Enema ion compositions for enhancing colorectal drug delivery

Abstract

Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (∼350 mOsm) compared to blood (∼300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations.

Local enema treatment to inhibit FOLH1 /GCPII as a novel therapy for inflammatory bowel disease

“…We previously found that, similar to what was observed in the human colorectum [25], sodium-driven water absorption continued to occur in the mouse colorectum for enema vehicles above the conventional isoosmolar point and up to 400–500 mOsm/kg [23]. Thus, our isotonic vehicle contained 2.5 mg/mL 2-PMPA dissolved in 1.32% w/v sodium chloride and titrated to pH 7.0 ± 0.1 using 3.5 M NaOH (final osmolality of 450 ± 5 mOsm/kg).…”

“…Having previously observed that hypotonic enema solutions provide improved colorectal drug distribution and absorption [23,30], we first tested whether administering 2-PMPA hypotonically would lead to increased colorectal tissue levels in mice with TNBS-induced colitis. Indeed, we found that at 30 mins after enema administration, the hypotonic vehicle provided a 1.6-fold increase in colorectal tissue 2-PMPA levels compared to the isotonic vehicle (Fig.…”

“…This is perhaps not surprising, given that enema formulations have the potential to directly access diseased tissues in the distal colorectum and locally deliver high amounts of drug. However, achieving adequate drug distribution in the colorectum is challenging due to the fact that the colorectal epithelium is highly folded and collapsed [23]. To achieve highly uniform drug delivery in the colorectum, we explored the administration of water soluble 2-PMPA in a hypotonic vehicle solution, an approach for modifying the enema vehicle composition that resulted in improved colorectal drug distribution and delivery in our previous study [23].…”

Multicompartmental Pharmacokinetic Model of Tenofovir Delivery to the Rectal Mucosa by an Enema

“…In the absence of prior rectal cleansing and fecal washout, enema spreading and drug delivery will be less homogenous in space (along the canal) and in time (in relation to enema application and expulsion). Future modeling of this more complex process will be informed by imaging studies of vehicle distribution along the rectum[21,34]. …”

Barriers to inhaled gene therapy of obstructive lung diseases: A review

“…Ensign et al demonstrated that by using hypotonic solution as delivery vehicle, muco-inert (i.e. densely PEGylated) nanoparticles were able to rapidly penetrate the luminal mucus layer and reached the immediate surfaces of vaginal [315] and colorectal [316] epithelium in vivo . However, the effect and safety of this approach is yet to be established for delivery of inhaled therapeutics, including gene vectors.…”