss 1-residual drug rate-drug release rate
  • Example 3 99.2 0.4 0.4 Example 4 98.3 1.3 0.4 Example 5 97.8 1.6 0.6
  • Example 6 99.0 0.3 0.7
  • Example 7 98.7 1.0 1.3 Comparative example 1 78.2 10.4 11.4 Comparative example 2 81.1 9.6 9.3
  • the in vitro drug release rate of Examples 1-7 was 98.35% ⁇ 0.85%, the residual drug dosage rate was 1.15% ⁇ 0.85%, and the drug loss was 0.85% ⁇ 0.45%; the in vitro drug release rate of Comparative Examples 1-2
  • the drug release rate was 79.65% ⁇ 1.45%, the residual drug dosage 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 invention is higher than that of the comparative example, and the residual drug dosage rate and drug loss are both lower than that of the comparative example.

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Abstract

一种药物涂层、药物球囊及药物球囊制备方法与应用，用于药物球囊的药物涂层包括药物和载体，载体为酚类化合物或吡喃酮类化合物，药物与载体的质量比为1:(0.01-10)。药物球囊由药物涂层涂覆在球囊表面获得。以酚类化合物或吡喃酮类化合物作为新的载体，提高了药物涂层的载体选择效率，能够得到理想中的晶型，显著提高了药物涂层的质量，延长了药物在治疗血管或其他管腔狭窄疾病时的留存时间，从而使药物球囊导管在治疗血管、尿道或输尿管狭窄时更好的抑制管腔的再狭窄。

Description

一种药物涂层、药物球囊及药物球囊制备方法与应用 技术领域
本发明涉及药物球囊的技术领域，具体涉及一种药物涂层、药物球囊及药物球囊制备方法与应用。
背景技术
药物球囊导管是一种介入型医疗器械，由导管、药物球囊组成。药物球囊由球囊和涂覆在其表面的药物涂层组成。药物球囊导管主要用于血管狭窄部位的扩张，在扩张血管的同时将药物释放到血管内膜上，起到抑制血管再狭窄的作用。
药物涂层的配方一般包括药物和载体，将药物和载体溶解至溶剂中后涂覆在球囊表面即可获得药物球囊。目前，国内外的技术中，获得药物球囊时使用的载体一般为造影介质、酯类化合物、肝素、蓖麻油或者亲水性染料、糖及糖类衍生物、聚合物等，药物一般为紫杉醇、雷帕霉素等。总之，药物涂层配方选择较多，但是，目前的配方获取的药物涂层大多难以控制其结晶状态，难以保证药物在治疗血管或其他管腔狭窄疾病时的留存时间。
发明内容
因此，本发明要解决的技术问题在于克服现有技术中的配方获取的药物涂层大多难以控制其结晶状态，难以保证药物球囊在治疗血管或其他管腔狭窄疾病时的留存时间的缺陷。
为此，本发明提供一种药物涂层，包括药物和载体，所述载体为酚类 化合物或吡喃酮类化合物，所述药物与所述载体的质量比为1:(0.01-10)。
进一步的，所述酚类化合物选自丁香酚、百里香酚、葡萄多酚、茶多酚和麝香草酚中的至少一种；所述吡喃酮类化合物选自麦芽酚、乙基麦芽酚、香豆素、酒酸、黄酮和类黄酮类化合物中的至少一种；
可选的，所述载体优选丁香酚、茶多酚、百里香酚、麦芽酚、乙基麦芽酚、酒酸中的一种或多种。
进一步的，所述药物选自紫杉醇、雷帕霉素、紫杉醇衍生物和雷帕霉素衍生物中的至少一种。
本发明提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得。
本发明提供一种药物球囊的制备方法，所述药物球囊为前述的药物球囊，其制备方法包括如下步骤：
将药物、载体溶解到溶剂中，获得溶液；
将溶液涂覆到球囊表面形成药物涂层。
进一步的，所述溶剂选自水、醇类化合物、脂肪烃类化合物、醚类化合物、卤化烃类化合物、酮类化合物、四氢呋喃和乙腈中的至少一种；所述脂肪烃类化合物包括正己烷和/或正丁烷；所述醚类化合物包括乙醚和/或环氧丙烷；所述卤化烃类化合物包括三氯甲烷；所述酮类化合物包括丙酮和/或甲基丁酮。
进一步的，所述药物和所述溶剂的质量比为1:(0.002-50)。
进一步的，所述醇类化合物为碳个数≤15的化合物；所述醇类化合物选自乙醇、甲醇、异丙醇、丙醇、正丁醇、异丁醇、仲丁醇中的至少一种。
进一步的，所述溶解步骤中，将药物和载体加入溶剂中后，接着进行 搅拌、超声震荡和静置。
进一步的，所述静置时间为0.5-1.5h。
进一步的，所述涂覆方式包括喷涂、浸涂或滴涂。
前述的药物球囊的制备方法制备的药物球囊应用于血管、尿道或输尿管管腔的狭窄扩张及再狭窄抑制；所述血管包括冠脉血管、外周血管、颅内血管和动静脉瘘血管；所述尿道包括前列腺部尿道、球部尿道、膜部尿道、阴茎尿道。
本发明技术方案，具有如下优点：
1.本发明提供的一种药物涂层，以酚类化合物或吡喃酮类化合物作为新的载体，提高了药物涂层的载体选择的效率，能够得到理想中的针状或柱状晶体，显著提高了药物涂层的质量，延长了药物在治疗血管或其他管腔狭窄疾病时的留存时间，从而使药物球囊导管在治疗血管狭窄时更好的抑制血管的再狭窄。
2.本发明提供的一种药物涂层，缩小了药物涂层配方的选择范围，简化了配方选择流程，且涂层制备方法简单，大大提高了药物涂层的牢固度。
3.本发明提供的一种药物球囊，应用于血管、尿道、输尿管管腔的狭窄扩张及再狭窄抑制。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获 得其他的附图。
图1是本发明所提供的实施例1的药物涂层的扫描电镜图；图中标尺为5μm；
图2是本发明所提供的对比例1的药物涂层的扫描电镜图；图中标尺为10μm。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
本发明实施例中所用球囊材质为尼龙材料的自制球囊，具体制备方法为：
预成型：将球囊料管两端拉细，中间预留一定比例的泡长，得到预成型球囊；
模具成型：将预成型的球囊放入球囊模具中进行吹塑，并向预成型球囊中冲入氮气即可，球囊模具的温度控制在110-120℃，预成型球囊中氮气的压力在300-400psi。
本发明实施例中所用茶多酚货号为T821916，购自麦克林；
本发明实施例中所用麦芽酚货号为M813318，购自麦克林；
本发明实施例中所用丁香酚货号为E809010，购自麦克林；
本发明实施例中所用乙基麦芽酚货号为E824420，购自麦克林。
实施例1
本实施例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为茶多酚，溶剂为丙酮，药物和载体的质量比为25:1，药物和溶剂的质量比为30：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置0.5h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例2
本实施例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为麦芽酚，溶剂为丙酮，药物和载体的质量比为20:1，药物和溶剂的质量比为30：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例3
本实施例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为丁香酚，溶剂为乙腈，药物和载体的质量比为1:10，药物和溶剂的质量比为500：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例4
本实施例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为乙基麦芽酚，溶剂为异丙醇，药物和载体的质量比为100:1，药物和溶剂的质量比为1：50。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例5
本实施例提供一种药物涂层，其包括药物和载体，药物为紫杉醇衍生 物，紫杉醇衍生物为多西他赛(具体货号为D807092，购自麦克林)，载体为麦芽酚，溶剂为丙酮，药物和载体的质量比为20:1，药物和溶剂的质量比为30：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例6
本实施例提供一种药物涂层，其包括药物和载体，药物为雷帕霉素，载体为麦芽酚，溶剂为丙酮，药物和载体的质量比为20:1，药物和溶剂的质量比为30：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1.5h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
实施例7
本实施例提供一种药物涂层，其包括药物和载体，药物为雷帕霉素衍生物，雷帕霉素衍生物为佐他莫司(货号为Z872686，购自麦克林)，载体 为麦芽酚，溶剂为丙酮，药物和载体的质量比为20:1，药物和溶剂的质量比为30：1。
本实施例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，超声频率为100Hz，温度为30℃，然后将震荡后的溶液静置1.5h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
对比例1
本对比例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为山梨醇(山梨醇的货号为D817607，购自麦克林)，溶剂为丙酮，药物和载体的质量比为25:1，药物和溶剂的质量比为30：1。
本对比例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，然后将震荡后的溶液静置0.5h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
对比例2
本对比例提供一种药物涂层，其包括药物和载体，药物为紫杉醇，载体为乙基麦芽酚，溶剂为丙醇，药物和载体的质量比为110:1，药物和溶剂的质量比为1：50。
本对比例提供一种药物球囊，由前述的药物涂层涂覆在球囊表面获得，具体药物涂层的制备方法包括如下步骤：
S1、将药物、载体溶解到溶剂中，接着搅拌3min、超声震荡15min，然后将震荡后的溶液静置1h；
S2、将溶液通过超声喷涂法喷涂到球囊表面即可；喷涂压力为0.01MPa，喷涂的流速为0.03mL/min，喷涂得到的球囊的名义药量为1μg/mm 2。
试验例1
使用扫描电子显微镜(SEM)分别观察实施例1和对比例1获得的药物涂层的形貌，其形貌图见图1和图2，如图1和图2所示，在图1中的药物涂层形成了晶体形貌直立生长的晶体，晶体尺寸均匀，尺寸主要分布在5μm左右，这使得药物涂层在血管、尿道或输尿管中扩张时，药物涂层能够更好的与管腔壁贴合，更多的晶体会贴附到管腔壁上，同时晶体在组织内的代谢时间较长；在图2中，形成的晶体不理想，大部分是晶粒，尺寸不到1μm，在组织内代谢时间很短。
试验例2
选取尺寸为2.75*12mm的球囊分别按照实施例1-7、对比例1-2的方法获取药物球囊，并对药物球囊在血管内的留存时间进行测试，具体测试方法为：对药物球囊进行动物体内测试，选取的动物为重量为30kg左右的白猪，测试血管部位为冠脉血管，通过将药物涂层球囊输送到动物冠脉位置，扩张30s后取出药物球囊，之后在30天时测试扩张段血管组织的药物含量，并计算剩余药物含量比例。剩余药物含量比例＝组织药物含量/球囊表面名义药量×100％，测试结果见表1；
测试扩张段血管组织的药物含量的方法为：获取血管组织，使用组织捣碎机在1000r/min下研磨支撑组织匀浆，将组织匀浆加入5mL甲醇和乙腈的混合溶液中(其中甲醇和乙腈的体积比为1:1)，然后加入200μg内标药物(内标药物为对应实施例或对比例所用药物)，涡流1min，在4000r/min的条件下离心15min，获得上清液，使用甲醇和水的1:1溶剂(体积比)稀释上清液，将上清液稀释两倍后，通过液相色谱-质谱联用来测试得到组织药物浓度数据。
表1.实施例1-7、对比例1-2血管内试验结果
样品组别 30天组织药物含量(μg/g) 剩余药物含量比例(‰)
实施例1 10.2 9.8
实施例2 7.8 7.5
实施例3 8.5 8.2
实施例4 14.0 13.5
实施例5 6.9 6.7
实施例6 9.2 8.9
实施例7 7.8 6.9
对比例1 0.6 0.6
对比例2 0.3 0.3
如表1所示，实施例1-7中的药物在冠脉血管中的30天存留量为10.45±3.55μg/g，剩余药物含量比例为10.1‰±3.4‰。对比例1-2中的药物在冠脉血管中的30天存留量为0.45±0.15μg/g，剩余药物含量比例为0.45‰±0.15‰。可见本发明中的药物在组织中的存留时间比对比例高。
试验例3
选取尺寸为8.0*40mm的球囊分别按照实施例1-7、对比例1-2的方法获取药物球囊，并对药物球囊在尿道内的留存时间进行测试，具体测试方 法为：对药物球囊进行犬(15kg左右的比格犬)尿道内扩张，扩张3min后取出药物球囊，之后在30天时测试扩张段尿道中的药物含量，并计算剩余药物含量比例；剩余药物含量比例＝组织药物含量/球囊表面名义药量×100％，测试结果见表2；
测试扩张段尿道中的药物含量的方法为：获取尿道组织血管组织，使用组织捣碎机在1000r/min下研磨支撑组织匀浆，将组织匀浆加入5mL甲醇和乙腈的混合溶液中(其中甲醇和乙腈的体积比为1:1)，然后加入200μg内标药物(内标药物为对应实施例或对比例所用药物)，涡流1min，在4000r/min的条件下离心15min，获得上清液，使用甲醇和水的1:1溶剂(体积比)稀释上清液，将上清液稀释两倍后，通过液相色谱-质谱联用来测试得到组织药物浓度数据。
表2.实施例1-7、对比例1-2尿道内试验结果
样品组别 30天组织药物含量(μg/g) 剩余药物含量比例(‰)
实施例1 16.2 8.1
实施例2 18.3 9.1
实施例3 19.2 9.6
实施例4 18.1 9.0
实施例5 18.6 9.3
实施例6 15.6 7.8
实施例7 16.1 8.0
对比例1 0.8 0.4
对比例2 0.5 0.5
如表2所示，实施例1-7中的药物在尿道中30天组织存留量为17.4±1.8μg/g，剩余药物含量比例为8.6％±0.9％；对比例1-2中的药物在尿道中30天的组织存留量为0.65±0.15μg/g，剩余药物含量比例为 0.45％±0.05％。可见本发明中的药物在组织中的存留时间比对比例高。
试验例4
选取尺寸为4.0×20mm的球囊分别按照实施例1-7、对比例1-2的方法获取药物球囊，并对药物球囊的药物释放率进行测试，具体测试方法为：将合适尺寸的模拟血管浸入牛血清蛋白PBS模拟溶液中，然后将上述药物球囊分别伸入模拟血管中并扩张至爆破压力(12atm)，保压60s，然后卸压，将扩张后的药物球囊从溶液中取出，放入5mL棕色容量瓶中，加入5mL甲醇，静置半小时后，得到药物的洗脱溶液。然后使用高效液相色谱仪对洗脱后的溶液进行药物含量测定，并计算残余药物率，测试结果见表3。
牛血清蛋白PBS模拟溶液的制备方法为：称取10g牛血清蛋白加入100mL的PBS缓冲液，配制成0.1g/mL的牛血清蛋白溶液。PBS缓冲液的配制方法为：称取8g NaCl、0.2g KCl、1.44g Na 2HPO 4和0.24g KH 2PO 4,溶于800ml蒸馏水中，用HCl调节溶液的pH值至7.4，最后加蒸馏水定容至1L即可。
残余药物率＝1-检测的药物含量/药物球囊名义药物含量。
用同样方法，将药物球囊扩张后的模拟血管进行药物含量测定，得到药物释放率，具体计算公式为：
药物释放率＝检测的药物含量/药物球囊名义药物含量
药物损失＝1-残余药物率-药物释放率
表3 体外药物释放模拟测试结果
样品组别 药物释放率(％) 残余药量率(％) 药物损失(％)
实施例1 98.1 1.4 0.5
实施例2 97.5 2.0 0.5
实施例3 99.2 0.4 0.4
实施例4 98.3 1.3 0.4
实施例5 97.8 1.6 0.6
实施例6 99.0 0.3 0.7
实施例7 98.7 1.0 1.3
对比例1 78.2 10.4 11.4
对比例2 81.1 9.6 9.3
如表3所示，实施例1-7的体外药物释放率为98.35％±0.85％，残余药量率为1.15％±0.85％，药物损失为0.85％±0.45％；对比例1-2的体外药物释放率为79.65％±1.45％，残余药量率为10％±0.4％，药物损失为10.35％±1.05％。可见本发明的药物释放率比对比例高，并且残余药量率和药物损失均比对比例低。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (12)

  1. 一种药物涂层，包括药物和载体，其特征在于，所述载体为酚类化合物或吡喃酮类化合物，所述药物与所述载体的质量比为1:(0.01-10)。
  2. 根据权利要求1所述的一种药物涂层，其特征在于，所述酚类化合物选自丁香酚、百里香酚、葡萄多酚、茶多酚和麝香草酚中的至少一种；所述吡喃酮类化合物选自麦芽酚、乙基麦芽酚、香豆素、酒酸、黄酮和类黄酮类化合物中的至少一种；
    可选的，所述载体选自丁香酚、茶多酚、百里香酚、麦芽酚、乙基麦芽酚和酒酸中的至少一种。
  3. 根据权利要求1或2所述的一种药物涂层，其特征在于，所述药物选自紫杉醇、雷帕霉素、紫杉醇衍生物和雷帕霉素衍生物中的至少一种。
  4. 一种药物球囊，其特征在于，由权利要求1-3任一项所述的药物涂层涂覆在球囊表面获得。
  5. 一种药物球囊的制备方法，其特征在于，所述药物球囊为权利要求4所述的药物球囊，其制备方法包括如下步骤：
    将药物、载体溶解到溶剂中，获得溶液；
    将溶液涂覆到球囊表面形成药物涂层。
  6. 根据权利要求5所述的一种药物球囊的制备方法，其特征在于，所述溶剂选自水、醇类化合物、脂肪烃类化合物、醚类化合物、卤化烃类化合物、酮类化合物、四氢呋喃和乙腈中的至少一种；
    可选的，所述脂肪烃类化合物包括正己烷和/或正丁烷；所述醚类化合物包括乙醚和/或环氧丙烷；所述卤化烃类化合物包括三氯甲烷；所述酮类 化合物包括丙酮和/或甲基丁酮。
  7. 根据权利要求5或6所述的一种药物球囊的制备方法，其特征在于，所述药物和所述溶剂的质量比为1:(0.002-50)。
  8. 根据权利要求5-7任一项所述的一种药物球囊的制备方法，其特征在于，所述醇类化合物为碳个数≤15的化合物；
    可选的，所述醇类化合物选自乙醇、甲醇、异丙醇、丙醇、正丁醇、异丁醇和仲丁醇中的至少一种。
  9. 根据权利要求5-8任一项所述的一种药物球囊的制备方法，其特征在于，所述溶解步骤中，将药物和载体加入溶剂中后，接着进行搅拌、超声震荡和静置。
  10. 根据权利要求9所述的一种药物球囊的制备方法，其特征在于，所述静置时间为0.5-1.5h。
  11. 根据权利要求5-10任一项所述的一种药物球囊的制备方法，其特征在于，所述涂覆方式包括喷涂、浸涂或滴涂。
  12. 权利要求5-11任一项所述的药物球囊的制备方法制备的药物球囊应用于血管、尿道或输尿管管腔的狭窄扩张及再狭窄抑制；所述血管包括冠脉血管、外周血管、颅内血管和动静脉瘘血管；所述尿道包括前列腺部尿道、球部尿道、膜部尿道、阴茎尿道。
PCT/CN2022/082303 2022-03-22 2022-03-22 一种药物涂层、药物球囊及药物球囊制备方法与应用 Ceased WO2023178519A1 (zh)

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