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LIALDA demonstrates prolonged release of mesalamine in an in vitro study using a simulated colon

Philadelphia, PA October 17, 2007 According to a study using a dynamic in vitro gastrointestinal tract system, Shire plc's (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) ulcerative colitis drug LIALDA (mesalamine) demonstrated a delivery system where the majority of the drugs active ingredient, 5-aminosalicyclic acid (5-ASA), is released over a prolonged period in the simulated colon. The colon is the site of inflammation in ulcerative colitis. In this in vitro model, after the LIALDA tablet passed through the simulated stomach, small intestine and colon compartments, the majority of 5-ASA within each tablet was released in the simulated colon (nearly 90 percent in simulated fasted state and 81 percent in the simulated fed state). Less than 1 percent of the 5-ASA was released from the tablet in the simulated stomach and small intestine. The study used the TNO Gastrointestinal Model, or TIM, which simulates a human stomach, small intestine and colon. The findings were published in the July/August issue of Advances in Therapy.

To our knowledge, traditional, delayed-release 5-ASA formulations have no mechanism for prolonging the release of 5-ASA once the tablet enters the colon, which may lead to the majority of 5-ASA being released immediately upon entering the colon instead of in the areas most likely to be inflamed, said lead study investigator and Senior Director of Pharmaceutical Sciences at Shire, Srini Tenjarla, PhD. Using the TIM system, a well-known and widely used system that mimics the fate of ingested products in the human adult GI tract, we were able to demonstrate that LIALDA tablets provide maximum release of 5-ASA in a prolonged manner, with minimal formulation disintegration and release in the simulated small intestine.

The TIM system allowed us to observe that after exposure to the simulated stomach and small intestine and immediately prior to being introduced into the simulated colon compartment, the LIALDA tablets had a swollen appearance and the first appearance of cracks on the outer tablet coating. This demonstrates that very little drug is released in the simulated stomach and small intestine and suggests that the majority of mesalamine is released in the simulated colon, said Dr. Tenjarla.

LIALDA with Multi Matrix System (MMX) Technology combines a pH-dependent gastro-resistant coating, which delays the release of the medication to the colon, with a tablet core containing mesalamine with hydrophilic and lipophilic excipients. LIALDA is the only ulcerative colitis treatment that utilizes MMX Technology.

In two pivotal phase III clinical studies, LIALDA was shown to be superior to placebo in inducing remission and treating the symptoms of mild-to-moderate UC. LIALDA was generally well tolerated.

About the Study

The release kinetics of 5-ASA from LIALDA were assessed using the TIM system that simulated the physiologic conditions in the adult human gastrointestinal tract under standardized fed and fasted conditions. In the analysis, the LIALDA 1.2g tablet was introduced to the TIM system, along with a mixture of artificial saliva and tap water (fasted state) or a mixture of artificial saliva and the standard FDA high-fat breakfast (fed state). The total intake was always 200g and all experiments were performed in duplicate.

After all samples were collected, a validated high-performance liquid chromatography method with ultra-violet detection was used to quantify levels of 5-ASA in the samples. Samples were analyzed using a Phenomenex Aqua 5 3m column (150mm by 3mm inner diameter) at 40 degrees Celsius (excitation/emission wavelength 315/430nm).

The analysis found that during passage through the gastric and small intestine compartments of TIM, on average less than one percent (0.25 percent in fasted state and 0.84 percent in fed state) of the 5-ASA was released from LIALDA. In contrast, during passage through the colon compartments of TIM, 78.01 percent of the 5-ASA was released from LIALDA in a fasted state and 68.49 percent in fed state. The remaining 11.64 percent (fasted state) and 13 percent (fed state) were recovered in the simulated colon residue. The apparent difference in recovery rates is minor in both simulated fasted and fed states as the results still show the continuing presence of high concentrations of 5-ASA in the colon. After an initial lag of about 23 hours, 5-ASA was released in the simulated colon consistently over approximately 20 hours. Analysis of the rate of 5-ASA release showed an initial linear increase that peaked at 67.5mg/hour within 56 hours in the simulated fed state and at 73.3mg/hour within 68 hours in the simulated fasted state.

Clinical relevance of in vitro data is unknown.


Contact: Sarah McGee
Shire plc

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