Elsevier

Advanced Drug Delivery Reviews

Volume 106, Part B, 15 November 2016, Pages 337-354
Advanced Drug Delivery Reviews

Lipid-based nanocarriers for oral peptide delivery

https://doi.org/10.1016/j.addr.2016.04.001Get rights and content

Abstract

This article is aimed to overview the lipid-based nanostructures designed so far for the oral administration of peptides and proteins, and to analyze the influence of their composition and physicochemical (particle size, zeta potential) and pharmaceutical (drug loading and release) properties, on their interaction with the gastro-intestinal environment, and the subsequent PK/PD profile of the associated drugs. The ultimate goal has been to highlight and comparatively analyze the key factors that may be determinant of the success of these nanocarriers for oral peptide delivery. The article ends with some prospects on the challenges to be addressed for the intended commercial success of these delivery vehicles.

Introduction

Since the launch of recombinant human insulin, protein/peptide therapeutics have gained increasing attention as an alternative to conventional small organic drug molecules. With hundreds of peptide/proteins molecules now commercialized, it is estimated that the market value of protein/peptide therapeutics will be €180 billion in 2018 [1], [2]. Despite this commercial success, it is widely acknowledged that the full clinical potential of these potent macromolecules has been greatly hampered by their necessity of parenteral administration. As a consequence, the search for new strategies, which may enable the oral delivery of peptide/proteins, is one of the main challenges in the drug delivery field.

Among the technological approaches explored to achieve efficient oral peptide delivery, those employing lipid excipients are particularly promising because of their wide diversity, favorable biocompatibility, and specific functionality. In particular, the fact that the majority of lipids excipients are derived from dietary oils/fats confers the advantages both in terms of biodegradability and the capacity to cross the intestinal barrier.

Starting with an overview of the physicochemical properties of the lipid materials available for drug delivery, this article will comparatively analyze the state of the art of nanostructured lipid-based systems intended for oral peptide delivery. The focus will be in four distinct categories of nanocarriers: (i) solid lipid nanoparticles (SLN); (ii) micro and nanoemulsions, including self-emulsifying systems; (iii) liposomes; and (iv) hybrid lipid–polymer systems, e.g., nanocapsules. These delivery carriers will be analyzed with regard to their capacity to associate and control the release of peptides, and to overcome the multiple biological barriers associated with oral administration. These barriers include (i) the intestinal fluids, which may compromise the stability of the nanocarriers and also that of the associated peptides; (ii) the mucus layer, which may hinder the access of the nanocarriers to the absorbing epithelium; and finally (iii) the intestinal epithelium. At the end, an attempt will be made to establish a relationship between the nanocarrier biopharmaceutical properties and the effectiveness in terms of PK/PD of the associated peptide

Section snippets

Lipids used in the formulation of oral peptide delivery systems

Defined by their intrinsic natural origin, lipids constitute a family of molecules largely exploited in the pharmaceutical field due to their favorable physicochemical and biopharmaceutical properties, as described in the following sections.

Peptide/protein loading and controlled release capacity of lipid-based nanocarriers

A variety of lipid-based systems have been explored with regard to their potential for enhancing oral peptide bioavailability. Interestingly, with the exception of the solid lipid nanoparticles (SLN), a common ingredient to most of them is the use of medium chain fatty acids and their glycerides. As indicated in Table 2, specific advantages of these lipids include their easy dispersibility in aqueous media and their capacity for peptide solubilization. However, this capacity is still limited,

In vivo performance: PK/PD analysis of lipid-based nanocarriers

Lipid NC consisting of an oily core and a PBCA coating was the first lipid-based nanocarrier proposed for oral administration of insulin [130]. Insulin-loaded PBCA NC induced significant long-term (6 or 20 days) hypoglycemic effect when injected orally to fasted diabetic rats (12.5 or 50 IU/kg); however, no significant drug efficacy was evidenced in normal rats [130]. The authors attributed the enhanced efficacy to the drug protection against enzymatic degradation and also to the internalization

Conclusion and future perspectives

In summary, an appropriate design and development of optimal lipid-based nanocarriers requires consideration of the distinct merits of various formulations and the peptide or protein characteristics. Using a range of lipid-based nanocarriers systems, adequate peptide entrapment has been accomplished and certain formulations have shown ability to control the drug release. It is also increasingly recognized that in order to overcome physiological, biochemical, and biopharmaceutical barriers to

Acknowledgments

The work is supported by the TRANS-INT European Consortium, which has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 281035. Z. Niu also thanks a scholarship from Chinese Scholarship Council.

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