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JP-2026514507-A - Drug coatings, and medical devices, systems, and manufacturing methods having them.

JP2026514507AJP 2026514507 AJP2026514507 AJP 2026514507AJP-2026514507-A

Abstract

The present invention provides a drug coating, and a medical device, system, and method for manufacturing the drug coating. The drug coating comprises a non-degradable fluoropolymer matrix and a drug dispersed therein, and has inner and outer layers with different drug-bearing concentrations along the thickness direction of the drug coating, the drug-bearing concentration of the inner layer being 10 wt% or more by weight, the drug-bearing concentration of the outer layer being less than 10 wt% by weight, and the thickness of the outer layer being 20 μm or less. The drug coating of the present invention can stably release the drug to the tissue wall in contact with it over a long period of time in order to achieve long-term therapeutic or preventive effects against diseases such as luminal stenosis.

Inventors

  • 王 静
  • 李 ▲亮▼

Assignees

  • 北京信立泰医▲療▼▲器▼械有限公司

Dates

Publication Date
20260511
Application Date
20240426
Priority Date
20230427

Claims (20)

  1. A drug coating comprising a non-degradable fluoropolymer matrix and a drug dispersed therein, wherein the drug coating is provided on a medical device, and the drug coating comprises an outer layer and an inner layer with different drug-bearing concentrations formed along the thickness direction of the drug coating, characterized in that the drug-bearing concentration of the inner layer is higher than that of the outer layer, and the thickness of the outer layer is 20 μm or less.
  2. The drug coating according to claim 1, characterized in that the drug coating is configured such that the drug release rate during the first 24 hours after implantation in a mammalian blood vessel is 40% or less, and the drug release rate during the first 30 days is 15% or more.
  3. The drug coating according to claim 1 or 2, characterized in that the mammal is a human or a pig.
  4. The drug-bearing concentration of the inner layer is 10 wt% or more by weight, and the drug-bearing concentration of the outer layer is less than 10 wt% by weight. Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 45 wt%, and the drug-loaded concentration of the outer layer is 1 wt% to 8 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 30 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 5 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 5 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 4 wt%, Alternatively, the drug-loaded concentration of the inner layer is 20 wt% to 30 wt%, and the drug-loaded concentration of the outer layer is 4 wt% to 5 wt%, Alternatively, the drug coating according to any one of claims 1 to 3, characterized in that the drug-loaded concentration of the inner layer is 10 wt%, 13 wt%, 15 wt%, 18 wt%, or 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt%, 4 wt%, or 5 wt%.
  5. The drug coating according to any one of claims 1 to 4, characterized in that the thickness of the outer layer is 1 μm or more and 10 μm or less, or the thickness of the outer layer is 1 μm to 8 μm.
  6. The drug coating according to any one of claims 1 to 5, characterized in that the thickness of the inner layer is greater than the thickness of the outer layer, or the thickness of the inner layer is 10 μm to 22 μm.
  7. The drug coating according to any one of claims 1 to 6, characterized in that the thickness of the inner layer is 12 μm to 16 μm, and the thickness of the outer layer is 2 μm to 4 μm.
  8. The drug coating according to any one of claims 1 to 7, characterized in that the total amount of drug loaded in the drug coating is 110 μg/ cm² to 500 μg/ cm² .
  9. The drug coating according to any one of claims 1 to 8, characterized in that the amount of drug carried in the inner layer is greater than the amount of drug carried in the outer layer.
  10. A drug coating according to any one of claims 1 to 9, characterized in that the drug-loading amount of the inner layer is 100 μg/ cm² to 400 μg/ cm² , the drug-loading amount of the outer layer is 2 μg/ cm² to 60 μg/ cm² , or the drug-loading amount of the inner layer is 150 μg/ cm² to 350 μg/ cm² , and the drug-loading amount of the outer layer is 2 μg/cm² to 30 μg/cm².
  11. The drug coating according to any one of claims 1 to 10, characterized in that the drug is selected from paclitaxel, rapamycin, heparin, probucol, dexamethasone, or an analog of the aforementioned drug.
  12. The drug coating according to any one of claims 1 to 11, characterized in that the drug is selected from lipophilic drugs.
  13. The drug coating according to any one of claims 1 to 12, characterized in that the drug coating is configured such that the drug release rate during the first 30 days after implantation in a mammalian blood vessel is 15% or more, and is 60% or less, 50% or less, or 40% or less.
  14. The drug coating according to any one of claims 1 to 13, characterized in that the drug coating is configured such that the drug release rate during the first 14 days after implantation in a mammalian blood vessel is 10% or more, and is 30% or less, 40% or less, or 50% or less.
  15. The aforementioned drug coating exhibits a weekly drug release rate of 6% to 2% from week 2 to week 17 after implantation in the blood vessels of mammals. Alternatively, the drug coating according to any one of claims 1 to 14, characterized in that it is configured such that the drug release rate is 30% or more, or 40% or more, or 50% or more, within 31 to 360 days after implantation.
  16. The drug coating according to any one of claims 1 to 15, characterized in that the drug coating is configured such that the drug release rate during the first 24 hours after implantation in a mammalian blood vessel is 15% or less, 20% or less, or 30% or less.
  17. The drug coating according to any one of claims 1 to 16, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 50% to 92% vinylide fluoride and 50% to 8% hexafluoropropylene by weight percentage.
  18. The drug coating according to any one of claims 1 to 17, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 55% to 65% by weight of vinylidene fluoride and 45% to 35% by weight of hexafluoropropylene.
  19. The drug coating according to any one of claims 1 to 18, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 70% to 90% vinylide fluoride and 30% to 10% hexafluoropropylene by weight percentage.
  20. A drug coating according to any one of claims 1 to 19, further comprising a drug-free bottom layer, wherein the inner layer is attached to the bottom layer.

Description

This invention relates to the technical field of medical devices, and more specifically to drug-carrying devices and coatings that enable long-term drug release, and in particular to implantable medical devices delivered intracavitary, such as drug-eluting stents, and related manufacturing methods. A drug-eluting stent (DES) consists of three parts: a metal framework, a polymer coating, and a restenosis prevention drug supported on it. Since the application of DES, the polymer coating has been a crucial component, functioning as a drug carrier, controlling drug release, and preventing thrombus formation and restenosis within the stent. DES are currently classified into two main categories: permanent polymers and biodegradable polymers. Biodegradable polymers, primarily made from materials such as polylactic acid, decompose into carbon dioxide and water in human tissue and blood environments once a DES is implanted. The coating decomposes with drug release, gradually thinning and eventually disappearing. The in vivo release kinetic profile of the supported drug is generally thought to be influenced by the degradation characteristics of the biodegradable polymer and the drug concentration. Permanent polymers, primarily fluoropolymers, do not decompose in the human body and possess good biocompatibility. The release of the supported drug is generally considered to be primarily determined by the drug concentration in the coating. Fluoropolymer coatings are widely used in applications requiring short-term drug release (usually less than 30 days), such as coronary DES. Research and reports on the application of permanent polymer DES to applications requiring long-term drug release (e.g., 30 days or more) are lacking. While biodegradable polymer coatings allow for extended drug release time by designing the degradation characteristics of the biodegradable polymer and the appropriate drug load, designing fluoropolymer coatings to achieve long-term drug release is more challenging. Directly increasing the drug concentration in the coating to extend drug release time is generally not considered feasible. This can lead to excessively high and rapid drug release in the early stages of drug delivery, resulting in drug waste and significant drug toxicity. In the mid-to-late stages of drug delivery, the amount of drug remaining on the coating decreases or the drug concentration declines, leading to reduced drug release and a slower release rate. This is insufficient to achieve the necessary effective drug amount within the desired treatment cycle, and thus prevents long-term effective drug release. A prime example of a need for long-term release of DES is the treatment of peripheral artery disease (PAD). PAD is a chronic disease primarily caused by atherosclerosis and Takayasu's arteritis, presenting as a systemic disease characterized by symptoms such as narrowing and reduced blood flow in the arteries of the lower and/or upper limbs, posing a significant threat to human health. DES possesses excellent biocompatibility and the ability to carry drugs, making it highly promising for broad applications in the treatment of peripheral artery occlusion. However, a greater challenge lies in the fact that peripheral arteries in the lower extremities are longer, larger in diameter, and have stronger impact forces due to blood flow compared to other blood vessels such as coronary arteries. For example, the subpericardial coronary artery typically has a diameter of 0.5–5 mm and a blood flow velocity of 10–30 cm/s, while the femoral artery typically has a diameter of 6–9 mm and a blood flow velocity of 70–90 cm/s. To achieve long-term, stable therapeutic effects for lower extremity PAD, it is necessary to load more drug onto the DES (Drug-Emitting Stem Cell). This exacerbates the rapid, burst release of large amounts of drug in the initial stages of drug release, and in medium- to long-term release cycles exceeding 30 days, it demands greater uniformity of drug coating and a higher drug release rate. Otherwise, achieving long-term effective therapeutic drug release may be difficult. One of the objectives of this invention is to provide a medical device having a drug coating that achieves a therapeutic or preventive effect by releasing a drug onto the tissue wall it comes into contact with. Here, the drug coating comprises a non-degradable polymer as both a coating matrix and a drug carrier, the drug is dispersed and distributed within the coating matrix, can be released outside the coating during the therapeutic cycle, and the coating matrix is substantially retained. This invention particularly proposes a drug coating or a medical device having said drug coating, wherein the drug coating comprises a non-degradable polymer matrix and a drug dispersed therein, and has an outer layer and an inner layer with different drug concentrations along the thickness direction of the coating, the drug concentration of the inner layer being highe