Methylene blue MMX® tablets for chromoendoscopy. Safety tolerability and bioavailability in healthy volunteers

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Abstract

Methylene blue-MMX® tablets are proposed as colonic diagnostic staining. Methylene blue taken prior to colonoscopy is expected to provide an effective staining of colonic and rectal mucosa leaving unstained the dysplastic or polypoid areas.

The present single dose, open-label study investigated the safety of methylene blue after single oral doses of 200 and 400 mg in healthy volunteers. The absolute bioavailability was also investigated after the intake of 2 L of bowel cleansing preparation in 2 h and by comparing the dose of 200 mg with a single iv dose of 100 mg in the same subjects.

Only non-serious adverse events occurred. Related events occurred to 8/22 subjects. Most of the events were mild and transient. Abnormal transaminases, gastrointestinal disorders and dysuria frequency were 13.6%. After intake of the laxative and the oral dose of 200 mg, systemic exposure to methylene blue was shown in all subjects with concentrations increasing for 12 h. The peak was reached in a median of 16 h. Peak blood concentration did not increase proportionally with the dose. AUC0–t was 32.94 μg/mL × h after 200 mg and 38.08 μg/mL × h after 400 mg. Half life ranged between 14 and 27 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative excretion was about 40% of the injected dose, 39.67% after 200 mg and 23.48% after 400 mg. Absolute bioavailability of methylene blue calculated as ratio between AUC0–t oral/iv corrected for the dose was on average Fabs = 139.19 ± 52.00%.

Introduction

Methylene blue is able to stain tissues without impairing their vital functions.

Currently, methylene blue is used in human medicine in a number of therapies and diagnoses.

Methylene blue MMX® tablets are a new oral modified release formulation manufactured using a multimatrix structure (MMX®, Cosmo Technologies, Ireland). MMX is a modified release technology that ensures a colonic drug delivery. In the MMX structure, microparticles of active ingredient are dispersed in a sequence of lipophilic and hydrophilic matrices. The multimatrix creates a partially hydrophobic environment which slows and controls the drug dissolution process. The outer tablet gastroresistant polymer film begins to disintegrate when the suitable intestinal pH is reached. Thus, the tablets arrive unaltered to the terminal ileum. When the colon fluids interact with the tablet after coating dissolution, the matrix structure forms an outer, viscous gel mass that controls the diffusion of the active ingredient. Whilst the tablet progresses in the colon towards the rectum, debris of the gel mass disaggregate and release the active ingredient in proximity to the mucosa. MMX formulations' gastrointestinal transit and colonic delivery was demonstrated by pharmaco-scintigraphic investigations of various drugs in healthy male volunteers [1], [2]. In the study of gastrointestinal transit and distribution of budesonide MMX® tablets, 153Sm-budesonide radioactivity incorporated into tablets was followed by means of pharmaco-scintigraphic imaging [2]. The relative percentage of budesonide absorption in the time during which radioactivity was detectable in the target region (i.e. the region comprised between the ascending and the descending-sigmoid colon) was 95.9 ± 4.2%. Budesonide tablets were detected in the ascending colon between 6 and > 24 h. The descending colon was left 12 to > 24 h post-dosing. Initial tablet disintegration started, on average, 9.48 ± 5.11 h after administration either in the small intestine (n = 2), the ileum (n = 5), the ascending (n = 2), transverse (n = 2) or sigmoid colon (n = 1). Times of tablet residence in the gastroenteric regions were 17–117 min (stomach), 37 min–9.95 h (small intestine), 0.5–12 h (ileum), 3 to > 15.5 h (ascending colon), 4 to > 17 h (transverse colon), and 12 to > 17 h (descending colon) [2].

Methylene blue has the property to be selectively absorbed and stain the intestinal columnar epithelium [3], [4], [5]. Normal, non-dysplastic mucosa generally exhibits a diffuse, homogeneous, dark blue staining, after methylene blue is absorbed into the columnar cytoplasm and abundant goblet cells. In contrast, severely dysplastic, inflamed or malignant epithelium exhibits decreased cytoplasm and reduced to absent goblet cells. These alterations result in decreased uptake of methylene blue and endoscopic appearance of focal light blue or pink (unstained) or heterogeneously stained (specked) mucosa within the diffusely stained epithelium. This property is applied to the detection of abnormalities of colonic mucosa. During the chromoendoscopy, different dyes, like methylene blue and indigo carmine, are topically applied by a spraying probe [4], [6]. Sprayed methylene blue has been used to screen colonic neoplasias at concentrations of 0.1–0.5% [7]. The new tablets would represent a potential alternative to the topical spray. When taken before the colonoscopy, methylene blue tablets are expected to provide an accurate staining in the colon and rectum. The colonic release would increase the contrast of the mucosal cells, lower the polyp detection failure rate and reduce the total time of the colonoscopy by ensuring the mucosal staining before initiating the endoscopy. The excessive prolongation of the endoscopy due to the dye spraying, absorption into the epithelium and excess removal would also be avoided.

The present study aimed at preliminarily investigating safety and absolute bioavailability of methylene blue administered as MMX tablets at doses of 200 and 400 mg to healthy male and female volunteers after the intake of a bowel cleansing preparation. The investigation of the colonic mucosa staining after a single dose of methylene blue tablets is the objective of ongoing trials.

Section snippets

Study design

The present study was a single ascending dose, open-label, randomised, safety, bioavailability study. Primary objective was the investigation of the safety of methylene blue after single oral doses of 200 and 400 mg as Methylene blue MMX tablets in healthy volunteers undergoing a standardised bowel cleansing preparation. The new formulation was administered for the first time. The study was also aimed at investigating the absolute bioavailability of methylene blue after a single oral dose of 200 

Disposition of subjects

Ten (10) male Caucasians and 12 female Caucasians, aged 24 to 61 y were enrolled. Baseline demographic data are summarised in Table 1.

All the 22 enrolled subjects concluded the study as per protocol and were considered in the safety and PK analysis.

Methylene blue blood concentration after single oral and iv dose

After single dose administration of either 200 or 400 mg of methylene blue tablets or single injection of 100 mg of methylene blue the blood methylene blue vs. time profiles were as in Fig. 1 in linear scale. The main kinetic whole blood parameters

Discussion

For the investigation of the safety and tolerability of methylene blue formulated as MMX® modified release tablets, single oral doses of 200 and 400 mg were administered for the first time to healthy male and post-menopausal female subjects after the intake of a 2 L bowel cleansing preparation. The bowel cleansing preparation was administered with the aim of reproducing conditions similar to those of the new product proposed use. Ten (10) subjects were exposed to 200 mg of methylene blue MMX

Acknowledgements

Cosmo Technologies Ltd., Ireland gave the financial support to the project. The relationships between the Sponsor, Cosmo Technologies, and Cross Research S.A. and ABL Laboratories were regulated by financial agreements.

The Sponsor reviewed and approved the study design, was informed about the collection of data, reviewed and approved the analysis and the interpretation of data, reviewed and approved the manuscript for publication.

MMR reviewed and approved the design of the study, was

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