Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation

Abstract

There is growing evidence that methane production, predominantly by Methanobrevibacter smithii, in the intestines is a cause of constipation, pain, and bloating in irritable bowel syndrome with constipation (IBS-C). M smithii resides primarily in the large intestine but can also colonize the small intestine. In vitro studies found that the prodrug lactone form of lovastatin, found in cholesterol-lowering drugs, inhibited methane production in stool samples from patients with IBS-C. However, the cholesterol-lowering lovastatin β-hydroxyacid was ineffective at inhibiting methane production in this system. A considerable amount of lovastatin is converted to hydroxyacid in the stomach and is absorbed. It was hypothesized that galenic innovations could protect lovastatin from the stomach and allow release in 2 strategic locations, the duodenum and the ileocecal region, to reach M smithii. The desired release profile was achieved by developing an oral dosage form containing lovastatin and coated with 2 different enteric polymers that enabled a pH-dependent "dual pulse" drug release. Combinations of the 2 coated tablets were encapsulated together to deliver the desired amount of lovastatin to the targeted intestinal locations. The capsules have been tested in vitro and in vivo and show promise in treating IBS-C.

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage

“…In contrast, pH-based systems employ ionic polymers responsive to low (cationic) or high (anionic) pH [15] and affect site-specific drug delivery by exploiting the pH gradient along the GI tract. The pH of the mammalian GI tract progressively increases from the acidic stomach (pH 1.0–3.5) to pH 5.0–6.0 in the duodenum and proximal small intestine, to a peak of pH 7.0–8.0 in the ileum in the distal small intestine, decreasing again to pH 5.0–6.0 in the cecum [16,17]. Such pH-mediated release systems have been shown to direct reliable drug delivery to specific sites along the GI tract, including the duodenum and ileum [16,18].…”

“…The L30-D55 coating remains intact at low, gastric pH, thus protecting the enzyme from acidic conditions of the stomach and dissolving rapidly to release the enzyme at pH ≥5.5, the pH of the duodenum and upper small intestine [11]. Furthermore, EUDRAGIT ® polymers can be engineered to dissolve at a selected pH, including pH >7.0, for release in the ileum [16,18]. Therefore, a pH-mediated release strategy was employed to generate new ribaxamase formulations intended for use with oral beta-lactam antibiotics.…”

Gut Microbiota beyond Bacteria—Mycobiome, Virome, Archaeome, and Eukaryotic Parasites in IBD

“…In a population with irritable bowel syndrome (IBS), the subjects with the constipation-dominant disease (IBS-C) were shown to have a higher proportion of methane producers than individuals with the diarrhea-dominant disease (IBS-D) [135]. It was also shown that IBS-C involves an increase in M. smithii abundance [136] and a specific formulation of lovastatin, a fungal metabolite found to inhibit methane production in methanogenic microorganisms, was recently tested as a possible way to treat those suffering from IBS-C [137]. The methanogenic archaea are also associated with the etiology of IBD.…”

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

“…SYN-007 employs a dual coating approach using enteric-coated ribaxamase pellets [8] packaged into enteric-coated capsules [15]. The enteric coating of the capsule dissolves at pH > 7.0, the pH of the ileum in the lower small intestine [17]. After capsule dissolution, enteric-coated enzyme pellets rapidly release an active enzyme capable of degrading the antibiotic prior to its reaching and harming the colonic microbiota [15].…”

“…In contrast, ribaxamase is composed of enteric-coated beta-lactamase pellets within an uncoated, hard capsule. After swallowing, ribaxamase pellets are released in the stomach, pass intact into the duodenum and rapidly dissolve at pH ≥ 5.5 releasing the beta-lactamase enzyme in the upper small intestine [17].…”