Particle-Size Reduction by Piston-Gap High-Pressure Homogenization
5.6 Lipid-Based Formulations
5.6.4 Development of Lipid-Based Solubilized Formulations
The simplest lipid formulation consists of drug solubilized in triglycerides. The manufacturing process is simple and the formulation is biocompatible. Stabilizers such as antioxidants and chelating agents are commonly included in lipid-based formulation to improve the stability of lipid vehicles and to prevent excipient-induced drug degradation. Solvent capacity of triglycerides is generally low (<10 mg/mL). In comparison with long-chain triglycerides, medium-chain triglyc-erides have higher solvent capacity. Triglyctriglyc-erides are mainly applicable for drug substances whose poor water solubility was attributed to their hydrophobicity (Log P > 5) and their instability to interact with water molecules. Triglycerides are not suitable for drugs whose poor water solubility is attributed to strong crystal lattice energy (high melting point and high enthalpy of fusion). Vesanoid ® (tretinoin, vita-min A analog, 10 mg) and Accutane ® (isotretinoin, 10, 20, and 40 mg) are two commercial examples where a mixture of hydrogenated soybean oil and soy bean oil is used as the formulation vehicle. Medium-chain triglyceride (fractioned trig-lyceride of coconut oil) is used for manufacturing Rocaltrol ® (vitamin D analog, 0.25 and 0.5 m g) capsules. Vesanoid ® and Accutane ® capsules contain butylated hydroxytoluene (BHT) and EDTA, while Rocaltrol ® contains BHT and butylated hydroxyanisol (BHA).
In gastro-intestinal tract, drug-containing triglycerides are initially dispersed into coarse oil droplets. Triglycerides are then rapidly digested by lipase/co-lipase to free fatty aids and 2-mono-glycerides. Even a small amount of long chain lipids (1–2 g), typically amount present in the dosage form, is suffi cient to stimulate gall bladder contraction and therefore elevate bile salts, phospholipid, and cholesterol level in small intestine (Kossena et al. 2007 ) . These biliary lipids in combination with the lipid digestion products create a variety of colloidal species, including emulsion droplet, micelles, mixed micelles, and vesicles. These colloidal species are capable of maintaining drug in the solubilized state to improve the absorption in intestine.
Since the digestion of lipid excipients plays a crucial role in the absorption of poorly soluble drug, absorption of drug in triglyceride-based formulations is depen-dent on the composition of lipid vehicle. Medium-chain triglycerides are digested more readily than long-chain triglycerides. Therefore, faster absorption is often observed with medium-chain glyceride-based formulations. Digestive products of long-chain triglycerides enhance lymphatic transportation to greater extent than that of medium-chain triglycerides. For compound with signifi cant lymphatic absorption,
long-chain triglyceride-based formulations provide better absorption. Porter and coworkers performed in vitro lipolysis of triglyceride formulation of halofantrine to investigate the types of lipids and the amount of lipids on the colloidal species formed in vivo (Porter et al. 2004 ) . The schematic diagram of likely colloidal spe-cies is presented in Fig. 5.2 . Higher bioavailability of probucol in rats was observed when long-chain triglyceride was used to replace medium-chain triglycerides (Palin and Wilson 1984 ) . Enhanced lymphatic transportation due to the digestive products of long-chain triglycerides was determined to be the contributing factor for greater absorption. In the case of griseofulvin, better absorption was observed with medium-chain than long-chain triglycerides (Dahan and Hoffman 2007 ) . This improvement in absorption was resulted from more rapid digestion of medium-chain triglyceride.
For triglyceride-based formulations, there is no concern over drug precipitation in vivo when the formulation is diluted by the aqueous contents in GI tract. However, triglycerides low solvent capacity has limited the application of lipid solutions for
Fig. 5.2 Schematic diagram to show the likely colloidal species formed on digestion of different quantities of medium- and long-chain lipids and the coincident drug distribution pattern obtained at the end of 60 min (50 mg lipid) or 30 min (250mg lipid) in vitro digests. The dotted lines encircle those species present in the aqueous phase obtained by centrifugation of the digests, the dashed line signifi es the pellet, and the solid lines any partially digested and poorly dispersed lipid phases. (The diagrammatic representations used to denote mixed micelles and vesicles are purely illustrative and are not meant to imply specifi c structural details.) (Porter et al. 2004 )
drug delivery. Solubility capacity of intestinal colloidal phases during the digestion of lipid formulations was far greater higher than the solubility capacity of lipid excipients in vitro. Suspension formulation in lipids may prove to be benefi cial as the solubilization capacity of the colloidal phases produced on digestion of the lipid vehicle is likely to be greater than the dose of drug that could otherwise be admin-istered as a lipid solution. The hypothesis was proved in delivering griseofulvin and danazol as oil suspensions (Kaukonen et al. 2004 ) . Commercial progesterone capsule (Prometrium ® ) is formulated as the micronized progesterone dispersed in peanut oil. When micronized progesterone was formulated as the oil suspension, its peak plasma concentration increased by threefold in a animal PK model (Hargrove et al. 1989 ) .
Even though triglycerides are not miscible with water, they always contain a small amount of water (<0.1%). It is important to understand the effect of water content on drug solubility in triglycerides. Hydration of triglycerides caused a signifi cant decrease in the solubility of estradiol and testosterone, which may form hydrate or hemihydrats with the water in triglycerides (Land et al. 2005 ) .
Mixed glycerides and fatty acids are more polar and have higher solubilizing capacity than triglycerides. For high-dose drug products, mixed glycerides and fatty acids are typically used. Fortovase ® (Saquinavir free base, 200 mg) is based on mono- and diglycerides. The formulation contains vitamin E as an antioxidant. Restandol ® (testosterone undecanoate 40 mg) contains drug solubilized in oleic acids. Oleic acid was used to improve the absorption of cinnarizine, a weak base compound. Oleic acid formulation improved C max and AUC over the traditional table formulation by 2.9- and 3-folds, respectively (Tokumura et al. 1987 ) . Holm et al. ( 2001 ) investigated the effect of fatty acids degree of unsaturation on absorption of halofantrine free base. Three different fatty acids (oleic acid, linoleic acid, and linolenic acid) were used in the study. Bioavailability was the same for all three formulations. However, lymphatic transportation was fatty acid dependent. Lymphatic transportation for linoleic formu-lation is 16.6× higher than that for linolenic acid formuformu-lation.
As shown in Table 5.3 , hydrophilic surfactants and water-soluble co-solvents are often added in simple lipid formulations to prepare self-emulsifying drug-delivery systems. This type of formulation is engineered to disperse into fi ne oil droplets (<10 m m) rapidly in the stomach and empty quickly into intestine. Emulsifi cation of this type of formulation does not rely on the bile salts in GI tract, and fi ne oil drop-lets provide large surface area for drug partition. Drug absorption of self-emulsify-ing delivery system is more rapid and more consistent from patient to patient. In comparison, drug absorption from type I system is slower and is infl uenced more by the GI environment. However, for compounds with a narrow therapeutic window and suffi cient solubility in lipids, type I systems are more desired.
Juppo ( 2004 ) developed a multiparticulate modifi ed release solubilized formulation of felodipine to improve the absorption and to achieve more consistent plasma con-centration. The matrix consisted of at least one hydrophobic matrix former and one hydrophilic matrix former. Cetyl alcohol, PEG 4000, Poloxamer 407, hydrogenated vegetable oil, glyceryl palmitosterare, glyceryl behenate, and stearic acid have all been demonstrated to be suitable carriers for preparing felodipine lipid solution.
Traditionally, in vitro characterization of lipid formulation focuses on the dispersability of oil phase and the particle size of the dispersed oil phase when the formulation contacts aqueous environment. As discussed previously, in vivo perfor-mance of the solubilized lipid formulation is dependent on the digestive products of the lipids. Biorelevant in vitro lipolysis models have been established to simulate lipid digestion in small intestine. In lipolysis processes, formulation is mixed with bile salt, phospholipid, and buffer at 37°C in a pH-stat using NaOH as titrant to maintain pH. Different levels of bile salt and phospholipid can be used to simulate fast or fed state. Lipolysis processes are initiated with the addition of pancreatic extract. The mixture is sampled at different time points to determine the amount of drug solubilized (Kaukonen et al. 2004 ) .