Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease
Introduction
Inflammatory bowel disease (IBD) is a term that refers to chronic inflammatory diseases that affect the gastrointestinal tract, further divided into ulcerative colitis (UC) and Crohn's disease (CD). IBD is generally characterized by immune system dysregulation, mucosal inflammation, and impaired integrity of the epithelial barrier [1]. Anti-inflammatory drugs, such as steroids, are commonly used to treat IBD symptoms, repair mucosal tissues, and induce remission. The current frontline steroid therapy is budesonide, which has low bioavailability and undergoes extensive first-pass metabolism when taken orally, but is considered to be more effective than other common steroids when dosed topically [2,3]. For two-thirds of UC patients and for patients with more diffuse disease that also affects the distal colorectum, topical enema therapy is used [4,5]. While enema products are considered more efficacious and associated with fewer side effects than oral formulations in treating disease in the distal colorectum, substantial room for improvement remains. Although more effective than placebo, rectal budesonide products have provided <40% remission after 6–8 weeks of daily treatment in clinical studies [6,7].
To achieve effective topical treatment for inflammation in the colorectum, sustained, therapeutic levels of drug must be delivered to the affected tissues and cells. Although the colorectum is relatively accessible by enema administration, additional barriers to effective local drug delivery exist. The mucus layers coating the colorectal epithelial surface are a major barrier that limits colorectal drug distribution and absorption into the local tissue [8,9]. Frontline enema formulations for a water insoluble drug like budesonide contain micronized drug particles [10,11]. However, we found that microparticles are too large to penetrate the protective mucus mesh lining the colorectum and, thus, are sterically restricted from reaching the epithelial surface [9,12], facilitating rapid clearance [8]. In contrast, we found that nanoparticles that are both (i) small enough to pass through the pores in the mucus mesh, and (ii) non-adhesive to mucus (mucus-penetrating particles, MPP), provide rapid, highly uniform epithelial distribution in the colorectum following enema administration in a hypotonic enema vehicle [9,13]. Hypotonic vehicles cause rapid, osmosis-driven, advective delivery of non-adhesive MPP through mucus, and right up against the epithelial surface [14,15]. Further, MPP administered in a hypotonic enema vehicle entered ulcerated tissues in the colorectum in a mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD more efficiently than microparticles or nanoparticles that were adhesive to mucus [9].
Here, we describe the design of budesonide nanosuspensions (NS) containing drug particles of the appropriate size and formulated with muco-inert coatings (Pluronic F127) for improved mucosal distribution and tissue penetration in IBD. We demonstrate that budesonide NS provide improved colorectal tissue levels of budesonide with minimal systemic exposure compared to a budesonide microsuspension (MS) formulated with the same stabilizer as the clinical product (polyvinylpyrollidone (PVP)). We further compare the budesonide formulations for efficacy in the TNBS-induced mouse model of IBD, because (i) the inflammatory injury is localized to the colorectum, which is optimal for enema delivery, and (ii) budesonide was previously shown to be efficacious in the TNBS mouse model of IBD [[16], [17], [18]]. The improved colorectal drug delivery and efficacy provided by the muco-inert budesonide NS suggest the potential for clinical utility.
Section snippets
Materials
Budesonide (99% purity), 5% w/v 2,4,6-trinitrobenzenesulfonic acid (TNBS) solution, sodium azide, dimethyl sulfoxide (DMSO), 1,4-Dithiothreitol (DTT), phosphate buffered saline (PBS), lipopolysaccharide (LPS), collagenase type VIII, and DNAse-I were purchased from Sigma-Aldrich (St. Louis, MO). Polyvinylpyrrolidone K30 (PVP) was purchased from TCI Chemicals (Portland, OR). Zirconium oxide beads (0.15 mm, 0.5 mm and 1.0 mm in diameter) were purchased from Next Advance (Averill Park, NY).
Colorectal distribution of model fluorescent particles
Fluorescent PS particles of the appropriate size and surface stablizers (Table S3) to serve as model probes for the budesonide NS and MS were intrarectally administered to both healthy mice and mice with TNBS-induced colitis. The lack of colorectal folds and presence of epithelial damage was immediately apparent in the mice with TNBS-induced colitis. Despite this, the 2 μm/1% PVP particles were largely dispersed in the lumen in the TNBS mice (Fig. 1a), similarly restricted from reaching much of
Discussion
Although oral administration is often considered the most acceptable mode of drug administration, topical drug administration results in much higher local drug levels with lower doses, as well as reduced systemic drug exposure. This is particularly true for IBD drugs like budesonide, which undergoes extensive first-pass metabolism, and has undesirable systemic side effects [2,3]. Topical enema therapy is more effective for IBD patients with disease affecting only the distal colorectum, and even
Declaration of interest
The mucus-penetrating particle technology is licensed and in clinical development for ocular indications by Kala Pharmaceuticals. J.H. is a founder of Kala Pharmaceuticals and serves as a consultant. J.H. and Johns Hopkins own company stock. Under a licensing agreement between Kala Pharmaceuticals and the Johns Hopkins University, L.E., J.H., and the University are entitled to royalty distributions related to the technology. These arrangements have been reviewed and approved by the Johns
Data availability
The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.
Acknowledgments
We thank BASF Inc. for providing free samples of Pluronic F127, the JHMI animal husbandry staff, the JHMI Reference Histology lab, the Wilmer Microscopy and Imaging Core Facility (MICF) funded by NIH grant P30EY001765, and the Drug Analysis Unit in the JHU Institute for Clinical and Translational Research (ICTR) funded in part by UL1 TR001079 from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical
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- 1
Authors contributed equally.
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Current address: The Daniel K. Inouye College of Pharmacy, University of Hawaii Hilo, 200 W. Kawili Street, Hilo, HI, 96720.