Mucoadhesive nanoparticulate systems for peptide drug delivery

Abstract

This chapter describes the preparation of and methods for evaluating mucoadhesive nanoparticulate systems, including liposomes and polymeric nanoparticles. Mucoadhesive ability is conferred on the particulate systems by coating their surface with mucoadhesive polymers such as chitosan and Carbopol. The feasibility of this surface modification was confirmed by measuring the zeta potential. Several methods of evaluating the mucoadhesive properties of particulate systems have been reported in the literature. We have also developed some novel evaluation procedures including a particle counting method using a Coulter counter for polymer-coated liposomes. The mucoadhesive properties of the polymer-coated liposomes and polymeric nanoparticles were confirmed by means of these mucoadhesion tests. In applying these mucoadhesive nanoparticles to the oral and pulmonary administration of peptide drugs, more effective and prolonged action was observed in comparison with non-coated systems, thereby confirming the usefulness of mucoadhesive nanoparticulate systems for the delivery of peptide drugs.

Introduction

The bioadhesion of the oral dosage forms of poorly absorbable drugs has received much attention as have transdermal and buccal systems. Bioadhesion to mucous membranes in the gastrointestinal tract can be described in term of mucoadhesion. Since mucoadhesion can prolong the residence time of drug carriers at the absorption sites, improved drug absorption is expected from a combination of mucoadhesiveness and controlled drug release from the devices used. Longer et al. [1] were the first to show that a delayed gastrointestinal transit induced by bioadhesive polymers could lead to the increased oral bioavailability of a drug.

A tablet for oral or buccal use is one of the most extensively studied mucoadhesive dosage forms [2], [3], [4]. These devices are prepared by formulating mucoadhesive polymers such as hydroxypropylmethylcellulose and Carbopol, which is a high molecular weight poly (acrylic acid) copolymer, loosely cross-linked with allyl sucrose. A multi-unit bioadhesive system has also been prepared by coating microspheres of poly (hydroxyethyl-methacrylate) with mucoadhesive polymers using laboratory-scale equipment [5], [6]. Akiyama et al. [7] prepared a polyglycerol ester of fatty acid-based microspheres coated with Carbopol^®934P (CP) and CP-dispersing microspheres to evaluate their mucoadhesive properties.

In developing colloidal drug delivery systems, Lenaerts et al. [8] demonstrated the mucoadhesive properties of poly (alkylcyanoacrylate) nanoparticles in a series of autoradiographic studies and confirmed that the bioavailability of vincamine was improved by the nanoparticulate systems. Pimienta et al. [9] investigated the bioadhesion of hydroxypropylmethacrylate nanoparticles or isohexylcyanoacrylate nanocapsules coated with poloxamers and poloxamine to rat ileal segments in vitro using a labeled compound. We have developed mucoadhesive liposomes by coating the anionic liposomal surface with a cationic mucoadhesive polymer, chitosan, to evaluate the mucoadhesive properties both in vitro and in vivo [10], [11]. The feasibility of chitosan coating for nanospheres of poly (lactic-co-glycolic acid) (PLGA) and the mucoadhesiveness of the resultant particles have been confirmed [12].

One of the most attractive applications of mucoadhesive nanoparticulate systems is for the oral administration of peptide drugs. Peptide drugs are intrinsically poorly absorbable owing to their high molecular weight and hydrophilicity; they are also susceptible to enzymatic degradation in the gastrointestinal tract. The drug carriers are expected to remain in the gastrointestinal tract while protecting the entrapped peptide drugs from enzymatic degradation until they are absorbed in released or intact particulate form. The concept of this system could be also applied to other peptide delivery systems, such as nasal and pulmonary administration systems via the mucous membranes.

In this chapter, we will review a variety of attempts to prepare and evaluate the function of mucoadhesive nanoparticulate systems mainly aimed at the delivery of peptide drugs via oral and pulmonary administration.