**2.1 Passive diffusion**

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

molecules within the mucus as they transit the GIT. [8, 9].

ness of drugs [12, 13].

different drugs.

**2. The GIT**

and bio-adhesive properties [16, 17].

either by passive diffusion or active transport.

accommodating various types of drugs, simplicity of administration and accessibility, patient compliance and safety profiles [5–7]. Additionally, the intestinal epithelium is an ideal platform for drug absorption due to the viscous mucosal layer lined with abundant enterocytes, goblet cells, and Peyer's patches that trap drug

In comparison to other routes of administration, the oral route is exceptionally complex in expression of anatomical features physiology throughout the GIT [10]. Furthermore, these expressions vary along the GIT in both intensity structure. For example, the mucus layer varies in composition and physical properties along the GIT and the pH varies significantly in the main sections of the GIT. The gastrointestinal motility also varies in intensity and form along the GIT and also depends on food status [11]. Even though, these features can impede drug delivery across the GIT, through careful interplay between formulation science and GIT physiology, scientists have been able to exploit this variance for improved drug delivery. In this regard, nanoparticle formulations have immerged as strong contenders able to surmount some of the constraints associated with GIT absorption. Nanoparticles have gained great interest by researchers in recent years as they can be used to improve drug solubility and bioavailability in the harsh GIT environment due to increased surface area to volume ratio, thus provide a rapid onset of therapeutic action [12]. They can also be used to targeting specific sites within the GIT and hence reduce the effects of enzymatic degradation, all of which can improve the safety and effective-

Nanoparticle formulations may be presented in various forms however, polymeric

In this chapter we will be discussing the interplay between the GIT physiology/ anatomy and drug physicochemical/biopharmaceutical factors in the absorption process that influence oral therapeutics. We, will also review the physicochemical properties of chitosan relevant for effective GIT delivery, including methods of formulation. The most utilised nanoparticle formulation methods used for chitosan-based nanoparticles are also examined. Finally, we will highlight the recent developments on chitosan-based nanoparticles used in the oral delivery of

The GIT, also known as the digestive tract or alimentary canal, is approximately 9 meters long and can be functionally divided into two parts, the upper and the lower GIT (**Figure 1**). The upper GIT; consisting of mouth, pharynx, oesophagus, stomach and small intestine, play a major role in the transport of the swallowed food bolus, enzymatic digestion and absorption of nutrients [18]. The lower GIT is usually referred to the large intestine and is responsible for the adsorption of water, fermentation of undigested sugars and the storage and evacuation of stool [19]. Following oral dosing, the drug traverses several semipermeable cell membranes through its trajectory to absorption and eventually enters the general circulatory system. Drugs cross cell membranes, which comprise of bimolecular lipid matrix,

nanoparticles present the versatility of polymers and can be tailored to achieve superior drug stability, enhanced drug payload capacity, longer circulation times and controlled drug release capabilities, when compared with other their colloidal counterparts [14, 15]. In this regard, chitosan-based nanoparticle formulation have been shown to present several of the desirable attributes listed above in addition to being biodegradable, having low toxicity, amenable to tuneable physical properties

**28**

The most prevalent form of absorption of the majority of orally administered drugs is by passive diffusion across cell membranes. This process comprises of a three-step process, whereby the permeant first transverses into the membrane, disperses across it and then is released into the cytosol [20]. Typically, drug molecules move down a concentration gradient, from a region of high concentration (e.g., GI fluids) to one of low concentration (e.g., blood), without the expenditure of energy [21]. Usually, a concentration gradient is manifested as a disparity in concentration of a substance within an area and is linearly related to the diffusion rate. The latter is also governed by the lipid solubility, size and polarity of the drug species.

Most drugs are either weak acids or bases and occur either in the unionized or ionized form as a function of pH [22]. For lipophilic drugs, the unionized form of drug, may penetrate cell membranes easily as the membrane is lipoidal. On the other hand, hydrophilic drugs, present an ionized form of the drug, which has high electrical resistance and thus cannot traverse the cell membranes easily but may diffuse through the para-cellular spaces. However, it is worth noting that the para-cellular junctions contribute to less than 0.01% of the entire GIT surface area and furthermore, the permeability of these junctures diminishes down the GIT [23]. Additionally, the capability of drugs to traverse a membrane also relies on the acid–base dissociation constant (pKa) of the drug in question. The pKa is the pH at which concentrations of ionized and unionized forms are equivalent [24]. So, if the pH is less than the pKa, the unionized form of a weak acid prevails, and *vice versa* for weak bases. Henceforth, when a weak acid is administered orally, nearly all the drug in the stomach remains unionized, preferring diffusion via the gastric mucosa. On the other hand, for a weak bases with a pKa = 4.4, majority of the drug in the stomach will be ionized [21].

Overall, the process by which molecules traverse cell membranes is by passive diffusion, down the concentration gradient. However large hydrophilic ionic molecules and charged molecules cannot freely traverse the phospholipid bilayer cell membrane passively. Their transport may be confined to protein channels and distinct transport mechanisms present within the membrane [25]. Such drugs gain access through the membrane by facilitated diffusion whereby molecules integrate with embedded protein carriers to shuttle them across the membrane. This process does not expend energy and is also down the concentration gradient though quicker than

would be anticipated by diffusion alone [26]. A frequent case of facilitated diffusion is the migration of glucose into cells during the production of adenosine triphosphate (ATP). Glucose is both large and polar thereby unable to pass the lipid bilayer via simple diffusion. Hence, glucose molecules are delivered into the cell via a unique carrier protein (glucose transporter) to promote its internalisation in cells [27].

## **2.2 Active Transport**

Active transport is an energy-dependent process that translocates drug molecules against their concentration gradient by a molecular pump [20]. Carrier-mediated active transport demand energy via ATP hydrolysis or by accompanying the cotransport of counter ions down its electrochemical gradient (e.g., Na+ , H+ , Cl− ) [28]. The most common active transport system is the sodium-potassium pump and receptor-mediated endocytosis. Energy can either be directly provided to the ion pump or indirectly by connecting a pump-action to an activated ionic gradient. It is often encountered in the gut mucosa, the liver, renal tubules and the blood–brain barrier [22]. Active transport is typically restricted to drugs that structurally resemble endogenous substances; e.g., vitamins and amino acids, and that are absorbed via specific sites in the small intestine. Targeting drugs to these transporters can enhance their bioavailability and distribution [21].

The sodium-potassium pump system (Na<sup>+</sup> /K+ ATPase), utilises ATP to move Na<sup>+</sup> and K+ in and out of the cell. It is a vital ion pump located in the membranes of various cell types, such as the Na+/amino acid symport in the mucosal cells of the small bowel [22, 29].

Cells control the endocytosis of certain substances via receptor-mediated endocytosis. The use of this form of endocytosis in the GIT is crucial for oral delivery of drugs because it delays the transit of drugs in GIT. Receptor-mediator endocytosis involves the internalisation of macromolecules by binding the latter to receptors considered as membrane-associated protein [30]. There are more than 20 different receptors involved in the internalisation of macromolecules [31]. Following binding to the receptor on the cell surface, the cell will endocytose the portion of the cell membrane enclosing the receptor-ligand complex via a clathrin-dependent endocytic process [28]. Clathrin plays a significant role in the formation of clathrincoated pits; invaginated regions of the plasma membrane, and pinch off to form clathrin-coated vesicles that transport molecules within cells [31].

In summary, drug adsorption may occur passively or via active transport. In either case, absorption occurs predominantly in the small intestine due to its more permeable membrane and larger surface area provided by the microvilli. Even though, the stomach has a relatively broad epithelial surface, yet the dense mucus layer and transient transit times expended by dosage forms contribute to an impeded absorption. Moreover, the colon with an absorptive surface area of about 5m<sup>2</sup> has negligible contribution to drug absorption in GIT, due to slow caecal arrival times of dosage forms, the presence of numerous gut bacteria and solid stool that impede lateral diffusion. All in all, absorption of oral drugs is interlinked and controlled by various intrinsic factors; like drug solubility, dissolution and permeability across the mucosal barriers, and physiological factors; such as gastrointestinal transit time, pH and gut microbiome [13, 32].

#### **2.3 Drug dissolution, solubility and permeability**

Drug dissolution, solubility and permeability are the three fundamental parameters used in the Biopharmaceutics Classification System (BCS) to predict the factors limiting drug absorption from GIT [33]. The BCS is recognised as a useful

**31**

*Gastrointestinal Delivery of APIs from Chitosan Nanoparticles*

tool for designing drug delivery systems and is adopted by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the World Health Organization (WHO) [34]. According to the BCS, all drug substances are classified into four categories: class I—high soluble and high permeable, class II low soluble and high permeable, class III—low soluble and high permeable and class

Drug solubility is crucial outcome in pharmaceutical dosage form. In the BCS system, a drug is deemed highly soluble when the maximal dose strength is soluble in 250mL of aqueous media across the pH range of 1 to 7.5 [35]. However, more than 40% of the established new chemical entities in the pharmaceutical sector are considered insoluble in water, causing inadequate bioavailability [36]. This makes solubility amongst the most important rate limiting parameters in GIT absorption. Drug dissolution reflects a dynamic consequence to drug absorption [33], whereby drug is released, dissolved and made accessible for absorption. With the exception of enteric formulations and drugs with low acid solubility, the dissolution process for majority of drugs starts in the stomach where the volume of gastric fluid is sufficient to attain effective drug dissolution [37]. Thus, the gastric fluid containing the disintegrated immediate-release dosage forms brings the solubilized drug into contact with the absorptive surface of the small intestine as absorption in the

Drug permeability represents the final frontier in the sequence of rate-liming steps to systemic drug availability. It is a measure of the ease of permeation of the drug across the intestinal wall. There is a positive association between the intestinal permeability and drug solubility GI milieu, which in turn depends on the physicochemical characteristics of the drug [38], including the pKa, particle size, lipophilicity, as discussed in the sections below. The ultimate amount of drug absorbed

The GI pH influences the extent of ionization of drug molecules and thereby impacts on its absorption across the epithelium. Variations in pH across the GIT can be exploited for delayed drug release in desired section of the GIT in order to achieve efficient absorption. The fasted stomach is acidic, with pH range of 1–3, which increases upon food or liquid intake. Food is known to buffer the acidic content of the stomach. A rise in pH resumes in response to the continual gastric secretion and then finally, the pH reverts to the original levels due to gastric emptying of content; [40]. The gastric emptying rate significantly affects the rate of drug absorption because it regulates arrival in the duodenum, where the epithelial surface is suited for absorption [41]. Moreover, the disparity in gastric pH conditions affects the drug delivery behaviour of modified release dosage forms such as enteric coated products, where the onset of release along with the overall release

The arrival of orally administered dosage forms into the small intestine is met by a pH of about 6 in the duodenum through to pH 7.4 at the terminal ileum [43]. This high pH variability is due to duodenal secretion of alkaline bicarbonate. During postprandial state, the initial intestinal pH drops due to the influx of acidic chyme, which is buffered by bicarbonate secretion as it travels distally [13]. Besides, the mean pH in proximal small intestine during the first hour of transit is usually 6.6,

Typically, the pH in the caecum drops to just below pH 6 owing to the fermentation processes of the colonic microbiota and then rises to pH 7 at the rectum [42]. The drop in the amount of short chain fatty acids at the distal colon causes the

which is further decreased to 5–6 in the distal duodenum [44].

from the GIT also bears dependence on its transit time in the GIT [39].

*DOI: http://dx.doi.org/10.5772/intechopen.95363*

IV—low soluble and low permeable [35].

stomach is generally minimal.

**2.4 Gastrointestinal pH**

kinetics may be changed [42].

#### *Gastrointestinal Delivery of APIs from Chitosan Nanoparticles DOI: http://dx.doi.org/10.5772/intechopen.95363*

*Chitin and Chitosan - Physicochemical Properties and Industrial Applications*

transport of counter ions down its electrochemical gradient (e.g., Na+

clathrin-coated vesicles that transport molecules within cells [31].

intestinal transit time, pH and gut microbiome [13, 32].

**2.3 Drug dissolution, solubility and permeability**

**2.2 Active Transport**

Na<sup>+</sup>

and K+

small bowel [22, 29].

their bioavailability and distribution [21]. The sodium-potassium pump system (Na<sup>+</sup>

would be anticipated by diffusion alone [26]. A frequent case of facilitated diffusion is the migration of glucose into cells during the production of adenosine triphosphate (ATP). Glucose is both large and polar thereby unable to pass the lipid bilayer via simple diffusion. Hence, glucose molecules are delivered into the cell via a unique carrier protein (glucose transporter) to promote its internalisation in cells [27].

Active transport is an energy-dependent process that translocates drug molecules against their concentration gradient by a molecular pump [20]. Carrier-mediated active transport demand energy via ATP hydrolysis or by accompanying the co-

[28]. The most common active transport system is the sodium-potassium pump and receptor-mediated endocytosis. Energy can either be directly provided to the ion pump or indirectly by connecting a pump-action to an activated ionic gradient. It is often encountered in the gut mucosa, the liver, renal tubules and the blood–brain barrier [22]. Active transport is typically restricted to drugs that structurally resemble endogenous substances; e.g., vitamins and amino acids, and that are absorbed via specific sites in the small intestine. Targeting drugs to these transporters can enhance

various cell types, such as the Na+/amino acid symport in the mucosal cells of the

In summary, drug adsorption may occur passively or via active transport. In either case, absorption occurs predominantly in the small intestine due to its more permeable membrane and larger surface area provided by the microvilli. Even though, the stomach has a relatively broad epithelial surface, yet the dense mucus layer and transient transit times expended by dosage forms contribute to an impeded absorption. Moreover, the colon with an absorptive surface area of

arrival times of dosage forms, the presence of numerous gut bacteria and solid stool that impede lateral diffusion. All in all, absorption of oral drugs is interlinked and controlled by various intrinsic factors; like drug solubility, dissolution and permeability across the mucosal barriers, and physiological factors; such as gastro-

Drug dissolution, solubility and permeability are the three fundamental param-

eters used in the Biopharmaceutics Classification System (BCS) to predict the factors limiting drug absorption from GIT [33]. The BCS is recognised as a useful

has negligible contribution to drug absorption in GIT, due to slow caecal

Cells control the endocytosis of certain substances via receptor-mediated endocytosis. The use of this form of endocytosis in the GIT is crucial for oral delivery of drugs because it delays the transit of drugs in GIT. Receptor-mediator endocytosis involves the internalisation of macromolecules by binding the latter to receptors considered as membrane-associated protein [30]. There are more than 20 different receptors involved in the internalisation of macromolecules [31]. Following binding to the receptor on the cell surface, the cell will endocytose the portion of the cell membrane enclosing the receptor-ligand complex via a clathrin-dependent endocytic process [28]. Clathrin plays a significant role in the formation of clathrincoated pits; invaginated regions of the plasma membrane, and pinch off to form

/K+

in and out of the cell. It is a vital ion pump located in the membranes of

, H+ , Cl− )

ATPase), utilises ATP to move

**30**

about 5m<sup>2</sup>

tool for designing drug delivery systems and is adopted by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the World Health Organization (WHO) [34]. According to the BCS, all drug substances are classified into four categories: class I—high soluble and high permeable, class II low soluble and high permeable, class III—low soluble and high permeable and class IV—low soluble and low permeable [35].

Drug solubility is crucial outcome in pharmaceutical dosage form. In the BCS system, a drug is deemed highly soluble when the maximal dose strength is soluble in 250mL of aqueous media across the pH range of 1 to 7.5 [35]. However, more than 40% of the established new chemical entities in the pharmaceutical sector are considered insoluble in water, causing inadequate bioavailability [36]. This makes solubility amongst the most important rate limiting parameters in GIT absorption.

Drug dissolution reflects a dynamic consequence to drug absorption [33], whereby drug is released, dissolved and made accessible for absorption. With the exception of enteric formulations and drugs with low acid solubility, the dissolution process for majority of drugs starts in the stomach where the volume of gastric fluid is sufficient to attain effective drug dissolution [37]. Thus, the gastric fluid containing the disintegrated immediate-release dosage forms brings the solubilized drug into contact with the absorptive surface of the small intestine as absorption in the stomach is generally minimal.

Drug permeability represents the final frontier in the sequence of rate-liming steps to systemic drug availability. It is a measure of the ease of permeation of the drug across the intestinal wall. There is a positive association between the intestinal permeability and drug solubility GI milieu, which in turn depends on the physicochemical characteristics of the drug [38], including the pKa, particle size, lipophilicity, as discussed in the sections below. The ultimate amount of drug absorbed from the GIT also bears dependence on its transit time in the GIT [39].
