Preparation and evaluation of fast-dissolving films of etilefrine hydrochloride for practical buccal dosing.

Etilefrine hydrochloride (ET) is an important drug in the treatment of hypotension, and parenteral injections and oral tablets are the conventional dosage forms. However, parenteral injections may cause abnormally high plasma levels as well as pain and necrosis, and oral tablets undergo first-pass metabolism. Although fast-dissolving buccal tablets were previously reported, the initial absorption rate was a little slow and the plasma levels were varied extensively. Recently, many films have been developed as novel dosage forms. Therefore, in the present study, film dosage forms containing ET were produced using water-soluble polymers and glycerin (GLY) as excipients to obtain a practical buccal dosage form. Films composed of ET, GLY, and sodium alginate (AL) exhibited good physical characteristics and rapid release in vitro (more than 70% at 2 min). The compacted AL film containing 2 mg ET (1 × 1 cm) exhibited rapid absorption (>19 ng/mL at 0.5 h), maintained an effective plasma level (>7 ng/mL) for a long time period (0.5-4 h), and had an adequate plasma concentration-time profile with a smaller standard error (<15.3 ng/mL). These results suggest that the present compacted buccal film is a superior dosage form of ET for practical use.

Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

INTRODUCTION: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites. METHODS: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis. RESULTS: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. DISCUSSION: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation.

Absorption behavior of etilefrine after buccal administration in rats.

Etilefrine hydrochloride (ET-HCl) is used in the treatment of hypotension. Dosage forms of orally administered tablets and parenteral injections are clinically available, but exhibit unfavorable characteristics, including cardiac toxicity, headaches, and damage at the injection site for the parenteral dosage form, and initially high plasma levels, fast elimination, and first-pass effects for its oral administration. Therefore, the buccal application of ET-HCl was herein investigated as an alternative to conventional administration routes. I.v., intragastric, and buccal administration were performed using rats, and absorption features were compared. Buccal application at open conditions for 1 h exhibited absolute bioavailability of more than 20%, while the intragastric administration gave much lower bioavailability (<10%). The drug residue and drug distribution in the oral mucosa were investigated in order to clarify drug transfer behaviors. In the application of ET-HCl solution using a cotton ball, higher plasma concentrations and their maintenance at higher levels were achieved at 10 mg/kg than at 2.5 mg/kg. In addition, absorption was greater with a longer application (4 h) than with a shorter application (1 h). Etilefrine (ET) was rapidly absorbed using aqueous buffer of pH 9.5 as the solvent. Open application was appropriate for achieving and maintaining higher plasma levels. Thus, in the buccal application of ET-HCl aqueous droplets, a wide distribution throughout the mucosal surface is important for achieving rapid absorption and the maintenance of plasma levels. These findings suggested that the buccal application should be feasible administration of ET-HCl.