Two-stage microparticle-based therapeutic delivery system and method
Inventors
Goldberg, Manijeh Nazari • Manzi, Aaron • LaPorte, Brandon • Birdi, Amritpreet
Assignees
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Publication Number
US-10398655-B2
Publication Date
2019-09-03
Expiration Date
Abstract
A system for delivery of a therapeutic agent to a site in mucosal tissue is provided. The system includes a porous, mucoadhesive polymeric matrix having a first and a second opposed surfaces. The matrix is formed by a composition including chitosan, a hydration promoter, a microparticle adhesion inhibitor, and a microparticle aggregation inhibitor. A plurality of microparticles are embedded within the matrix. The microparticles contain a therapeutic agent and have a coating around the therapeutic agent. The first surface of the matrix is configured to be attached to the site in the mucosal tissue and the matrix is configured to provide controlled release of the microparticles through the first surface. The coating of the microparticles includes chitosan so as to provide controlled release of the agent from the microparticles.
Core Innovation
A porous, mucoadhesive, freeze-dried polymeric matrix for delivery of a therapeutic agent to a site in mucosal tissue is formed from chitosan and distinct compounds including a hydration promoter, a microparticle adhesion inhibitor comprising HPMC, and a microparticle aggregation inhibitor. The matrix has first and second opposed surfaces, and includes a plurality of microparticles embedded within the matrix so that the microparticles are directly surrounded by and in contact with the matrix.
The microparticles contain a therapeutic agent and include a coating around the therapeutic agent, and the coating includes chitosan so as to provide controlled release of the agent from the microparticles. The first surface of the matrix is configured to attach to the site in mucosal tissue, and the matrix is configured to provide controlled release of the microparticles through the first surface when the first surface is attached.
The hydration promoter, the microparticle adhesion inhibitor, and the microparticle aggregation inhibitor are mutually distinct from one another and are present in amounts sufficient to achieve the controlled release of the microparticles without preventing formation of the freeze-dried matrix. In described embodiments, the hydration promoter is selected from ethylene glycol, propylene glycol, beta-propylene glycol, glycerol, or combinations thereof, and the microparticle aggregation inhibitor is chosen from monosaccharides, disaccharides, sugar alcohols, chlorinated monosaccharides, chlorinated disaccharides, or combinations thereof.
In related refinements, microparticles can include sodium tripolyphosphate, the matrix can include a second surface permeable to water, and a free amount of the therapeutic agent embedded directly in the matrix can constitute between 20% and 80% of the total amount of the therapeutic agent.
Claims Coverage
The independent claim coverage centers on a two-level, chitosan-based mucosal delivery system with five inventive features. Dependent claims refine the identity of the hydration promoter and aggregation inhibitor, add specific components to the microparticles and matrix, and can set quantitative constraints for a free therapeutic-agent fraction.
Porous mucoadhesive freeze-dried chitosan matrix with distinct additives
A porous, mucoadhesive, freeze-dried polymeric matrix having first and second opposed surfaces, formed by a composition including chitosan, a hydration promoter, a microparticle adhesion inhibitor comprising HPMC, and a microparticle aggregation inhibitor in a concentration of 0.1% to 50% by weight.
Embedded therapeutic-agent-loaded microparticles directly surrounded by matrix
A plurality of microparticles embedded within the matrix so as to be directly surrounded by, and in contact with, the matrix, wherein the microparticles contain a therapeutic agent and have a coating around the therapeutic agent.
Matrix first surface attachment and controlled release through first surface
The first surface of the matrix is configured to be attached to the site in the mucosal tissue and the matrix is configured to provide controlled release of the microparticles, through the first surface, when the first surface of the matrix is thus attached to the site.
Chitosan coating for controlled release from microparticles
The coating includes chitosan so as to provide controlled release of the agent from the microparticles.
Mutually distinct additive functions without preventing freeze-dried matrix formation
The hydration promoter, the microparticle adhesion inhibitor, and the microparticle aggregation inhibitor are compounds mutually distinct from one another and present in amounts sufficient to achieve the controlled release of the microparticles without preventing formation of the freeze-dried matrix.
Overall claim coverage centers on a chitosan-based porous mucoadhesive freeze-dried matrix that attaches to mucosal tissue and provides controlled release through its first surface, while embedded therapeutic-agent-loaded microparticles with a chitosan coating provide controlled release from the agent; distinct hydration-promoting, adhesion-inhibiting (HPMC), and aggregation-inhibiting additives support controlled release without interfering with freeze-dried matrix formation.
Stated Advantages
Controlled release of the microparticles through the first surface when the first surface is attached to the site in the mucosal tissue.
Controlled release of the agent from the microparticles via the coating that includes chitosan.
Use of mutually distinct additive compounds in amounts sufficient to achieve controlled release of the microparticles without preventing formation of the freeze-dried matrix.
Documented Applications
Delivery of a therapeutic agent to a site in mucosal tissue.
Local therapy in oral mucosa, including for oral mucositis.
Delivery in the gastrointestinal tract, including colorectal/anal delivery with pH-targeting and pH-programmable particle/mesh systems, and intestinal mucosa.
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