International Journal of Pharmaceutics 502 (2016) 80–97 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l homepage: www.elsevier.com/locate/ijpharm Review Lipid-based nanoformulations for peptide delivery a, b a a b Nada Matougui *, Lukas Boge , Anne-Claire Groo , Anita Umerska , Lovisa Ringstad , b a,c Helena Bysell , Patrick Saulnier a Inserm U1066 (Micro et Nanomédecines biomimétiques), Angers, France b SP Technical Research Institute of Sweden, Stockholm, Sweden c Centre Hospitalier Universitaire (CHU), Angers, France A R T I C L E I N F O A B S T R A C T Article history: Nanoformulations have attracted a lot of attention because of their size-dependent properties. Among Received 29 October 2015 the array of nanoformulations, lipid nanoformulations (LNFs) have evoked increasing interest because of Received in revised form 28 January 2016 the advantages of their high degree of biocompatibility and versatility. The performance of lipid Accepted 13 February 2016 nanoformulations is greatly influenced by their composition and structure. Therapeutic peptides Available online 17 February 2016 represent a growing share of the pharmaceutical market. However, the main challenge for their development into commercial products is their inherent physicochemical and biological instability. Keywords: Important peptides such as insulin, calcitonin and cyclosporin A have been incorporated into LNFs. The Nanoformulations association or encapsulation of peptides within lipid-based carriers has shown to protect the labile Lipids Peptides molecules against enzymatic degradation. This review describes strategies used for the formulation of fi Drug delivery peptides and some methods used for the assessment of association ef ciency. The advantages and drawbacks of such carriers are also described. ã 2016 Elsevier B.V. All rights reserved. Contents 1. Introduction . 80 2. Lipid-based carriers . 82 2.1. Nanoemulsions and micellar systems . 82 2.1.1. Nanoemulsions (NEs) . 82 2.1.2. Micellar systems: phospholipid micelles . 83 2.2. Liposomes . 84 2.3. Liquid crystalline nanoparticles (LCNPs) . 86 2.4. Solid lipid nanoparticles (SLNs) . 88 2.5. Nanostructured lipid carriers (NLCs) . 90 2.6. Lipid nanocapsules (LNCs) . 92 3. Conclusion . 93 Acknowledgements . 93 References . 93 1. Introduction submicronic size of the particles is another parameter that favors cell internalization (Yuan et al., 2008). They have also been Lipidic systems have the potential to enhance the internaliza- explored as potential vehicles for specific-site drug delivery to tion of drugs into the cell due to the affinity of the lipid materials to various organs/tissues/systems such as the lymphatic system, the membrane. In the case of lipid nanoformulations, the brain, lung and the skin (Khan et al., 2013; Liu et al., 2007b; Müller and Keck, 2004; Pandey and Khuller, 2005). In the field of nanomedicine, they offer interesting alternatives to other colloidal fi * Corresponding author at: INSERM UMRS-U1066 MINT “Micro et nanoméde- systems, enhancing drug ef cacy, and providing controlled and ” cines biomimétiques Bâtiment IBS-IRIS 4, rue Larrey, 49933 Angers cedex 9, France. convenient drug release. E-mail address: [email protected] (N. Matougui). http://dx.doi.org/10.1016/j.ijpharm.2016.02.019 0378-5173/ã 2016 Elsevier B.V. All rights reserved. N. Matougui et al. / International Journal of Pharmaceutics 502 (2016) 80–97 81 The lipid components of lipid-based nanoformulations (LNFs) preferred to conventional surfactants. The latter are known to are generally phospholipids, cholesterol and triglycerides (Copland insert themselves into the membrane bilayers and induce et al., 2005; Rawat et al., 2008), but also bile salts and free fatty hemolysis when incubated with erythrocytes. Lipid surfactants acids (Liu et al., 2007a). These excipients are relatively innocuous, act via the formation of steric barriers to prevent colloid biocompatible and biodegradable in vivo. They are extracted from destabilization (coalescence, aggregation, . ) (Sarker, 2005). natural sources or can be the derivatives of natural substances. A Lipid nanoparticulate delivery systems can be adjusted so as to number of these lipids, such as phosphatidylcholine, stearic acid, have drugs adsorbed or linked to the particle surface, incorporated cholesterol and glycerol monooleate have been used in FDA- into the polymer/lipid shell, or encapsulated within the particle approved pharmaceutical applications and have well-established core. As a consequence, the pharmacokinetic and pharmacody- safety profiles with appropriate toxicological data (Rowe et al., namic parameters of the drug can be improved and release can be 2009; Working and Dayan, 1996); this is their major advantage controlled. Furthermore, drugs can be protected from a harsh compared to other carriers such as polymeric particles (e.g., environment, and undesired side effects can be avoided due to dendrimers), carbon nanotubes, quantum dots and metal nano- targeted delivery. particules (e.g., gold and iron nanoparticles) (Goodman et al., 2004; Significant advances in biotechnology and molecular biology Hu et al., 2011; Jain et al., 2010; Kostarelos, 2008; Soenen and De over recent years have resulted in the emergence of novel Cuyper, 2010). Although lipid nanoparticles can be considered as molecules with the potential to offer significant improvement in relatively safe, and the type of lipid is an important factor affecting the treatment and prevention of diseases. The new biotherapeutics toxicity. Cationic lipids promote non-specific binding to circulating include novel peptide and protein drugs. Therapeutic peptides are blood cells such as erythrocytes, lymphocytes and endothelial cells typically molecules made of 2–100 amino-acids, presenting (Pedroso de Lima et al., 2001). Cationic liposomes also demonstrate interesting biological functions and, being derived from natural a greater activation of the human complement system compared to components, are well tolerated following administration. Peptides neutral liposomes (Semple et al.,1998). Conversely, the presence of can be used to treat a broad range of diseases including cancer, negatively charged lipids (e.g., phosphatidylglycerol, phosphati- cardiovascular diseases, infection, metabolic diseases and central dylserine) on nanoparticle surfaces decreases their ability to nervous system disorders (Parmar, 2004). penetrate the negatively-charged cell membranes (Fischer et al., Since Lypressin, a vasopressin analogue, was launched by 2003; Larson et al., 2007). They can also constitute binding sites for Novartis (Pichereau and Allary, 2005); efforts have not ceased to plasma opsonins, which favor nanoparticle uptake by macro- multiply in an attempt to exploit the therapeutic potential of many phages (Nichols, 1993). Coating the nanocarrier with hydrophilic peptides. Peptide-based therapeutics now constitute one of the polyethylene glycol (PEG) is a prevalent strategy used to decrease fastest-growing classes of new drugs. In fact, almost half of the the immunogenicity of charged particles (Nichols, 1993; Samad molecules in the pipelines of pharmaceutical companies are et al., 2007). Currently-approved liposomal products are composed peptides (Dimond, 2010). However, the therapeutic potential of of neutral lipids with or without PEGylated phospholipids (Samad peptides is hampered by a number of physico-chemical and et al., 2007; Sarker, 2005). biological instabilities that impede their development and When formulating nanoemulsions and nanosuspensions, translation to the clinic. These inherent limitations include: Low PEGylated lipids, glycerophospholipids and derivatives are stability (proteolytic degradation); low oral bioavailability Fig. 1. A hypothetical, pseudo-ternary phase diagram of an oil/surfactant/water system with emphasis on nanoemulsions, the emulsion phase, and the existence fields of conventional micelles and reverse micelles. 82 N. Matougui et al. / International Journal of Pharmaceutics 502 (2016) 80–97 (injection required); risk of immunogenic effects; as well as a Partearroyo and Ostolaza, 1990). Therefore, biocompatible amphi- challenging and costly synthesis process. philic lipid surfactants are usually preferred to conventional Moreover, peptides can be prone to chemical and/or physical synthetic ionic and non-ionic ones. Lipid surfactants have low, instability, mainly related to manufacturing and formulation critical micellar concentrations (CMCs). This property may processes such as solvents, pH, temperature, ionic strength, high decrease the risks of erythrocyte lysis (which also concerns many pressure, detergents, agitation and shearing (Hillery, 2001). other cells) in contrast with conventional synthetic surface active Several peptide modifications have been explored to improve agents (Ashok et al., 2004; Torchilin, 2007). Three methods may be peptide in vivo half-lives: The addition of carbohydrate chains; applied for the preparation of NEs: (i) high pressure homogeniza- synthetic amino acids; polyethylene glycol molecules; as well as tion (an appropriate choice of surfactant and co-surfactant is lipidation or cyclization strategies (Gentilucci et al., 2010). necessary), (ii) the low energy emulsification method at constant However, altering the chemical structure of the peptide drug temperature and (iii) the phase inversion temperature method can potentially impair its therapeutic effect (Gante, 1994; Hruby (Tadros et al., 2004). and