Methods for effectively and rapidly desensitizing allergic patients
Inventors
Laulicht, Bryan E. • Bakhru, Sasha H. • Steiner, Solomon S. • Mathiowitz, Edith
Assignees
Perosphere Technologies Inc • Perosphere Pharmaceuticals Inc
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Publication Number
US-10092641-B2
Publication Date
2018-10-09
Expiration Date
Abstract
Methods and compositions for delivering antigens to the lymphatic system in doses that desensitize patients to future exposure to antigens have been developed. Rapid desensitization is achieved by introducing small quantities of antigen into the lymphatic system. In preferred embodiments, the compositions are administered to yield therapeutically effective levels of antigen within the lymph, where macrophages reside in the greatest concentration, by intradermal administration, using for example, microneedles or micro articles, oral administration, using for example, enteric coated capsules or tablets, or autologous transfusion. In some embodiments, the methods and compositions for delivering antigens orally achieve uptake by the Peyer's patches of the small intestines.
Core Innovation
The invention provides a method for selective delivery to the lymphatic system by administering microparticles comprising one or more antigens through hollow microneedles via intradermal injection. The microparticles have a mean equivalent circle diameter in the range of one to ten microns and comprise chitosan or a chitosan derivative. The chitosan derivative is described as an enzymatically cleavable polymer sensitive to degradation by macrophage lysozomal enzymes, with delivery to cells in the lymph system.
The method requires that less than twenty-five percent of the one or more antigens is released within forty eight hours after administration prior to uptake by macrophages. The microparticles further comprise a net charge altering agent to promote macrophage engulfment, where the net charge altering agent is one or a combination of charged amino acids. This design links lymphatic targeting and macrophage-associated uptake with controlled antigen release to support tolerance.
The disclosed immunologic outcomes include increased allergen-specific IgG without significant IgE increase, and reduced Th2/Th2 cytokines and/or increased Th1 cytokines. The lymphatic targeting is tied to delivery to macrophage-rich sites to promote tolerance through macrophages and dendritic cells. The document also describes microparticle formulation features including preferential phagocytosis by macrophages/DC, using enzyme-cleavable chitosan polymer systems and net charge alterations to enhance macrophage engulfment.
Claims Coverage
The document includes one independent claim that defines a selective lymphatic system delivery method using antigen-loaded chitosan-based microparticles administered via hollow microneedles, with additional independent-claim-delineating constraints on particle size, antigen release timing, macrophage-facilitating net charge, and enzyme sensitivity. Dependent claims refine this independent claim by specifying allergen selection, particle size distribution constraints, tighter antigen release limits, delivery through high pressure, and a specific chitosan crosslinking chemistry.
Selective lymphatic system delivery via hollow microneedles
Administering by intradermal injection of microparticles comprising one or more antigens through a hollow microneedles, to deliver the microparticles to the cells in the lymph system.
Chitosan microparticles with macrophage-lysosomal enzyme sensitivity
Using microparticles comprising chitosan or a chitosan derivative, the chitosan derivative being an enzymatically cleavable polymer sensitive to degradation by macrophage lysozomal enzymes.
Controlled antigen release prior to macrophage uptake
Requiring that less than twenty-five percent of the one or more antigens is released within forty eight hours after administration prior to uptake by macrophages.
Net charge altering agent of charged amino acids to promote engulfment
Adding a net charge altering agent to promote macrophage engulfment, wherein the net charge altering agent is one or a combination of charged amino acids.
Overall, the independent claim coverage centers on intradermal delivery through hollow microneedles of antigen-loaded chitosan (enzyme-cleavable to macrophage lysozomal enzymes) microparticles of specified small size, with antigen release constrained within 48 hours before macrophage uptake and enhanced macrophage engulfment via charged-amino-acid net charge alteration.
Stated Advantages
Increased allergen-specific IgG without significant IgE increase.
Reduced Th2/Th2 cytokines and/or increased Th1 cytokines.
Documented Applications
Rapid allergen desensitization through delivery of antigen-loaded microparticles to macrophage-rich lymphatic sites to promote tolerance.
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