The oral drug delivery is the dominant and most
convenient drug delivery route for patients due to its administration
simplicity and patient compliance; it is safe, affordable, and cost-efficient
manufacturing process (P. Kumar & Singh, 2013). Despite these advantages of oral drug delivery, oral formulations
face various barriers. Most of the active
pharmaceutical ingredients are poorly water-soluble drug with poor gastrointestinal
dissolution. This phenomenon decreases
oral bioavailability, therapeutic
efficiency and patient adherence. Thus, improve the drug solubility is crucial
to achieve optimum oral drug delivery (Chen, Khemtong, Yang, Chang, & Gao, 2011; Patel,
Liu, & Brown, 2011).
To overcome the poor drug solubility,
intrinsic modification of drug properties or extrinsic modification of drug
formulations are developed. The modifications include complexation (e.g.
cyclodextrins) (O. Kumar & Rani, 2017; P. Tang et al., 2017),
liposomes (Al-Remawi, Elsayed, Maghrabi, Hamaidi, & Jaber,
2017; Pumerantz, Betageri, & Wang, 2017), amorphous solid dispersions (Renuka, Singh, Gulati, & Narang, 2017; Sawicki et
micronization (Rasenack & Müller, 2004; Vandana, Raju, Chowdary,
Sushma, & Kumar, 2014; H.-X. Zhang et al., 2009), and nanonization (Attari, Bhandari, Jagadish, & Lewis, 2016; Guan
et al., 2017; Zhao et al., 2016).
Recently, nanotechnology emerged as a promising approach to improve drug
solubility (Attari et al., 2016; Yongjie Wang et al., 2017). Nanosuspension
is applied as one form of a nanotechnology.
Nanosuspension is used to solve the solubility associated bioavailability problems (He et al., 2017; B. Mishra, Sahoo, & Dixit, 2017). It is defined as a solid
dispersion of drug particles in sizes smaller
than one micrometer that is stabilized
either by polymer or surfactant for oral,
topical, parenteral or pulmonary administration (Chingunpituk, 2011; Yadav & Singh, 2012).
In this thesis, a nanosuspension of a poorly
soluble drug (omeprazole) is prepared on a laboratory scale; specific features
such as increased dissolution and oral bioavailability are evaluated.
Drug Absorption after Oral
The drug is absorbed
in the Gastrointestinal Tract (GIT) via mucosal epithelium; where it presents in
the mouth to the anus. Many drugs are absorbed sublingually, buccally or
rectally. The small intestine remains the main absorption site due to presence of microvilli that increases the
surface area for drug absorption (Barthe,
Woodley, & Houin, 1999). The dug is transported across the intestinal
membrane using either passive diffusion (most common mechanism), facilitated
diffusion or active transport (Jones, Butler,
& Brooks, 2011; Mottier, Alvarez, Ceballos, & Lanusse, 2006). Before the drug is transferred to blood
circulation, it may be faced a metabolism that is known as first pass effect. For
the drug that is transferred to lymph reaches the blood circulation without
first pass effect (O’Driscoll,
1992; Ungell, 1997). Drug absorption is affected by physiological
and physicochemical factors (Kinget, Kalala,
Vervoort, & Van den Mooter, 1998). A brief description of physiological factors are
presented in Section 1.3. The physicochemical factors will be explained in different sections in this chapter
and following chapters.
Affecting Drug Absorption after Oral Drug Delivery
morphological and physiological factors that reduce the transfer the drug to
blood circulation (Said, 2012). Morphological factors involve: mucus,
epithelial and endothelial cells. The physiological factors involve: GIT
conditions (enzymes and pH), counter absorption mechanisms (mucus, epithelial
cells, intestinal wall metabolism and efflux transporters) and presystemic biotransformation (Shargel,
Andrew, & Wu-Pong, 2005).
Gastrointestinal Tract conditions
The GIT conditions
influence the drug absorption by altering the drug dissolution rate. The pH
differs along the GIT: 1-3 in the stomach, 5-6 in the duodenum, 7-8 in the
proximal jejunum and 8 in the large intestine (Doluisio,
Billups, Dittert, Sugita, & Swintosky, 1969). The pH controls the drug absorption by
altering the chemical stability or ionization (K. Park &
Mrsny, 2000). Pepsin is a fundamental enzyme in the
stomach; lipase, proteases and amylases
are secreted by the pancreas to the small intestine (Said, 2012). Many drugs —particularly
peptides— are responsive to degradation
by GIT enzymes (Marschütz &
Bernkop-Schnürch, 2000; Washington, Washington, & Wilson, 2000). The food hinders the drug absorption either
by delay the gastric emptying, form a viscous environment or increase the acid
and enzyme secretion (Toothaker &
Welling, 1980; Welling, 1984).