Ex-vivo application of solid microparticulate therapeutic agents
Inventors
Kipp, James E. • Rabinow, Barrett E.
Assignees
BXTER HEALTHCARE SA • Baxter Healthcare SA • Baxter International Inc • University of Nebraska Medical Center UNMC
Publication Number
US-8333959-B2
Publication Date
2012-12-18
Expiration Date
2025-06-09
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Abstract
The present invention is concerned with a method of preparing and delivering small particles of a pharmaceutically active material to a mammalian subject for treating diseases or disorders. A preferred embodiment entails: (i) the collection of tissue cells from an animal donor, (ii) selective or non-selective growth of these cells in a cell culture medium to which is added solid particles of a therapeutically active compound, mostly free of a drug carrier (about 10% or less, by weight), and having an average particle size of less than about 100 microns, (iii) contacting the cells in the cell culture medium with the solid particles of therapeutically active compound causing the particles to be taken up by the cells into either the intracellular compartment of the cultured cells, attachment of the active compound as particles to the periphery of such cells, or a combination of intracellular uptake and attachment to the cell surface, (iv) optionally, isolation and/or resuspension of the cells prepared in steps i through iii, (v) administering the cells to the mammalian subject. The pharmaceutically active material can be administered intravenously, intramuscularly, subcutaneously, intradermally, intra-articularly, intrathecally, epidurally, intracerebrally, via buccal route, rectally, topically, transdermally, orally, intranasally, via pulmonary route, intraperitoneally, or combinations thereof. After administration, the loaded cells transport the pharmaceutical composition as particles.
Core Innovation
The invention relates to a method for the ex-vivo preparation and delivery of small solid particles of pharmaceutically active agents to a mammalian subject through cellular transport. This method involves collecting tissue cells from a mammalian donor, cultivating these cells in a culture medium containing solid, substantially carrier-free particles of therapeutically active compounds (about 10% or less carrier by weight, with an average size less than about 100 microns), and allowing the cells to take up these particles either by phagocytosis or adsorption onto the cell surface.
The cells loaded with the solid drug particles can then be optionally isolated or resuspended and subsequently administered to the mammalian subject. Upon administration, these cells can transport the pharmaceutical composition in particulate form to target tissues, where the therapeutic agent can be released. The approach can be used with a wide variety of cell types, including but not limited to phagocytic cells such as macrophages, monocytes, granulocytes, neutrophils, basophils, eosinophils, dendritic cells, as well as red blood cells, muscle cells, bone marrow and bone cells, vascular cells, organ tissue cells, and neuronal cells.
The problem addressed by this invention is the inefficiency and safety concerns associated with in-vivo drug delivery methods, particularly those involving genetic material or small molecule drugs that often require carrier matrices or exhibit low cellular uptake through simple diffusion. Existing ex-vivo drug delivery strategies are limited, particularly in achieving high drug loading and burst delivery without employing significant carrier matrices that can dilute the active agent or pose toxicity concerns.
By leveraging the natural phagocytic ability of certain cell types and using solid drug particles that are mostly carrier-free, the invention permits higher drug concentration within cells, more efficient delivery to diseased tissues, and site-specific drug release. This enables targeted therapy for numerous indications, including infections, neoplasms, lysosomal storage disorders, autoimmune and metabolic diseases, as well as providing new approaches for gene and antisense oligonucleotide delivery.
Claims Coverage
The patent contains one independent claim that defines the main inventive features of the invention related to ex-vivo preparation and delivery of small solid particles of therapeutically active agents using phagocytic cells.
Ex-vivo loading of phagocytic cells with substantially carrier-free solid therapeutic particles
The invention claims a method comprising: 1. Collecting phagocytic cells from a mammalian donor. 2. Nurturing the collected phagocytic cells in a cell culture medium which contains a pharmaceutical composition made of substantially carrier-free particles of one or more therapeutically active agent(s), resulting in phagocytic uptake of these particles by the cells to form loaded cells. 3. Administering an effective amount of the loaded cells, formed by phagocytic uptake of the particles, to a mammalian subject in need thereof. The inventive feature requires that the particles are substantially free of a carrier and that the uptake occurs ex-vivo in phagocytic cells, which are then administered to the subject for delivery of the therapy.
In summary, the independent claim covers the ex-vivo method of loading phagocytic cells with substantially carrier-free solid particles of therapeutic agents for subsequent administration to a mammalian subject, specifically focusing on the phagocytic cellular uptake step and delivery mechanism.
Stated Advantages
High drug loading is achieved and a high burst of drug may be delivered through ex-vivo loading of cells with solid drug particles.
More efficient and targeted delivery to sites of infection, inflammation, or diseased tissue is permitted by using loaded cells that are naturally directed to these regions.
Excessive liver metabolism of drugs can be avoided, potentially reducing therapy costs.
Allows for delivery of poorly water-soluble drugs that are otherwise difficult to administer in aqueous form.
Permits site-specific drug release in a region where it is therapeutically most needed, utilizing chemotaxis of phagocytic cells.
Reduces the toxicity concerns and inefficiency seen in in-vivo drug delivery and carrier-based formulations.
Documented Applications
Treatment of bacterial, viral, and fungal infections using ex-vivo loaded phagocytic cells capable of targeting sites of infection or inflammation.
Treatment of neoplasms (cancer) through cellular transport of antineoplastic agents.
Therapy for lysosomal storage disorders by delivering relevant pharmaceutical agents via loaded cells.
Treatment of autoimmune disorders and inflammatory conditions, including but not limited to osteoarthritis, rheumatoid arthritis, Crohn's disease, cystitis, ileitis, colitis, lupus, multiple sclerosis, and amyotrophic lateral sclerosis.
Gene delivery and delivery of antisense oligonucleotides (ATO) to mammalian subjects by ex-vivo loaded cells.
Delivery of diagnostic agents, such as contrast media for x-ray imaging or magnetic resonance imaging (MRI) aids, via cell-mediated transport.
Delivery of therapeutic agents for genetically acquired or inherited diseases, including sickle-cell anemia, Burkitt lymphoma, Gaucher disease, hemophilia A, chronic myeloid leukemia, Niemann-Pick disease, and other diseases listed in the patent.
Treatment of metabolic disorders through administration of cells loaded with relevant active agents.
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