Devices and methods for local delivery of tacrolimus
Inventors
Washington, Kia M. • Wagner, William R. • Steketee, Michael Brandt • Van der Merwe, Yolandi • Gu, Xinzhu
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11529318-B2
Publication Date
2022-12-20
Expiration Date
2038-06-18
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Abstract
Devices for local delivery of tacrolimus or a derivative thereof are provided, wherein the devices comprise a polymeric matrix containing tacrolimus or a derivative thereof that provides for delayed and extended release of tacrolimus or a derivative thereof. The devices can locally deliver tacrolimus or a derivative thereof to injured nervous system tissue upon implantation in a subject. Thus, techniques for local delivery of tacrolimus or a derivative thereof and methods of treatment using such devices are also provided.
Core Innovation
The invention provides devices and methods for the local delivery of tacrolimus or its derivatives to nervous system tissue using a polymeric matrix containing tacrolimus that enables delayed and extended release upon implantation. The device is often configured as a sheet or wrap and includes a biodegradable polymer, such as poly(ester urethane) urea (PEUU), which allows sustained delivery of tacrolimus directly to injured nervous system tissue, for example, nerves in the central or peripheral nervous system.
The problem being solved is the difficulty in treating nervous system injuries due to limited nerve regeneration, particularly in the central nervous system, and the side effects of systemic tacrolimus administration. Systemic administration can cause severe side effects, including nephrotoxicity and neurotoxicity, limiting its use. Existing local delivery methods like hydrogels or nerve wraps can fail to adequately deliver tacrolimus or match the mechanical properties of nervous tissue, leading to poor retention and suboptimal therapeutic effects. There remains a need for improved local delivery methods that provide effective, sustained release of tacrolimus to nervous system tissues while minimizing systemic exposure.
Claims Coverage
The patent includes 4 independent claims related to a device for local delivery of tacrolimus, methods for its local delivery to nervous tissue, methods of treating nervous system injury with the device, and methods of making the device. The main inventive features cover the composition and form of the device, its mechanical and drug loading properties, methods of application for local delivery, and manufacturing via electrospinning.
Device composition and structure for local tacrolimus delivery
A device comprising a polymeric matrix with an effective amount of a biodegradable polymer and tacrolimus, configured as an electrospun nerve wrap. The device has specific mechanical properties including a Young's modulus from about 5 MPa to about 50 MPa, suture retention strength of at least 100 gram-force, ultimate stress between about 3 MPa to about 9 MPa, and strain at break between about 50% to about 300%. Tacrolimus is impregnated in an amount from about 1 mg to about 100 mg with a weight ratio to polymer of about 1:20 to about 1:50.
Method of local delivery of tacrolimus to nervous system tissue
Applying the described device to an implantation site in a subject to locally deliver tacrolimus. The method includes securing the device to the site, releasing tacrolimus over a period from about 10 to about 15 days, targeting nerves including optic or infra orbital nerves, and maintaining tacrolimus blood concentration below about 20 ng/mL.
Method of treating nervous system injury with local tacrolimus delivery
Applying the described device to nervous system tissue injured in a subject and releasing an effective amount of tacrolimus at or near the injury. Target nervous tissue includes nerves such as optic nerves. Tacrolimus blood levels are maintained below about 20 ng/mL during treatment.
Method of making the device by electrospinning
Preparing a first solution with tacrolimus and a first solvent (e.g., dimethyl sulfoxide) and a second solution with a biodegradable polymer (e.g., poly(ester urethane) urea) and a second solvent (e.g., hexafluoroisopropanol), combining these solutions, and electrospinning the polymeric matrix containing tacrolimus from the mixture. The method can include forming the polymer in solution by reacting defined reagents and sterilizing the device by radiation or ethylene oxide treatment.
The claims cover a biodegradable electrospun nerve wrap device impregnated with tacrolimus, methods for its local application to nervous tissue with controlled release over approximately two weeks, treatment of nervous system injury with the device, and its method of manufacture via electrospinning suitable polymer and drug solutions, emphasizing device mechanical properties, drug loading ratios, and local delivery while minimizing systemic exposure.
Stated Advantages
Provides a cost-effective, clinically translatable device using materials already employed in FDA-approved products.
Enables delayed and extended local release of tacrolimus to nervous system tissues, maintaining effective drug concentrations over time.
Minimizes systemic exposure and associated serious side effects, such as nephrotoxicity and neurotoxicity, encountered with systemic administration of tacrolimus.
Mechanical properties of the device mimic those of nervous tissue to ensure pliability, kink-resistance, and retention at the implantation site during movement.
Local delivery improves nerve regeneration and neuroprotection by increasing markers such as GAP-43 and reducing inflammation as indicated by GFAP expression.
Documented Applications
Local delivery of tacrolimus or derivatives to injured nervous system tissue including nerves of the central nervous system such as the optic nerve and peripheral nerves including infra orbital nerve.
Treatment of nervous system injuries and conditions that impair axonal regeneration, such as optic nerve ischemia and peripheral nerve transection and repair.
Fabrication of electrospun polymeric wraps for use as drug delivery devices to enhance neuroregeneration and reduce adverse systemic drug effects in subjects.
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