Method for delivering particulate drugs to tissues
Inventors
Rabinow, Barrett E. • Gendelman, Howard E. • Kipp, James E.
Assignees
Baxter Healthcare SA • Baxter International Inc • University of Nebraska Medical Center UNMC • University of Nebraska System
Publication Number
US-8986736-B2
Publication Date
2015-03-24
Expiration Date
2024-06-15
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Abstract
The present invention is concerned with delivering a pharmaceutical composition to a tissue target of a mammalian subject for treating brain diseases or disorders. The process includes the steps of: (i) providing a dispersion of the pharmaceutical composition as particles having an average particle size of from about 150 nm to about 100 microns, and (ii) administering the dispersion to the mammalian subject for delivery to the tissue target of a portion of the pharmaceutical composition by cells capable of reaching the tissue target. The dispersion of the pharmaceutical composition as particles, for example, can be phagocytized or adsorbed by the cells prior or subsequent to administration into the mammalian subject. The dispersion of the pharmaceutical composition can be administered to the central nervous system or the vascular system. After administration, the loaded cells transport the pharmaceutical composition as particles into the tissue target.
Core Innovation
The invention provides a method for delivering a pharmaceutical composition to target tissues of a mammalian subject using cellular transport. This method involves providing the pharmaceutical composition as particles with an average size from about 150 nm to about 100 microns and administering the dispersion so that a portion of the composition is delivered to the tissue target by cells capable of reaching those tissues. The invention also contemplates intracellular uptake of the particles by cells, such as through phagocytosis or adsorption, either before or after administration to the subject.
A preferred embodiment includes isolating cells like macrophages, monocytes, granulocytes, neutrophils, basophils, or eosinophils from the subject, contacting these cells with the pharmaceutical particle dispersion, allowing time for intracellular uptake, and then administering the loaded cells to the subject. The loaded cells can be administered parenterally or directly into the central nervous system, vascular system, or other routes, enabling delivery of the pharmaceutical composition to the tissue target.
This invention addresses issues with traditional drug delivery such as poor oral bioavailability, inefficient targeting of the brain, and significant loss to liver metabolism that necessitate higher, potentially toxic doses. By delivering drugs as particles that are taken up by cells capable of reaching tissues like the brain, the invention provides more efficient targeting, bypasses liver metabolism, and may allow for sustained drug release at the target site.
Claims Coverage
The independent claims focus on five inventive features that characterize the method and composition for delivering particulate pharmaceutical agents via cellular transport to brain tissue, particularly for HIV infection.
Delivery of particulate pharmaceutical compositions to the brain using phagocytic cells
The method comprises providing a dispersion of the pharmaceutical composition as particles with an average particle size from about 150 nm to about 100 microns and administering the dispersion to the mammalian subject for delivery to the brain by cells capable of reaching the brain—where the particles have a solubility in water of less than about 10 mg/mL and are selected from protease inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors, and where the subject has HIV infection in the brain.
Pharmaceutical composition in particulate form for brain delivery via phagocytic cells
A composition for delivery to a brain comprising a dispersion of a pharmaceutical composition as particles (about 150 nm to 100 microns), adapted for administering to the subject for brain delivery via cells capable of reaching the brain, where the particles include a poorly water-soluble compound (solubility less than about 10 mg/mL, selected from the specified drug classes), and the subject has HIV infection in the brain.
Ex vivo loading and administration of cells carrying pharmaceutical particles
A method that involves: (i) isolating cells from the subject; (ii) contacting the cells with a dispersion of pharmaceutical composition as particles (about 150 nm to about 100 microns); (iii) allowing cell uptake to form loaded cells; and (iv) administering the loaded cells to deliver a portion of the pharmaceutical composition to the tissue target—where the particles are as defined above and the subject has HIV infection in the brain.
Method of treating CNS HIV infection with anti-HIV particle-loaded macrophages
A method of treating a patient with HIV infection in the central nervous system by: (i) providing a dispersion of the anti-HIV composition as particles (about 150 nm to about 100 microns); and (ii) administering the dispersion to the CNS for delivery of an effective amount by macrophages to the brain, where the particles are poorly water-soluble (solubility less than about 10 mg/mL) and are from the specified drug classes.
Particle characteristics: poorly water-soluble anti-HIV drugs in phagocytozable size range
The particles used must meet two criteria: being in the size range of about 150 nm to about 100 microns and comprising a compound (protease inhibitor, nucleoside reverse transcriptase inhibitor, or non-nucleoside reverse transcriptase inhibitor) having a solubility in water of less than about 10 mg/mL.
The inventive features are directed to methods and compositions for delivering specific classes of poorly water-soluble anti-HIV drugs in particulate form to the brain, utilizing cellular transport (phagocytic cells or macrophages) for effective treatment of HIV infection in the central nervous system.
Stated Advantages
The method increases the loading and amount of drug delivered due to high packing in particulate form that can be phagocytized by cells.
Liver metabolism is avoided because the drug is not exposed to systemic circulation, allowing for direct administration to target tissues and reducing toxic side effects.
Once administered to the tissue target, the drug can persist as an extended release depot for weeks or months.
By loading drugs into phagocytic cells, infecting organisms like viruses and bacteria are exposed to higher concentrations of drug, potentially improving efficacy.
Macrophages can carry drugs across barriers such as the cerebrospinal fluid-brain barrier, enabling delivery of therapeutic agents into the brain.
Administering the drug in this manner allows increased utilization within the brain at lower overall drug levels.
The approach may reduce the emergence and perpetuation of drug-resistant organisms in the body.
Cost of therapy can be reduced due to more efficient drug utilization and targeted delivery.
Documented Applications
Delivery of anti-HIV compounds (protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors) to the brain for treating HIV infection in the central nervous system.
Treatment of central nervous system disorders including Parkinson's disease, Alzheimer's disease, cancer, viral infection, fungal infection, bacterial infection, and spongiform encephalopathy.
Delivery of diagnostic agents and contrast media (including x-ray imaging agents and MRI contrast agents) to the brain and other tissues.
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