Lipid as a Vehicle/Carrier for Oral Drug Delivery

*Jagruti Desai, Tapan Desai and Ashwini Patel*

## **Abstract**

The drug administered by an oral route has to withstand a harsh environment of gastrointestinal media, absorb through intestinal epithelium and circumvent first-pass metabolism in liver before reaching portal blood circulation. Moreover, hydrophobic drug molecules offer challenges for formulation with respect to their solubility and hence bioavailability. Various approaches have been developed to overcome this barrier. One of them is the use of lipids in formulation. Incorporation of the drug in lipids can result in increased solubility, absorption and thereby enhanced bioavailability. Intestinal lymphatic route of absorption has also been explored for increasing bioavailability of hydrophobic drug moieties. In this chapter, we have discussed the pathway of lipid digestion in the human body as well as the mechanism of lipid particles upon oral administration. The various lipid formulations developed and the excipients used in the formulations have also been described. The importance of lipid chain length and the effect of food in increasing the bioavailability of drug is discussed. The lymphatic pathway of lipid carriers has also been discussed.

**Keywords:** oral drug delivery, M-cell uptake, drug absorption, lymphatic transport, lipid chain length

## **1. Introduction**

Although many advancements occur in other routes, the oral route pathway of drug administration still remains the most preferred route. It is because of its costeffectiveness, safety and convenience of administration, ease of production, suitability for long-term or life-long use and does not require sterilization and flexibility in dose adjustment [1, 2]. Intravenous administration delivers the drug directly to blood circulation, but there is the possibility of extravasation of blood or drug, thrombosis and catheter infections [3]. So, oral route has always remained the first preference for drug administration. However, there are certain limitations of this route which need to be circumvented. It includes poor solubility of drug, poor permeability, instability, first-pass metabolism, intestinal metabolism and slow commencement of action compared to intravenous route. Additionally, drug absorption starts from stomach, but it has short residence time of 2 h. So, only weakly acidic and neutral drugs are absorbed efficiently from stomach lining. Thus, major drug absorption after oral administration, thus occurs from intestine as it imparts a high absorptive surface area and greater residence time [1, 4, 5]. The common mechanism of absorption

includes passive diffusion and enterocyte-mediated active transport through stomach and intestine [6, 7]. BCS Class I drugs, having high solubility and permeability are absorbed efficiently by oral route. However, the drug molecules that are being discovered belong to BCS Class II having poor aqueous solubility and good permeability [8]. This leads to their poor oral bioavailability. Many advancements to increase bioavailability have been made including size reduction, recrystallization, complexation, solid dispersion and use of solubility enhancers [9].

Use of lipid as an excipient to enhance oral bioavailability has been widely explored. They are majorly derived from dietary oils and/or fats and are biocompatible, biodegradable in nature and non-toxic [10]. Further, they not only help in increasing the solubility of drug in gastrointestinal media but various lipids have been shown to decrease proteolytic degradation [11], increase lymphatic absorption [12] and modulate various mechanisms including P-gp activity [13]. It has also been shown to enhance transcellular absorption of drug molecules [14]. The various lipid-based formulations have been developed so far are described in this chapter. Since the lipids have varied properties, their appropriate selection and design of formulation affect the success of the formulation [15]. Moreover, absorption of drug through the lymphatic system greatly affects the bioavailability of formulation and its efficacy. In general, the drug upon oral administration is either absorbed via intestinal epithelium to portal blood circulation, or is taken up by lymphatic vessels to the lymphatic system. The drug entering portal blood circulation has to pass through liver before reaching heart thus chances of metabolism are high. While the drug entering into the lymphatic system is directly get drained to heart avoiding first-pass metabolism. Hence, the lymphatic system can be an alternate and a safe route to enhance drug delivery [16]. Since this system mainly transports lipids and fats, the lipidic drug delivery systems have greater chances of absorption through this route [17]. In particular, for selective lymphatic uptake, high lipophilicity (log P > 5) and the presence of triglycerides having long carbon chains are desired [18]. The possible parameters of lipid-based drug delivery system to enhance lymphatic absorption are described in this chapter. Moreover, the in vivo lysis lipid in the human body has also been discussed. Another pathway of absorption exclusively to the lymphatic system is through Microfold cells (M-cells) present in intestinal epithelium [19, 20]. It uptakes lipid nanoparticles as well. Hence, this route becomes important for nanosized lipid drug delivery system. The mechanism of absorption of nanoparticles through this route has been described in this chapter.
