Study Evaluates Once-Daily Delivery System for GERD

A study in male Wistar rats found that the microparticulate dosage form of lansoprazole provided effective drug concentration for a longer duration than the conventional extended-release dosage form. Furthermore, the dosage form showed sufficient anti-acid secretion activity to treat acid-related disorders including the enrichment of nocturnal acid breakthrough based on the novel once-daily administration, according to findings published online January 8, 2013, in the Journal of Microencapsulation.

Gastroesophageal reflux disease (GERD) is considered one of the most common conditions affecting the gastrointestinal (GI) tract. Patients with GERD experience more acid output in the late evening, reaching a maximum in the early nighttime hours and diminishing toward the early morning. A majority of GERD patients are treated with the class of compounds called proton pump inhibitors (PPIs). Single-daily doses of PPIs decrease secretion of gastric acid to treat GERD symptoms; however, when dosed before breakfast, all PPIs are unable to effectively control the increasing gastric acidity that occurs during the night. Alternative treatment strategies, including twice-daily doses (before breakfast and before dinner) of PPIs have not resulted in complete control of nocturnal gastric acidity.

“Therefore, there is a need of a dosage form containing a PPI that can reliably provide full-day effect, including the enrichment of nocturnal acid breakthrough, while being administered on a once-daily basis,” said the researchers.

Lansoprazole is a PPI indicated for the treatment of acid-related disorders such as gastric ulcer, duodenal ulcer, and GERD. The mechanism of action of lansoprazole, a benzimidazole derivative, is inhibition of the H⁺/K⁺-adenosine triphosphate (the proton pump), an enzyme present in the gastric parietal cells that effectively decreases gastric acid secretion regardless of primary stimulus. After intestinal absorption, lansoprazole accumulates in the highly acidic environment of the parietal cell for activation. Thus, lansoprazole has to be absorbed intact by the GI tract. Because lansoprazole is unstable in acidic environments, dosage forms with lansoprazole are generally designed to protect lansoprazole from the stomach’s acidic environment, according to background information presented in the study.

Lansoprazole also belongs to class II drugs of the Biopharmaceutical Classification System, a feature of which is low aqueous solubility. Due to poor water solubility, its absorption is dissolution rate-limited, which often results in irregular and delayed absorption. Therefore, preparation of a multiparticulate dosage form of lansoprazole, such as microparticles, can be beneficial. A microparticles-based system may protect the active constituent from the gastric environment. Because of its small size, microparticles have a large surface area and could

provide extended circulated half-lives for various drugs. This means the least amount of the drug is required to achieve therapeutic effectiveness, thereby providing patients with relief from the side effects caused by nonspecific tissue uptake, explained the investigators.

Given all of this information, the researchers sought to formulate and evaluate lansoprazole-loaded microparticles to prevent nocturnal acid breakthrough in the case of GERD. In vivo pharmacokinetic performance and ulcer healing response of developed microparticles were investigated. The microparticulate delivery system was prepared with an oil-in-water solvent evaporation method using Eudragit^® RS 100 as a matrix polymer followed by enteric coated with Eudragit^® S 100 and hydroxypropyl methylcellulose phthalate HP55 using spray drying technique. The enteric-coated microparticles were stable in gastric pH condition.

The study included male Wistar rats obtained from the National Laboratory Animal Center in Taipei, Taiwan. For the in vivo pharmacokinetic study, the rats were fasted but given access to water overnight. The rats were divided into 2 groups and each group consisted of 4 rats. A hard gelatin capsule filled with enteric-coated microparticles (HP-ES-ERSMP03-F68) or a RICH^® capsule equivalent to lansoprazole (5 mg/kg) was orally administered to the rats. Blood samples were collected from tail veins of rats before dose administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after dosing. The results showed that the area under the serum concentration values were 2363.15±288.72 and 2260.37±272.90 ng·h/mL for HP-ES-ERSMP03-F68 and RICH^®, respectively, without significant difference (P>.05). The mean C_max values were 243.45±32.8 and 710.02±63.58 ng/mL for HP-ES-ERSMP03-F68 and RICH^®, and the corresponding T_max were 6 hours and 2 hours, respectively. The results suggested that the absorption of lansoprazole from HP-ES-ERSMP03-F68 was notably slower compared with RICH^®. The sustained release behavior of HP-ES-ERSMP03-F68 accounted for a longer time to reach C_max.

For the in vivo pharmacodynamic study, gastric ulcer was induced in the rats by oral administration of absolute ethanol (5 mL/kg). The rats were divided into 2 groups and each group had 4 rats. Each group received saline solution 1 mL (control) or hard gelatin capsule filled with enteric-coated microparticles (HP-ES-ERSMP03-F68) at a dose equivalent to lansoprazole (5 mg/kg) 1 hour after administration of ethanol. Multiple doses were administered once daily for 7 days. The gastric ulcer indexes were calculated to be 14.6±1.4 for the control group and 2.1±0.3 for HP-ES-ERSMP03-F68. If the control group was considered as 100%, the HP-ES-ERSMP03-F68 was 14.4%±2.1% relative to the control group.

The results showed that the induced gastric ulcer was healed gradually within 1 week after lansoprazole microparticles (5 mg/kg). The healing of disrupted tissues involved several steps including granulation tissue, contraction of ulcerated tissue, and re-epithelialisation. Along with acid inhibition, it may be possible that lansoprazole promoted the healing of gastric ulcers by affecting some of these steps, noted the investigators.