Taro Kanamaru

Evaluation of regional gastrointestinal absorption of edoxaban using the enterion capsule

Two studies in healthy subjects assessed the absorption of edoxaban when delivered to specific locations within the gastrointestinal tract using Enterion capsules. In study 1 (single‐dose, 4‐way crossover), 8 participants received edoxaban 60 mg as immediate‐release (IR) tablets (treatment A), as powder formulation delivered to the distal small bowel (treatment B) or ascending colon (treatment C), or as an aqueous suspension delivered to the ascending colon (treatment D). In study 2 (single‐dose, 2‐way crossover), 10 participants received edoxaban 30 mg as IR tablets (treatment E) or in granulate formulation with fumaric acid 50 mg, added to acidify the local gastrointestinal tract and enhance solubility, delivered to the ascending colon (treatment F). Peak and total exposure following targeted drug delivery to the distal gastrointestinal tract were significantly lower than with IR tablet delivery. In study 1, total exposure ratios of treatments B, C, and D compared with A were 14.9%, 7.9%, and 6.1%, respectively. In study 2, relative total exposure was 12.6% for treatment F despite the fumaric acid. Time to peak concentration was longer with higher variability for edoxaban delivered to the distal gastrointestinal tract compared with the IR tablet. These data indicate that edoxaban absorption occurs predominantly in the proximal small intestine.

Dosage form design and in vitro/in vivo evaluation of cevimeline extended-release tablet formulations

The objective of the present work is to develop an extended-release dosage form of cevimeline. Two types of extended-release tablets (simple matrix tablets and press-coated tablets) were prepared and their potential as extended-release dosage forms were assessed. Simple matrix tablets have a large amount of hydroxypropylcellulose as a rate-controlling polymer and the matrix is homogeneous throughout the tablet. The press-coated tablets consisted of a matrix core tablet, which was completely surrounded by an outer shell containing a large amount of hydroxypropylcellulose. The simple matrix tablets could not sustain the release of cevimeline effectively. In contrast, the press-coated tablets showed a slower dissolution rate compared with simple matrix tablets and the release curve was nearly linear. The dissolution of cevimeline from the press-coated tablets was not markedly affected by the pH of the dissolution medium or by a paddle rotating speed over the range of 50-200 rpm. Furthermore, cevimeline was constantly released from the press-coated tablets in the gastrointestinal tract and the steady-state plasma drug levels were maintained in beagle dogs. These results suggested that the designed PC tablets have a potential for extended-release dosage forms.

Improvement of low bioavailability of a novel factor Xa inhibitor through formulation of cationic additives in its oral dosage form

A clinical trial of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphtyl) propanoic acid (DX-9065) revealed that its oral bioavailability was only 3% when it was administered as a conventional capsule formulation. The low bioavailability of DX-9065 was likely caused by both its poor membrane permeability and its electrostatic interaction with anionic bile acids. We hypothesized that DX-9065 absorption would be enhanced when the cationic drug was free from the complex through its replacement with other cationic substances. Polystyrene nanospheres coated with cationic poly(vinylamine) and cholestyramine, which is clinically used as a cholesterol-lowering agent, dramatically prevented DX-9065 from interacting with chenodeoxycholic acid in vitro. Successive animal experiments showed that bioavailability of DX-9065 administered with these cationic substances was 2-3 times that of DX-9065 administered solely. A dry syrup formulation with one-half of a minimal cholesterol-lowering equivalent dose of cholestyramine was designed, and the clinical trial was resumed. A 1.3-fold increase in bioavailability of DX-9065 was observed when the dry syrup was administered. We successfully demonstrated that DX-9065 absorption was enhanced when the drug was administered with cationic additives; however, it appeared that the absorption-enhancing function of cholestyramine largely depended on its dose. The dose escalation is probably prerequisite for the significant improvement of DX-9065 absorption in humans.

Enteric-coated tablets improve oral bioavailability of DX-9065, a novel anticoagulant.

Oral bioavailability of DX-9065, a factor Xa inhibitor, was only 3% when it was administered as a conventional capsule formulation in fasted humans, and was further reduced to about one-tenth when it was administered to fed humans. The poor absorption of DX-9065 probably resulted from its low membrane permeability and its electrostatic interaction with bile acid. We designed enteric-coated tablets with the expectation that this pharmaceutical technology will prevent DX-9065 from interacting with bile acid. More than 85% of DX-9065 was released from the tablet coated with hypromellose acetate succinate within 10min in simulated intestinal fluid (pH 6.8). Monkey experiments demonstrated that AUC of DX-9065 after oral administration of its enteric-coated tablet was about 5 times that of its aqueous solution in the fasted state. The food effect on drug absorption was also reduced when DX-9065 was administered as an enteric-coated tablet. The average ratio of AUC in a fed state to that in a fasted state was approximately 0.5, even though the ratio was 0.1 when the enteric-coated tablet was substituted with the drug solution. Enteric coating could be a useful method for improving oral absorption of DX-9065 with reduced food effects on drug absorption.

Colonoscopic method for estimating the colonic absorption of extended-release dosage forms in dogs

The purpose of this study was to develop a new method using beagle dogs in order to evaluate the colonic absorption properties of oral extended-release (ER) solid dosage forms. The established method is not only noninvasive and inexpensive but full-sized ER dosage forms are also directly administered to the colons of conscious dogs through the anus with an endoscope and modified bioptome. In the method, it was possible to administer the ER dosage forms into the ascending colon of dogs within 30 s-1 min. The colonic absorption of Voltaren-XR (Diclofenac sodium), Glucophage-XR (metformin), Pacif (morphine hydrochloride), Herbesser-R (diltiazem hydrochloride) and Plendil (felodipine), which are currently on the market, were investigated by this method. The relative bioavailabilities of these ER dosage forms to oral drug solution were 100.3%, 42.5%, 60.6%, 46.3% and 29.8%, respectively. Some of these results reflected the human colonic absorption profiles reported in the literature. This newly developed method could provide researchers with an alternative way to predict the human colon absorption performance of oral ER delivery systems.

Impact of gastrointestinal residence time of extended-release (ER) tablets on in vivo evaluation of ER tablets

Extended-release tablets (ER) of cevimeline hydrochloride were prepared and in vivo absorptions following oral administration to beagle dogs were investigated. These in vivo studies were conducted with or without taking into account the gastrointestinal (GI) residence time of the ER tablet. The GI residence time of the ER tablets was identified from the fecal excretion time of the ER tablets for individual dogs after administration. It was difficult to investigate the in vivo performance of the slow-release ER tablets without knowing the GI residence time of the tablets. On the other hand, by combining the drug plasma concentration profiles and the fecal excretion time of the tablet, it was possible to adequately determine whether the designed ER formulation is possible for once-daily dosing. These results suggested that this approach was useful for the estimation of the in vivo performance of ER tablets.