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-10159651-B2
Publication Date
2018-12-25
Expiration Date
Abstract
A method for manufacturing a therapeutic agent delivery system includes forming a first mixture with a plurality of microparticles, the microparticles containing a therapeutic agent and having a coating around the therapeutic agent, the coating including chitosan. The method also includes forming a second mixture from ingredients including the first mixture, chitosan, a hydration promoter, a microparticle adhesion inhibitor, and a microparticle aggregation inhibitor, freezing the second mixture in a bath containing an aqueous alcoholic solution at a temperature above the freezing temperature of the aqueous alcoholic solution and at most −40° C., to form a frozen layer precursor, and drying the frozen layer precursor to form a porous polymeric matrix with microparticles embedded within the matrix.
Core Innovation
The invention relates to a method for manufacturing a therapeutic agent delivery system using chitosan-based porous mucoadhesive polymeric matrices that embed microparticles containing a therapeutic agent. The method forms a first mixture of microparticles that include a therapeutic agent with a coating around the therapeutic agent, where the coating includes chitosan, and then forms a second mixture from the first mixture and additional formulation components including chitosan, a hydration promoter, a microparticle adhesion inhibitor, and a microparticle aggregation inhibitor.
The method freezes the second mixture in a bath containing an aqueous alcoholic solution at a temperature above the freezing temperature of the aqueous alcoholic solution and at most 40°C, to form a frozen layer precursor. The frozen layer precursor is subsequently dried to form a porous polymeric matrix with microparticles embedded within the matrix.
The resulting porous matrix is configured for mucosal delivery, and the description states that higher and more reproducible microparticle release/permeation is obtained when a hydration promoter is present. The invention further addresses microparticle behavior during formulation and freezing by using a microparticle adhesion inhibitor to mitigate adhesion of chitosan-matrix particles, and using a microparticle aggregation inhibitor as cryoprotection against particle aggregation during freezing.
Claims Coverage
1 inventive feature is covered by the independent claim, defining a two-mixture manufacturing process that embeds chitosan-coated therapeutic-agent microparticles into a porous matrix via freezing in an aqueous alcoholic bath and drying. The dependent claims further refine the method with specific processing conditions, component selections, and optional structural or quantitative constraints.
Two-mixture manufacturing with chitosan-coated therapeutic-agent microparticles
forming a first mixture comprising a plurality of microparticles, the microparticles containing a therapeutic agent and having a coating around the therapeutic agent, the coating including chitosan; forming a second mixture from ingredients including the first mixture, chitosan, a hydration promoter, a microparticle adhesion inhibitor, and a microparticle aggregation inhibitor.
Freeze in aqueous alcoholic bath to form frozen layer precursor, then dry to porous matrix
freezing the second mixture in a bath containing an aqueous alcoholic solution at a temperature above the freezing temperature of the aqueous alcoholic solution and at most 40°C, to form a frozen layer precursor; and drying the frozen layer precursor, to form a porous polymeric matrix with microparticles embedded within the matrix.
The claim coverage centers on producing a porous polymeric matrix for therapeutic agent delivery by incorporating chitosan-coated therapeutic-agent microparticles into a second formulation containing a hydration promoter plus adhesion and aggregation inhibitors, then creating a frozen layer precursor by freezing in a chilled aqueous alcoholic solution and drying to obtain the embedded porous matrix.
Stated Advantages
Higher and more reproducible microparticle release/permeation when a hydration promoter is present.
Mitigation of chitosan-matrix particle adhesion via microparticle adhesion inhibitors.
Cryoprotection against particle aggregation during freezing via microparticle aggregation inhibitors.
Improved particle performance using pure chitosan and optionally sodium tripolyphosphate (STPP) as a crosslinker.
Improved safety/efficacy compared to systemic therapy for described local rectal/anal delivery use cases.
Documented Applications
Mucosal delivery of therapeutic agents using oral and GI indications, including intestinal targeting with pH-dependent stability/release and programmable release timing.
Rectal/anal delivery using a topical mesh for microparticle penetration and local retention of therapeutics.
Treatment kit use cases including oral cancer and anal/rectal cancer.
Described local retention of therapeutics including cisplatin, 5-fluorouracil (5-FU), and mitomycin, and combination regimens identified as FOLFOX and CapeOx [as referenced in the provided text].
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