Chapter 2 of the Oral Delivery of Therapeutic Proteins and Peptides Research – Term Paper

Chapter 2 of the Oral Delivery of Therapeutic Proteins and Peptides Research

2. 0 State of Art: review of previous studies

2.1 Mechanisms of drug absorption

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2.1.1 Transcellular passive diffusion

Mechanisms of drug absorption represent a situation where drug molecules transfer from areas of high accumulation (the gastrointestinal tract lumen) via the cellular lipid membrane (bilayer) to an area of low accumulation in the blood. The molecules of the drug pass across the apical membrane found in epithelial cells, the go through the cytoplasm before exiting the cell via the basolateral membrane (Hernandez & Rathinavelu, 2006, p. 71). The drug first dissolves from aqueous liquids found in the gastrointestinal tract and partition into the epithelium (in the lipoid-like membrane). Subsequently, the solute diffuses across the epithelial cells cytoplasm and ends up in a network of blood vessels (blood capillaries). A much lower accumulation will be sustained in the blood in comparison to the concentration at the site of absorption due to the speedy flow of the blood and quick allocation into the tissues (Hart & Ksir, 2011, p. 61). 

Carrier-mediated transport

A profound level of uptake transporter proteins is represented in the small intestinal mucosa, and these facilitate the transfer of specific drugs, vitamins, and nutrients (Hernandez & Rathinavelu, 2006, p. 71). Transportation proteins can be categorized functionally into pumps, channels, and carriers based on the differences in the mechanism through which they use to facilitate the transfer of non-electrolytes and ions. Principally, two dedicated carrier-mediated transfer frameworks are present in the body of a human being, including facilitated diffusion and active transport (Hernandez & Rathinavelu, 2006, p. 71).


Endocytosis defines a procedure where a cells plasma membrane invaginates, paving the way for the formation of a tiny intercellular membrane-covered vesicle (that surrounds a volume of materials). Endocytosis depends on energy to facilitate the uptake process, in a situation where the invaginated matter is transferred to lysosomes or vesicles. The content of some vesicles evades the enzymatic digestion and transfer to the basolateral membrane of the cell after which it undergoes exocytosis. The uptake process (endocytosis) can further be categorized into receptor-mediate endocytosis, pinocytosis, transcytosis, and phagocytosis (Hart & Ksir, 2011, p. 61).

2.1.2 Paracellular pathway

The paracellular pathway is best conceptualized as the sole route that allows the passage of drug molecules through extracellular, aqueous paths rather than through cell membranes. The process depends on three key mechanisms, including the electrochemical potential gradient, electrical potential, and hydrostatic pressure to take place. These three mechanisms act as forces enabling the transfer of drug molecules across the paracellular pathway (Fox, 2009, p. 6).

2.2 Factors that hinder the absorption of peptide and protein drugs in the gastrointestinal tract

The principle function of the gastrointestinal tract otherwise termed as the digestive tract is to ensure that the body gets sufficient supply of materials that are necessary for biological processes. As such, it is ,more than justifiable to note that the very adaptation and design of the intestinal tract is to facilitate digestion and absorption (uptake) of fluids electrolytes, and nutrients (including food substrates and vitamins) from their original position (within the tract) into the systemic circulation of the body that allows their transportation to various points of need. Even so, it should not be ignored that the same tract has multivalent responsibilities. For example, while efflux (the infiltration of molecules and droplets from the systemic circulation into the digestive tract) takes place at a low level within the digestive tract, the digestive tract is well adopted to prevent the health effects that might amount form the uptake of harmful substances that living organisms, such as human may have administered. The gastrointestinal tract of a human being is well adapted for this function too, and is committed to preventing the body from the systemic attack on dangerous agents such as antigens, toxins, and pathogens, and this may affect the bioavailability of therapeutic protein and peptides (Baechler, 2014, p. 12). 

The presence of a drug in the intestinal tract subjects it to the fluid and aqueous environment. As such, the drug is traditionally in a dissolved form in the gastrointestinal tract. The gastrointestinal tract ensures that drugs exist as molecules suspended in gastrointestinal fluids, which ensures that such do not become bound to other contents (including food materials) that are available in the gastrointestinal tract lumen. It should not be ignored that the gastrointestinal tract has numerous substances that affect the pH therein. Different points of the digestive tracts function under variant levels of acidity or basicity, and the drug molecules must be resilient to the pH variations and refuse to give in to the degradation effects of enzymatic activities to remain effective.

 Additionally, the molecules of the drug must diffuse through the layer of mucus without binding to it to remain in the right quantity (Krishna & Yu, 2007, p. 11). This mucus layer is just one of the challenges that drug molecules have to overcome before they have to diffuse through the unstirred layer of water that stands in their path to the principal cellular obstruction, the gastrointestinal membrane that contains barriers including the tight junction. The notion that the gastrointestinal membrane presents the biggest challenge to the uptake of drug molecules does not mean that molecules that cross it are passed all challenges. On the contrary, these molecules must encounter other challenges including metabolic and liver enzymes once they enter the systemic circulation, which presents additional challenges in the quest of retaining the intended effectiveness and functionality of the drug. Factors including the mucus layer, the varied pH at different points of the digestive tract, digestive enzyme in the gastrointestinal tract lumen, unstirred layer of water, and the tight junction may prevent parts or the entire volume of drug from reaching the systemic circulation, the metabolic and liver enzymes presents additional concerns and challenges that must be factored in to ensure the drugs are as effective as intended, all of which lower the absorption of drug molecules in the gastrointestinal tract (Mcclements & Decker, 2009, p.41).

2.3 Ways of augmenting the bioavailability of therapeutic peptides and proteins

The understanding of factors that hinder of presents challenges to the abruption and the ultimate bioavailability of peptide and protein drug molecules may deploy in devising strategies to enhance the delivery of such drugs. As such, numerous strategies have the potential for use in the quest of overcoming the limitations of peptide and protein drugs. From a general perspective, such strategies can be divided into two sets including; formulation action plans and chemical modification methods. Protein therapeutics can be subjected to chemical improvements that may be achieved through the synthesis of prodrugs; structural transformations that target particular receptors or transporters or the preparation of peptidomimetics. The issue of low bioavailability can also be met through the formulation of novel dosage forms that include absorption enhancers or enzyme inhibitors (Fox, 2009, p. 6). These mechanisms are explained in the current section.

2.3.1Chemical approaches

The intestinal uptake of peptide and protein molecules can be improved through the co-intake of low molecular mass, amphiphilic absorption facilitator agents that operate as functional adjuvants. Absorption boosters initiate their purpose by implementing one or a series of mechanisms including opening the tight junction, decreasing the viscosity of mucus layer, and improving membrane fluidity. Even so, chemical methods to improve the bioavailability of peptide and protein drugs include prodrug strategies and chemical modification such as structural transformations, peptidomimetics, and targeting membrane receptors and transporters (Douroumis & Fahr, 2012).

A pro-drug entails a pharmacological inert chemical rooting of a parent medication that needs biomodification to turn out to be pharmacologically active (Whitney & Rolfes, 2011, p. 27). The utilization of pro-drugs may be constrained to peptides and proteins because of the structural complication of their micromolecules. As such, the majority of pro-drug methods used for such drugs traditionally focus on changing one functional group. For example, prodrugs focusing on membrane transporters are chemically designed to become substrates for membrane transporters- a feature that facilitates their ability to improve the uptake of peptide and protein drugs (Krishna & Yu, 2007, p. 11). Chemical modifications   

Chemical transformations such as lipidation, PEGylation, and amino acid substitution have proven advantageous considering the intestinal permeability and enzymatic stability of peptide and protein drugs (Mcclements & Decker, 2009, p.41). Amino Acid Substitution

Chemical transformation that depends on amino acid replacement can be attained by using an alternative amino acid or placing the D-amino acid where L-amino acid was originally positioned and reducing the sequence of amino acid by 6 (from 14 to 8) (Gaginella, Mozsik, & Rainsford, 2007, p. 78). Lipidisation

Lipidisation occurs by conjugating a fatty acid to peptide or protein molecule, which improves the availability of the micromolecule by enhancing its lipophilicity (Whitney & Rolfes, 2011, p. 27). The chemical method in question involves irreversible lipidisation, reversible lipidisation, and albumin binding. PEGylayion 

Polyethylene glycol (PEG) defines a biocompatible and non-toxic polymer that can dissolve in aqueous and organic solvents. The pharmacokinetic characteristics of peptide and protein drugs can be enhanced through covalent connection of PEG to the structure of a micromolecule in a mechanism known as PEGylation (Mcclements & Decker, 2009, p.41). PEGylation is renowned for its benefits in boosting the in vivo circulation half-duration of peptides and proteins, preventing them from in vivo breakdown, reducing their renal disposal and enhancing their physiochemical characteristics. 

2.3.2 Formulation approaches

2.3.2. 1 Absorption enhancers

Absorption enhancers permit the transfer of drugs across epithelial cells into the systemic circulation through diverse mechanisms that may include changing the membrane fluidity, reducing mucus viscosity, the opening of the tight junction, and distributing the integrity of cell membrane. The principal consideration for effective drug uptake facilitation includes ensuring that the drug permeability is predictable, reversible, and reproducible. The absorption booster should further enhance intestinal permeability without risking long-range or toxic outcomes. Drug absorption facilitators exist in diverse and numerous forms including fatty acids, chelating agents, salicylates, toxins, surfactants, venom extracts, anionic polymers, and cationic polymers (Hernandez & Rathinavelu, 2006, p. 71). Polymeric hydrogels

Natural polymers have been studied for potential carrier delivery systems for the delivery of insulin, as they are inherently non-toxic and biocompatible (Johnson & Byrne, 2003, p. 812). Insulin was added into a hydrogel that included the dispersion of a solution of biopolymer (such as gelatin, chitosan or pectin) into liquid particles and solidification of the particles to form droplets ranging between 40 nm and 1.8 mm. The investigation was geared to prevent the insulin from chemical breakdown. A hydrogel sealed droplet design including alginate-covered zinc calcium phosphate nanoparticle demonstrated a sustained blood glucose decrease for 12 hours in vivo experiments following an oral delivery of the particles to a diabetic rat (Whitney & Rolfes, 2011, p. 27).

2.3.3 Mucoadhesive Systems

Bioadhesion explains the extended connection between the gastrointestinal mucosa and drug delivery systems caused by increasing adhesion. Two synonymous words are common in bioadhesive including; cytoadhesion (high specific connection between the receptor-ligand and an adhesive agent comparable to the surface of the cell) and mucoadhesion (the connection between the drug delivery system and the mucus layer) (Fox, 2009, p. 6).

 The creation of bioadhesive medication delivery paradigms aims at prolonging the residence duration of a medication delivery paradigm at targeted site of absorption. This enhanced contact with the mucosa causes high drug concentration variation that ensures instantaneous uptake without dilution or degradation in gastrointestinal fluids and localizing the delivery of the drug at a specific site (Johnson & Byrne, 2003, p. 812).

Enhanced absorption and permeability of protein and peptide drugs are expected when Fluorescein isothiocyanate (FITIC)-labelled insulin-loaded hydrophobic/anionic transformation of chitosan nanoparticles are orally ingested by diabetic rats. The nanoparticles are expected to show mucoadhesive characteristics and enhance the gastrointestinal transfer time, extending the period of absorption (Fox, 2009, p. 6).  

2.3.4 Nanoscale technologies

Nanoparticle-based oral administration of peptide and protein drugs has proven to be useful in efforts to enhance bioavailability because they can sum up the drug and provide prevention against biochemical obstruction. An oral peptide or protein drug formulation, such as the Cp-PEG-Insulin-Casein (PAPIC), was designed by structuring caseins surrounding a PEG-insulin structure. Casein provides mucoadhesive characteristics as well as defense against the acidic surrounding. For example, administering a dose of CAPIC directly in the gastrointestinal tract (stomach) of a fasted diabetic mouse reduces the glucose level by 80% in the first hour, and enhances the half-time of insulin, which enhances therapeutic action (Hart & Ksir, 2011, p. 61).