Lipid-based nanocarriers for oral peptide delivery☆
Graphical abstract
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.
References (245)
Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective
Adv. Drug Deliv. Rev.
(2008)- et al.
Lipid-based colloidal systems (nanoparticles, microemulsions) for drug delivery to the skin: materials and end-product formulations
J. Drug Deliv. Sci. Technol.
(2011) - et al.
Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies
Adv. Drug Deliv. Rev.
(2008) Oral lipid-based formulations
Adv. Drug Deliv. Rev.
(2007)- et al.
Recent developments in oral lipid-based drug delivery
J. Drug Deliv. Sci. Technol.
(2013) Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems
Eur. J. Pharm. Sci.
(2000)- et al.
Approaches for enhancing oral bioavailability of peptides and proteins
Int. J. Pharm.
(2013) Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism
J. Pharm. Sci.
(1993)- et al.
Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo
Int. J. Pharm.
(2004) - et al.
A comparison of the permeation enhancement potential of simple bile salt and mixed bile salt: fatty acid micellar systems using the Caco-2 cell culture model
Int. J. Pharm.
(2000)
Intestinal permeation enhancers
J. Pharm. Sci.
Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells
Eur. J. Pharm. Sci.
Epithelial transport of drugs in cell culture. VIII: effects of sodium dodecyl sulfate on cell membrane and tight junction permeability in human intestinal epithelial (Caco-2) cells
J. Pharm. Sci.
Physiological mechanism for enhancement of paracellular drug transport
J. Control. Release
Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic
Adv. Drug Deliv. Rev.
Partially unfolded proteins efficiently penetrate cell membranes—implications for oral drug delivery
J. Control. Release
Effect of simulated intestinal fluid on drug permeability estimation across Caco-2 monolayers
Int. J. Pharm.
Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin
Int. J. Pharm.
Goblet cell targeting nanoparticle containing drug-loaded micelle cores for oral delivery of insulin
Int. J. Pharm.
Biological activity of insulin in GMO gels and the effect of agitation
Int. J. Pharm.
Stabilization of insulin against agitation-induced aggregation by the GMO cubic phase gel
Int. J. Pharm.
Liquid crystalline systems of phytantriol and glyceryl monooleate containing a hydrophilic protein: characterisation, swelling and release kinetics
J. Pharm. Sci.
A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats
Int. J. Pharm.
Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art
Eur. J. Pharm. Biopharm.
Solid lipid nanoparticles as a drug delivery system for peptides and proteins
Adv. Drug Deliv. Rev.
Solid lipid micro-particles carrying insulin formed by solvent-in-water emulsion-diffusion technique
Int. J. Pharm.
Preparation of solid lipid nanoparticles by a solvent emulsification–diffusion technique
Int. J. Pharm.
Preparation of submicron drug particles in lecithin-stabilized o/w emulsions I. Model studies of the precipitation of cholesteryl acetate
Int. J. Pharm.
Design of lipid nanoparticles for oral delivery of hydrophilic macromolecules
New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin
Int. J. Pharm.
Solid lipid nanoparticles loaded with insulin by sodium cholate-phosphatidylcholine-based mixed micelles: preparation and characterization
Int. J. Pharm.
Strategic approaches for improving entrapment of hydrophilic peptide drugs by lipid nanoparticles
Colloids Surf. B: Biointerfaces
Design and evaluation of solid lipid nanoparticles modified with peptide ligand for oral delivery of protein drugs
Eur. J. Pharm. Biopharm.
A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly(ethylene glycol) as carriers for oral calcitonin delivery
Eur. J. Pharm. Sci.
Transmucosal macromolecular drug delivery
J. Control. Release
Preparation and characterization of solid lipid nanoparticles containing peptide
Int. J. Pharm.
Solid lipid particles for oral delivery of peptide and protein drugs I—elucidating the release mechanism of lysozyme during lipolysis
Eur. J. Pharm. Biopharm.
Fate of polymeric nanocarriers for oral drug delivery
Curr. Opin. Colloid Interface Sci.
Design and production of nanoparticles formulated from nano-emulsion templates-a review
J. Control. Release
Emulsification by ultrasound: drop size distribution and stability
Ultrason. Sonochem.
Challenges for industrialization of miniemulsion polymerization
Prog. Polym. Sci.
The Stability of o/w type emulsions as functions of temperature and the HLB of emulsifiers: the emulsification by PIT-method
J. Colloid Interface Sci.
The effect of temperature on the phase equilibria and the types of dispersions of the ternary system composed of water, cyclohexane, and nonionic surfactant
J. Colloid Interface Sci.
Global Markets and Manufacturing Technologies for Protein Drugs
In vitro and in vivo evaluation of a water-in-oil microemulsion system for enhanced peptide intestinal delivery
AAPS J.
Lecithin-based microemulsion of a peptide for oral administration: preparation, characterization, and physical stability of the formulation
Drug Deliv.
Chapter 6—plant glycolipids: structure, isolation and analysis
Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression
J. Clin. Endocrinol. Metab.
Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial
J. Clin. Endocrinol. Metab.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “SI: Oral delivery of peptides.”