**8.1. Lipid metabolism**

ides, polar oils, surfactants and/or cosolvents (LFCS Type II and III), it is likely to improve the solvent capacity of the formulation. Therefore, formulators are always preferred to add water soluble surfactants and cosolvents against pure oils, ultimately sometimes resulting in the complete exclusion of oily excipients to produce oil‐free formulations (LFCS Type IV). However, the formulator must keep well balance between oils and surfactants/cosolvents in the formulation to avoid risk of drug precipitation on aqueous dispersion. Several studies showed that small changes in formulation compositions are not expected to cause large changes in drug solubility, but there could be a dramatic drop in solvent capacity upon aqueous dilution [4, 12, 42]. Dilution of a cosolvent implies a substantial loss of solvent capacity, while the loss of solvent capacity may not be suffered with the use of surfactant. This could be possible due to the linearity between solubilized drug to the number of micelles present and therefore to the surfactant concentration. Drugs which are more soluble in surfactant or cosolvent than pure oil are at high precipitation risk because solvent capacity of surfactant and cosolvent decreases upon dilution but not pure oil. Hence, increasing the solubility of a drug by including a cosolvent is generally a poor strategy than using a nonionic surfactant [11, 43]. **Figure 4** shows the extreme precipitation of an anticancer drug, paclitaxel using LFCS Types

**Figure 4.** Percentage of the original dose of paclitaxel remaining in solution after 1:100 dilutions in the dispersion me‐ dium (paclitaxel was originally dissolved at 80% of the equilibrium solubility in the anhydrous mixture). One gram formulation was dispersed in 100 ml water, and then, the samples were withdrawn periodically over 24 h to examine

It is quite difficult to predict the fate of the PWSDs on dispersion of a typical LFCS Type IIIA lipid formulation. The hydrophilic surfactant used in Type IIIA systems is substantially separated from the oily components, forming a micellar solution in the continuous phase.

the drug precipitations. Data are presented as mean ± SD (n = 3).

III and IV formulations.

42 Advanced Technology for Delivering Therapeutics

Following ingestion of a lipid‐based dosage form (capsule/tablet), the formulation is initially dispersed in the stomach where the digestion of exogenous dietary lipid is started by the action of gastric lipase on the lipid‐water interface. Gastric lipase releases about 15% of free fatty acids from lipids [45]. Within the small intestine, pancreatic lipase together with its co‐lipase completes the breakdown of dietary glycerides to diglyceride, monoglyceride and fatty acid. The presence of exogenous lipids in the small intestine also stimulates secretion of endogenous biliary lipids including bile salt, phospholipid and cholesterol from the gallbladder [45]. In the presence of elevated bile salts concentrations, lipid digestion products are subsequently incorporated into a series of colloidal structures including multilamellar/unilamellar vesicles, bile salt phospholipid mixed micelles and micelles [46]. Together these species significantly expand the solubilization capacity of the small intestine for both lipid digestion products and drugs, and this can be studied relatively easily as a preformulation exercise.

## **8.2. Drug absorption**

Sufficient aqueous solubility along with good intestinal permeability is crucial for adequate drug absorption, ultimately leading to sufficient bioavailability. On the other hand, PWSDs are associated with poor and variable absorption and often affected by the various food intakes. Several studies have already documented lipid‐based nanoformulations, particularly SNEDDS, as an absorption enhancer for PWSDs when administered orally [4, 47]. Possible mechanisms for improving drug absorption include: (i) an increase in the membrane fluidity facilitating transcellular absorption, (ii) larger surface area provided by the fine emulsion droplets, hydrolysis and formation of mixed micelles, (iii) paracellular transport by opening tight junction mainly for ionized drugs or hydrophilic macromolecules, (iv) inhibition of P‐gp and/or CYP450 to increase intracellular concentration and residence time, and (v) stimulation of lipoprotein/chylomicron production. The natural process of digestion offers the possibility that very lipophilic drugs could be taken up into the lymphatic system by partitioning into chylomicrons in the mesentery. This is expected to be a mechanism of absorption for drugs with log *P* values >6.0 and has been demonstrated to be crucial in a past study for the absorption of the antimalarial compound halofantrine [48, 49].

The mixed micelles substantially transport digestion products across the unstirred water layer and reach the vicinity of the aqueous‐microvillus interface to allow for lipid absorption through the mucosal cells. However, it is possible that digestion of a lipid formulation could reduce the solubility of the drug in the gut lumen, which would result in the precipitation of the drug and a decrease in the absorption rate. Therefore, more investigation on *in vitro* lipolysis is needed to clearly understand drug precipitation during digestion for better absorption.
