Office of Technology Transfer – University of Michigan

Biomimetic Microcrystalline Formulations for Lung Macrophage-Targeted Anti-Inflammatory Drug Delivery

Technology #6544

Targeted drug delivery for chronic and acute pulmonary conditions is currently one of the biggest challenges in the pharmaceutical industry, but has great potential to rapidly improve the outcomes for one of the largest segments of patients once solved. The World Health Organization estimates that ~15% of the world’s population may suffer from lung disease, making it one of the biggest causes of mortality and morbidity worldwide. The largest segment of these diseases are those linked to disregulation of the macrophage inflammatory response within lung tissue, including Chronic Obstructive Pulomonary Disease(COPD), Asthma, and Acute Respiratory Distress Syndrome(ARDS). Current treatments for diseases in this category rely on soluble anti-inflammatory drugs that have serious off-target side effects that must be remediated in next-generation medicines. Upon the discovery that lung macrophages bioaccumulate the anti-inflammatory drug Clofazimine as crystalline inclusions, we set out to determine if the presence of these crystals in lung macrophages altered their anti-inflammatory properties, and whether this response could be mimicked by a synthetic formulation of crystalline clofazimine. Indeed, macrophages carrying crystal-like drug inclusions(CLDIs) of clofazimine display increased anti-inflammatory properties, and these properties are also elicited using biomimetic inclusions administered directly to the macrophages for phagocytosis. These biomimetic CLDIs represent the first of a new class of compounds that are easily amenable for treatment a variety of pulmonary conditions, and without the unwanted off-target side effects of current drugs.

Crystal-like Drug Inclusions are Incredibly Selective, and Have Attractive Pharmacokinetic Properties

We found that administration of biomimetic CLDIs of clofazimine to pulmonary tissue caused recruitment of lung macrophages which subsequently phagocytosed the CLDI. Our studies showed that clofazimine CLDIs were not taken up by non-macrophage cells, indicating levels of selectivity for this potential drug class far superior to classical, soluble drugs. Moreover macrophages carrying CLDIs displayed several phenotypic changes that increased their anti-inflammatory function, including inhibited TNFα production, enhancement of IL-1RA production, and down-regulation of Toll-like receptors. Utilizing variable crystal packing, lipid or polymer coatings, and cellular recognition moieties, we have begun to optimize the pharmacokinetic and selectivity properties of biomimetic CLDIs to make them viable drug candidates. By leveraging oral, respiratory, and intravenous routes of administration and tuning the composition as well as pharmacokinetic properties of CLDIs, therapies for many common and orphan lung conditions may be rapidly developed in coming years.

Applications

  • Therapeutic drug delivery to treat Acute respiratory distress syndrome (ARDS) *Therapeutic drug delivery to treat the acute, inflammatory phases of these lung diseases:
  • Asthma (acute exacerbation)
  • Bronchiolitis and bronchiolitis obliterans (acute exacerbations)
  • Chronic obstructive pulmonary disease (COPD including chronic bronchitis and emphysema)- acute exacerbations
  • Hypersensitivity pneumonitis
  • Idiopathic pulmonary fibrosis
  • Pneumoconiosis (Black Lung Disease)
  • Silicosis
  • Therapeutic drug delivery to treat Chronic lung diseases:
  • Asthma (acute exacerbation)
  • Bronchiolitis and bronchiolitis obliterans (acute exacerbations)
  • Chronic obstructive pulmonary disease (COPD including chronic bronchitis and emphysema)- acute exacerbations
  • Hypersensitivity pneumonitis
  • Idiopathic pulmonary fibrosis
  • Pneumoconiosis (Black Lung Disease)
  • Silicosis

Advantages

  • Highly selective for lung macrophages
  • Targets multiple anti-inflammatory pathways simultaneously
  • Highly tunable pharmacokinetics