Lipids and Lipid Self Assembly in Oral Drug Delivery

There are a number of considerations associated with the use of lipids in dosage form design. In particular, the following properties and behaviors can play key roles, as well as forming the basis for lipid classifications:

• Lipids can act as solvents, leading to drug being present in the gastrointestinal tract (GIT) (at least initially) in solution thereby overcoming the drug dissolution step [1].

• Lipids may have amphiphilic structures that determine their capability to self-assemble in aqueous environments. Such behavior can have a critical effect on drug disposition kinetics in the GIT.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC, Australia e-mail: [email protected]

C.G. Wilson and P.J. Crowley (eds.), Controlled Release in Oral Drug Delivery, Advances in Delivery Science and Technology, DOI 10.1007/978-1-4614-1004-1_15, © Controlled Release Society 2011

• Lipids may or may not be digestible. Digestion of dietary and formulation lipids can lead to generation of colloidal structures in the GIT, providing transient solubilization of drug, and reducing the propensity for precipitation prior to absorption.

Understanding these issues can provide valuable insights into potential applications and choice of lipids for controlled drug delivery. These are discussed in the following sections.

15.1.1.1 Classification of Lipids

Structurally, lipids may be assigned to nine distinct groups viz. fatty acids, glycero-lipids, glycerophospholipids, sphingolipids, sterolipids, prenol lipids, lycolipids, saccharolipids, and polyketides [2]. Fatty acids, glycerolipids, glycerophospholipids, and sterolipids are present in most human foods and are therefore most likely to be encountered in the GIT. Glycerolipids (acylglycerols) comprise mono-, di- or triesters with glycerol, with either short (<C8), medium (C8-C12) and long (>C12) fatty acid side chains. The majority of dietary and formulation lipids are glycerolipids of varying chain length and degree of branching.

Small et al. classified lipids based on their propensity for self-assembly with water [3]. Polar Class I lipids are usually present in animal tissue, are consumed in the diet, and are frequently components of lipid-based formulations. They include tri- and di-acylglycerides, protonated long-chain fatty acids and alcohols, waxes, cholesterol and fat soluble vitamins which neither swell nor dissolve in the bulk phase. However, the presence of hydrophilic groups allows these amphiphilic structures to spread at the air/water interface, differentiating them from nonpolar lipids. Class II lipids comprise monoacylglycerides and lecithins, which are also insoluble in water, but are capable of swelling, depending on the temperature, and aliphatic chain length, saturation and branching. To minimize the thermodynamically unfavorable interactions between the hydrophobic aliphatic chains and water Class II lipids can self-assemble, forming liquid crystal phases in bulk liquids and/or monolayers at air/water interfaces. Such assemblies are often formed during lipid digestion where digestion products such as free fatty acid salts and monoglycerides form liquid crystals prior to solubilization by endogenous amphiphilic Class III lipids.

Free fatty acids may be introduced to the GIT as formulation components, products of digestion, or impurities in formulation lipids. Their ionization influences lipid self-assembly, which in turn may influence in vivo release relative to in vitro performance. Protonation by gastric acid may cause formation of "inverse" structures by modifying the curvature of lipid assemblies, favoring smaller aqueous domains. Conversely, ionization in the small intestine favors micelle formation.

15.1.1.2 Lipid Dispersion and Digestion

Lipids encounter a number of biological and mechanical processes in the GIT. These include emulsification, lipolysis, and intestinal absorption. Preliminary emulsification

Schematic Diagrams Fat Absorption

Fig. 15.1 Schematic diagram outlining the process of lipid digestion and absorption. As the lipid droplet is digested, lipid digestion products accumulate at the surface as liquid crystalline structures. The digestion products are solubilized into vesicles and micelles prior to absorption via the portal blood and lymphatics. Coadministered drug would transfer within the solubilized phases prior to absorption

Fig. 15.1 Schematic diagram outlining the process of lipid digestion and absorption. As the lipid droplet is digested, lipid digestion products accumulate at the surface as liquid crystalline structures. The digestion products are solubilized into vesicles and micelles prior to absorption via the portal blood and lymphatics. Coadministered drug would transfer within the solubilized phases prior to absorption of the lipid droplets occurs through shear forces generated by gastric peristaltic contractions against the closed or partially open pylorus [4]. Gastric shearing reduces the size of crude lipid to droplets 20-40 mm in diameter [5].

The subsequent digestion and absorption of lipids is illustrates schematically in Figure 15.1. The digestion of dietary or formulation lipids, in amounts as low as 2 g may influence processes such as gastric motility [6] and secretion of digestive fluids [6]. Changes to the nature of gastric chyme such as pH [7, 8], osmolality [9-11], and energy content [8, 12, 13] may stimulate digestive processes. Ingested nutrients such as long-chain fatty acids activate duodenal receptors [14], releasing mediators such as apolipoprotein A-IV [15], cholecystokinin (CCK), neurotensin, peptide YY, and proglucagon-derived peptides.

The contribution of gastric digestion to overall lipid digestion is uncertain but has been reported as approximating 30% of total postprandial digestion of dietary triglycerides [4, 16]. Gastric lipolysis results in hydrolysis of triacylglycerols to diacylglycerols and fatty acids [4, 17]. It has been shown, in rats [18, 19], rabbits [20], and humans [21] that gastric lipolysis is more significant for medium-chain than long-chain triglycerides.

The change in pH on transit from stomach to the more neutral duodenum (pH 5.4-7.5 [22, 23]) induces partial ionization of fatty acids, leading to migration of their polar head groups to the surface, lipid droplet size being concurrently reduced to <0.5 mm [24]. The presence of triacylglycerides and free fatty acids in the GIT also stimulates release of bile salts, biliary lipids, and phospholipids from the gall bladder and secretion of digestive enzymes from the pancreas [25, 26].

Lipid digestion in the small intestine is largely mediated by triacylglycerol acyl hydrolase (more commonly referred to as "colipase-dependent pancreatic lipase" [27]). Acting at the oil/water (o/w) interface, pancreatic lipase hydrolyses triacylglyceride into diacylglyceride and fatty acid, with the diacylglyceride further hydrolysed to another fatty acid and 2-monoacylglyceride (Fig. 15.1) [24, 25, 27, 28]. Pancreatic lipase efficiency is relatively independent of droplet size; lipid droplet sizes ranging from 0.7 to 10 mm did not significantly affect duodenal digestion [29].

As digestion progresses, amphiphilic digestion products accumulate at the emulsion droplet surface [24] and at liquid crystalline structures, which eventually separate from the droplet surface. These liquid crystalline structures interact with increasing proportions of bile salts and phospholipids to form uni- and multilamellar vesicles that are subsequently solubilized into mixed bile salt-phospholipid micelles [1, 27, 30-33]. The lipid digestion products are solubilized to mixed micelles, providing a concentration gradient that promotes absorption across the intestinal mucosa [30].

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