Mucoadhesive nanoparticulate systems for peptide drug delivery
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.
Section snippets
Polymeric nanoparticles
Polymeric nanoparticles with biodegradable and biocompatible polymers are good candidates for particulate carriers to deliver peptide drugs. Such particles are expected to be adsorbed in an intact form in the gastrointestinal tract after oral administration [13]. Various preparation methods for polymeric nanoparticles, such as polymerization and solvent diffusion methods, have been reported [14]. We have successfully prepared nanoparticles with poly (lactic-co-glycolic acid) (PLGA) containing
Evaluation of mucoadhesive particulate systems
Various methods have been proposed to evaluate the mucoadhesive properties of tablets or mucoadhesive polymers themselves [28]. However, the number of studies dealing with the mucoadhesion of particulate systems is limited. In particular, special methods may be required to evaluate the mucoadhesive properties of nanoparticulate systems.
Effectiveness of polymer-coated liposomes for the absorption of peptide drugs
We evaluated the effectiveness of polymer-coated liposomes as carriers of peptide drugs following their oral administration in rats [11]. Insulin-encapsulating liposomes were prepared by the thin-film method with 1 mg/ml of insulin solution, obtained by mixing a 0.01 N HCl insulin solution with the same volume of acetate buffer (pH 4.4). Polymer coating was carried out in the same manner as described above. The insulin liposomal suspension (24 IU/rat) was administered intragastrically to male
Conclusion
We have developed mucoadhesive nanoparticulate systems, including liposomes and PLGA nanoparticles, to improve peptide delivery via mucus membranes, e.g. oral administration. PLGA nanoparticles were prepared by a novel emulsion solvent diffusion (ESD) method in water or in oil as well as the phase separation method. In the ESD methods, PLGA nanoparticles were prepared by coprecipitation of drug and polymer in emulsion droplets of an organic phase miscible with the dispersing medium either
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