Review
Recent advancements in oral administration of insulin-loaded liposomal drug delivery systems for diabetes mellitus

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Abstract

Diabetes is a chronic medical condition, which is characterised by high blood sugar level. Exogenous insulin is commonly administered subcutaneously for the management of diabetes. However, daily injections of insulin could result in poor patient compliance and various side-effects. Although oral administration offers benefits, insulin is vulnerable to enzymatic degradation, chemical instability and poor gastrointestinal absorption. There is an absence of reviews on insulin-loaded liposomal drug carriers, despite that fact that liposomes have gained considerable attention recently for oral delivery of insulin. They demonstrate favourable characteristics, such as versatility, biocompatibility, protective effect against enzymatic degradation, and cell-specific targeting. In this review, we will explore the status quo for oral delivery of insulin-loaded liposomal formulations, followed by discussing the state of art of these vesicles. This review will provide a detailed overview on insulin-loaded conventional liposomes, and 7 types of current novel formulations. Lastly, the future direction for oral bioavailability enhancement and development of such nanoscale drug delivery systems will be discussed. Further optimisation in the drug entrapment efficiency and gastrointestinal absorption will be required to develop a clinically successful oral liposome-insulin formulation.

Introduction

Diabetes is a metabolic medical condition, which is characterised by dysfunction of beta cells in the pancreas, leading to high sugar level in blood. It can be classified into type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Patients with diabetes have abnormal secretion of insulin from the islets of Langerhans. Exogenous insulin is a therapeutically active agent that is commonly administered subcutaneously for the management of diabetes. The insulin molecules consist of 51 amino acids and two individual polypeptide chains. These polypeptide chains are composed of chain A and chain B with 21 and 30 amino acids respectively (Joshi et al., 2007). However, daily injections of insulin could result in poor patient compliance, hypoglycaemic event, allergic reaction, pain, discomfort, peripheral hyperinsulinemia and weight gain (Arbit, 2004). Other common skin-related complications include lipoatrophy, lipohypertrophy, erythema, pruritus, induration, abscess and lipodystrophy around the injection site (Richardson and Kerr, 2003).

Therefore, alternative non-invasive, safe, patient-compliant and convenient drug delivery systems are essential to eliminate the clinical problems associated with insulin injection (Niu et al., 2014). The strengths and limitations of several non-invasive route of administrations, such as oral, buccal, nasal, pulmonary, peritoneal and transdermal, have been extensively investigated and reviewed (Wong et al., 2016, Shah et al., 2016). In fact, oral administration of insulin offers benefits including simplicity, absence of pain, and better patient compliance as compared to insulin injections. However, insulin is vulnerable to enzymatic degradation, chemical instability and poor gastrointestinal (GI) absorption when administered orally. A number of strategies have been developed to protect therapeutic peptides against physiological instability and enzymatic attack (Wong et al., 2016). For instance, insulin can be encapsulated into nanoparticulate (Wong et al., 2017a, Wong et al., 2018), microparticulate (Wong et al., 2017b) and liposomal drug delivery systems. In order to facilitate the oral bioavailability of protein, multiple enhancing mechanisms, for example, enteric coating (Wong et al., 2017c) and colon-specific targeting, are employed in accordance with the sub-micron drug carriers.

Liposomes are defined as spherical vesicles consisting of one or more lipid bilayers. The lipid bilayers are formed by the self-assembly of phospholipids. Owing to the low permeability, drug molecules can be encapsulated either in the hydrophilic interior aqueous core or hydrophobic lipid bilayers, or bind to the surface of the vesicle. Previous studies indicated that liposomes can be administered via various administration routes such as oral (Niu et al., 2014), pulmonary (Chattopadhyay, 2013), intravascular (Gabizon et al., 2004) and ocular (Dai et al., 2018). As compared to other sub-micron sized drug delivery systems, liposomes seem to be potential oral drug delivery systems because of their biocompatibility, protective effect against enzymatic degradation, stable bilayer membranes, and cell-specific targeting. Such delivery system could encapsulate both hydrophobic and hydrophilic drugs. Most importantly, liposome is versatile in encapsulating peptides (Kowapradit et al., 2012), nucleic acids (Safinya et al., 2014), antibiotics, genes (Liu and Huang, 2002) and anticancer agents (Koning et al., 2010) with narrow therapeutic indices (Li et al., 2009). When these molecules are encapsulated into liposomes, it minimises enzymatic degradation and unwanted immune response (Kisel et al., 2001).

Conventional and novel liposomes have been extensively investigated for oral delivery of peptides in the past decades. Conventional liposomes are solely prepared by indispensable phospholipid and cholesterol, whereas novel liposomes are constituted of partially substituted phospholipid and cholesterol (Schlegel et al., 2011). In general, phospholipids and cholesterol are primarily acquired from botanical (soy beans) and animal sources respectively. With regard to cholesterol, it is the major cell membrane component that can be found in considerable amounts in human brain and nerve tissues. In this review, we will present the status quo for oral delivery of insulin-loaded liposomal formulations, followed by discussing the state of art of these vesicles. This review will provide a detailed overview on insulin-loaded conventional liposomes, and novel formulations including surface coating liposomes, cell-specific targeting liposomes, bilosomes, botanic-sterol containing liposomes, proliposomes, double liposomes, and archaeosomes. Lastly, the future direction for oral bioavailability enhancement and development of such nanoscale drug delivery system will be discussed.

Section snippets

Insulin-loaded liposome and its composition

Liposomes can be classified into conventional and novel liposomes (Fig. 1). These sub-micron carriers have attained substantial attention to encapsulate peptide and protein drugs. In order to optimise the particle size and entrapment efficiency of insulin into the core, several factors, including phospholipid/cholesterol ratio, phospholipid/drug ratio, pH of buffering agent during hydration, and phase ratio of water-in-oil emulsion, should be taken into account. An appropriate

Conventional liposomes

Conventional liposomes could protect insulin against enzymatic degradation (pepsin, chymotrypsin and trypsin) as compared to free insulin (Kisel et al., 2001, Weingarten et al., 1985). It should be noted that the method of preparation for conventional liposomes could influence the oral bioavailability and hypoglycaemic effect of insulin (Kawada et al., 1981). For example, liposomes that were prepared under acidic conditions could enhance the entrapment efficiency and uptake of insulin from the

Surface-coating liposomes

In order to maintain the physical properties (size, integrity) of liposomes in the hostile physiological environments and enhance the oral bioavailability of insulin, the chemical composition of liposomes have been modified by several methods (Hanato et al., 2009). These approaches included coating of liposomes with natural polymers, silica, polyethylene glycol (PEG) and mucin (Iwanaga et al., 1997), manipulation of saturated lipid as membrane bilayer (Kokkona et al., 2000), or forming a

Cell-specific targeting liposomes

Oral absorption of growth factors, proteins, fats, hormones can be facilitated by transcellular pathway in the intestine, such as receptor-mediated endocytosis, wherein extracellular molecules bind and internalize into the specific receptors that are expressed on the cell surface of the enterocytes (Peppas and Kavimandan, 2006). Receptors that are involving in endocytosis include vitamin B12 (cyanocobalamin), vitamin B9 (folate) and transferrin (Hamman et al., 2007, Joanitti et al., 2018,

Bile salt-containing liposomes

Recently, ‘bilosomes’ containing bile salts, such as sodium deoxycholate, demonstrated promising result in oral immunization (Shukla et al., 2010b, Senior, 2001, Ahmad et al., 2017, Aburahma, 2016, Arafat et al., 2017, Shukla et al., 2016). It was well-known that physiological bile salts could destabilise the lipid bilayer membranes of liposome (Schubert et al., 1983). However, the stability of bilosomes, fluidity of epithelial membranes (Song et al., 2002), and internalization of insulin in

Botanic sterol-containing liposomes

Sufficient evidence is present to suggest that plant sterols could reduce low-density lipoprotein cholesterols in patients at a high risk for cardiovascular disease (Katan et al., 2003, O'Neill et al., 2005). Botanic sterols possess similar structure as compared to cholesterol, but could hinder the absorption of extrinsic cholesterol in the GI tract. Therefore, botanic sterols, such as β-sitosterol or stigmasterol, are favourable to substitute cholesterol in oral liposomal formulation. Other

Proliposomes

Proliposomes are dry and free-flowing particles that can form liposomes once in contact with the physiological condition (Veerapu et al., 2014, Parhizkar et al., 2018, Khan et al., 2018a, Wang et al., 2018, Khan et al., 2018b). Table 6 illustrates the physical characteristics, in vitro testing and in vivo observation of insulin-loaded proliposome formulations. At refrigerated conditions (2–8 °C), the physical characteristics (particle size, zeta potential and entrapment efficiency) and chemical

Archaeosomes

Archaeosomes are liposomes that are produced from archaeal-type lipids consisting of diether tetraether structures (Patel et al., 2000, Akache et al., 2018). Archaeobacterial lipids present a few ideal characteristics (Sprott, 1992), including biodegradable (Omri et al., 2003, Patel et al., 2002), and high stability against oxidative stress, bile salts and lipases degradation, high temperature and extreme pH (Choquet et al., 1994, Sprott et al., 1996, Patel and Sprott, 1999). When antigens were

Conclusion and prospects

A significant number of patients are diagnosed with diabetes especially in developed countries. This chronic metabolic condition requires daily subcutaneous injection of insulin to control the BSL. However, insulin injection has low patient compliance rate, and leads to unwanted side-effects such as pain, allergic reaction, discomfort and bacterial infection. Therefore, alternative non-invasive, safe, patient-compliant and convenient drug delivery systems are favourable. This review illustrates

Conflict of interest

The authors declare that they have no conflicts of interest to disclose.

Acknowledgements

The work is partially supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 690876.

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