Anticoagulant compounds and methods and devices for their use
Inventors
Sirhan, Motasim • Zheng, Xiaoxia • Bhat, Vinayak D. • Yan, John
Assignees
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Publication Number
US-11654036-B2
Publication Date
2023-05-23
Expiration Date
Abstract
Devices, systems, and methods are provided including a structure having one or more surfaces configured for internal use within a patient's body and one or more therapeutic compositions comprising one or more active substances including a direct factor Xa inhibitor, and a direct factor IIa inhibitor disposed in or on the structure. The structure is configured to be positioned adjacent an injury site in the patient's body. The one or more active substances optionally include an anti-proliferative agent. The therapeutic composition is formulated to release the one or more active substances to the injury site to provide one or more of inhibit clot formation, promote clot dissolution, inhibit or dissolute inflammation, inhibit vessel injury, increase time before clotting, and/or inhibit cell proliferation.
Core Innovation
The invention relates to an implant comprising a structure for implantation in a patient's body that delivers local anticoagulant activity. The implant includes a first therapeutic composition and a second therapeutic composition, each comprising a polymer and at least one drug selected from direct factor IIa inhibitor(s) and direct factor Xa inhibitor(s). The first therapeutic composition is formulated for rapid release into an implanted environment, while the second therapeutic composition is formulated for extended release into the implanted environment.
A layered configuration is used to control the local pharmacological timing. The second therapeutic composition is layered over a surface of the implantable structure, and the first therapeutic composition is layered over at least a portion of the second therapeutic composition. The first drug-to-polymer weight ratio is in a range from 5:1 to 1:3.
In a vasculature-expanding embodiment, the implantable structure has a surface configured to be expanded in the patient's vasculature. The first therapeutic composition includes at least argatroban and a direct factor Xa inhibitor including at least one of apixaban and rivaroxaban, and the second therapeutic composition includes at least argatroban and a direct factor Xa inhibitor including at least one of apixaban and rivaroxaban in a polymer configured for extended release into the vascular environment.
The disclosed concept is focused on improving local anticoagulation and anticoagulant-related inhibition at an implanted environment. The local release design is described as providing rapid local Xa/IIa release to improve inhibition of fibrin/clotting, extend time before clotting, and reduce smooth muscle cell proliferation compared with slower release profiles or monotherapies.
Claims Coverage
The independent claim set includes two independent claims. The inventive coverage centers on layered polymer-containing therapeutic compositions with rapid-release versus extended-release behavior, direct factor IIa inhibitor and/or direct factor Xa inhibitor drug formulations, and a first drug-to-polymer weight ratio range of 5:1 to 1:3.
Layered rapid-release and extended-release polymer therapeutic compositions
An implant comprising a structure for implantation having a first therapeutic composition formulated for rapid release into an implanted environment and a second therapeutic composition formulated for extended release into the implanted environment, wherein the second therapeutic composition is layered over a surface of the implantable structure and the first therapeutic composition is layered over at least a portion of the second therapeutic composition, and wherein the first and second therapeutic compositions each comprise a polymer.
Direct factor IIa and direct factor Xa inhibitor drug formulations
The first therapeutic composition comprises a first drug formulation including at least one drug selected from a direct factor IIa inhibitor and a direct factor Xa inhibitor, and the second therapeutic composition comprises a second drug formulation including at least one drug selected from the direct factor IIa inhibitor and the direct factor Xa inhibitor.
Defined first drug-to-polymer weight ratio for layered compositions
The first therapeutic composition has a first drug-to-polymer weight ratio and the second therapeutic composition has a second drug-to-polymer weight ratio, and the first drug-to-polymer weight ratio is in a range from 5:1 to 1:3.
Vasculature-expanding surface with argatroban and apixaban/rivaroxaban layered rapid-release and extended-release
An implantable structure having a surface configured to be expanded in the patient's vasculature, with a first therapeutic composition including at least argatroban and a direct factor Xa inhibitor including at least one of apixaban and rivaroxaban configured to rapidly release into a vascular environment, and a second therapeutic composition including at least argatroban and a direct factor Xa inhibitor including at least one of apixaban and rivaroxaban in a polymer configured for extended release into the vascular environment.
The independent claims require an implant with polymer-containing therapeutic compositions layered to provide rapid release from a first composition and extended release from a second composition into an implanted or vascular environment. The claim set further requires direct factor IIa inhibitor and/or direct factor Xa inhibitor drug formulations and a first drug-to-polymer weight ratio range of 5:1 to 1:3.
Stated Advantages
Unexpected inhibition of fibrin/clot formation and smooth muscle cell proliferation with specific fast/slow release formulations.
Improving local anticoagulation and anticoagulant-related inhibition at an implanted environment.
Improve inhibition of fibrin/clotting, extend time before clotting, and reduce smooth muscle cell proliferation compared with slower release profiles or monotherapies.
Documented Applications
Localized anticoagulant therapy from drug-eluting medical devices to control fibrin formation, thrombin formation, and clot formation and to address smooth muscle cell proliferation in implanted environments.
Drug-eluting medical devices including drug eluting stents (DES), drug coated balloon catheters, and valve/valve repair implant concepts, using layered polymer coatings and therapeutic compositions.
Vascular environment use for an implantable structure having a surface configured to be expanded in a patient's vasculature.
Ex vivo shunt model to assess clot control and related anticoagulant performance.
Locally delivered rivaroxaban, apixaban, novolimus, and rapamycin from coated balloon catheters to coronary and superficial femoral arteries, with in vivo tissue concentration results over time.
Anticoagulant-eluting valve implant and valve repair implant.
Drug-eluting stents and balloons using polymer matrices and micro-/nano-carriers for vascular delivery.
Coated balloon catheter vascular delivery involving polymer coatings and drug-eluting configurations.
Implants using reversible ester-linked drug-polymer conjugates and hollow nanoparticle self-assembly carriers as drug delivery structures.
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