Oral drug delivery : Gastrointestinal tract adaptations , barriers and strategies for delivery enhancement-a review

The mouth is a vital route of drug administration with over 84 % of all medicines reportedly administered through it. The gastrointestinal system is equally imbued with a lot of adaptive features that make the oral route even more conducive for systemic drug delivery. The usefulness of the oral route is, however challenged by the existence of numerous absorption barriers which limit the ef fective absorption and delivery of drugs to their target sites in the body systems. Understanding these adaptive attributes , systemic barriers, and available strategies for overcoming such barriers will not only be helpful in drug development and design but also useful to the formulation scientists desirous of optimizing drug delivery. The objective of this work was to review the gastrointestinal route of drug administration with respect to some biochemical and physio-anatomic features that impede or enhance drug absorption and to highlight current strategies that have been deployed to achieve optimum per oral drug delivery. The current review reveals the emerging roles of nanocarriers in oral drug delivery. Polymeric nanocarriers enhance the solubility, targeting and safety prof iles of many important pharmacological agents. Novel systems that of fer protection against gastro enzymes and as such, promote oral ad ministration of biologicals are being widely investigated. Mechanical, magnetic, and acoustic energy – induced membrane perturbation are other delivery options receiving research attentions. It may be concluded that, with the avalanche of research ef forts in the area, the oral route will maintain its prominence among other routes of drug administration.


INTRODUCTION
Numerous literatures show that the oral route is the most f requently used route of drug administration and is generally pref erred by patients, clinicians, health practitioners and even pharmaceutical manuf acturers (Alqahtani et al., 2021;Liu et al., 2017). The route is reported to be, by f ar, the most popular of all other routes with over 84 % of all medicines estimated at a value of $35 billion and a growth rate of 10 % reportedly administered through it (Prasad et al., 2017). The pref erence f or this route is attributed to the f act that it predominantly mimics the natural f eeding process. It is simple, convenient, amenable to patient's self -administration and enjoys f lexible dosing schedule. Oral drug ingestion is also a non-invasive procedure associated with no pain and/or discomf ort (Shreya et al., 2018;Homayun et al., 2019). More so, most dosage f orms f or oral administration are very simple to handle and do not need sterilization to maintain stability. Considered f rom saf ety perspective, overdose or poisoning by orally administered drugs may be controlled by simple induction of vomiting or immediate ingestion of an antidote.
Generally, the gastrointestinal system is naturally endowed with a lot of anatomic and physiologic features that enhance the passage, release, and absorption of drugs within the system. However, drugs administered orally encounter a lot of delivery barriers which limit their absorption, membrane permeation and systemic bioavailability. Some of the drugs are subject to hepatic f irst pass ef f ect, f irst pass metabolism, f ood, and ef f lux system ef f ects as well as inf luence of pathological conditions that may exist in the gastrointestinal tract. Other limitations of the oral route of drug administration include inappropriateness for use in vomiting and unconscious patients, f requent incidence of nausea, vomiting and other stomach disturbances and, challenge of pill burden especially in chronic and/or syndromic diseases as well as poor patient dosing compliance in cases of selfadministered drugs. Some drugs do also induce local irritation within the GIT (Rubbens et al., 2018). Poor aqueous solubility of many drugs is also a major challenge to their oral administration. About 40 -70% of new drug entities (NDE) and about 90% of those at developmental stages are known to exhibit poor aqueous solubility, (Kumar, 2016).
A lot of strategies have been explored by both researchers and drug manuf acturers to improve the absorption and bioavailability of orally administered drugs. Most of ten documented strategies involve solubility enhancement , modif ied release systems and other novel drug delivery approaches (Boyd et al., 2019). Strategies currently employed to enhance drug solubility include particle size reduction, pH adjustment, complexation, emulsif ication, lipid dispersion pegylation, solid dispersion among others. These approaches have led to signif icant improvement in the gastrointestinal solubility, absorption, and systemic bioavailability of many hitherto poorly watersoluble drugs.

Gastrointestinal tract adaptations for systemic absorption and delivery of orally ingested drugs.
The gastrointestinal tract is naturally structured to f acilitate its major f unctions of transportation, digestion and absorption of f ood , drugs and other relevant materials introduced into it. The specif ic activities that take place and the bioactive chemicals recruited upon introduction of a material into the GIT depend partly on the nature, state, and chemical composition of the material. A lot of physiologic and anatomic characteristics of the GIT adequately adapt it to these f unctions. The f ollowing GIT f eatures have been identif ied as usef ul adaptations that support gastrointestinal drug absorption and permeation:

The length and convoluted structure of the gastrointestinal tract
The gastrointestinal tract is about 9 meters in length with the small intestine constituting 6 meters of the total length, (Hua, 2020). The small intestine is particularly windy in packing a f eature that allows the long structure to be accommodated in a relatively small portion of the abdomen. The length and convoluted packing of the intestine ensure delayed transit time, longer retention time and more intimate contact between the ingested drugs and the digestive enzymes and absorptive surf aces of the GIT. The implication of these f eatures is that enough surf ace area and absorption time are available f or maximum drug permeation (Brunton et al., 2018). This is even more so with the small intestine which is the major digestive and absorptive portion of the GIT constituting two thirds (2/3) of the entire length of the GIT. The peristaltic movement of the GIT not only f acilitates physical disintegration of the dosage f orms and movement of the drugs and their digestive products along the GIT but also provide the agitation required f or needed emulsif ication of some stomach contents.

Presence of large absorptive cells.
Availability of numerous absorptive cells in f orm of the villi along the intestinal luminal surf aces f acilitates absorption of drugs f rom the gastrointestinal solutions (Brunton et al., 2018).

Presence of digestive enzymes and other bioactive chemicals
The GIT has a lot of digestive chemicals, enzymes and gastric f luids, all which aid in the breakdown, digestion, dissolution, and absorption of drugs. These chemicals are released pref erentially according to the nature of the f ormulation (lipid, carbohydrate or protein based). Presence of endogenous emulsif iers like bile salts f acilitates f ormation of emulsions which is necessary f or the solubilization of poorly water-soluble drugs.

Presence of membrane transport molecules
A lot of membrane transport molecules are present within the GIT membranes where they perf orm the trans-membrane transportation of some natural molecules like glucose, amino acids, neurotransmitters, and some natural ions. Such transporter molecules are also capable of binding to some drug molecules and f acilitating their trans-membrane movement. In this regard, Trepat et al., (2007) listed L-dopa, gabapentin, 5-f luorouracil, and baclof en as examples of drugs transported by attaching to amino acid transporters, and beta-lactams transported by molecules designed to transport naturally occurring oligopeptides. The ef f ect of membrane transporters may however be inhibitory in some cases as shall be discussed later.

Gastrointestinal tract drug absorption barriers
Orally administered drugs encounter a lot of barriers against their absorption and f ree passage into the systemic circulation and ultimately to their sites of action. These barriers may arise f rom: (i) the peculiar physiologic and anatomic f eatures of the gastrointestinal tract (ii) the physicochemical properties of the drug molecules and (iii) the design of the pharmaceutical dosage f orms. Drugs molecules must overcome these barriers to gain access to the circulatory system. Some of these barriers are described below:

Gastrointestinal membrane mucus barrier
The gastrointestinal membrane mucus is made of water, mucin, and high molecular weight glycoproteins. It is present on the GIT surf aces in the f orm of entangled network of tissues. Boegh and Nielsen (2015) noted that this network is hydrophilic in nature and so creates stearic and interactive barrier against the absorption of hydrophobic drug molecule. The mucus which is continuously secreted by the goblet cells of the GIT also constitutes dynamic barriers to the absorption of both hydrophilic and hydrophobic drugs due to its continuous shedding and clearance because of cell turnover f rom the mucosal surf aces (Homayun et al., 2019).

Epithelial cells barriers
The inner surf ace of the GIT is lined with many columnar shaped cells known as epithelium. The epithelia are the main absorptive cells of the intestine. The epithelial cells responsible for gastrointestinal f ood and drug absorptions are the enterocytes which are heavily distributed at the apical region of the intestinal villi, (Engman, 2013). In humans, the epithelial layer is thought to be continuous in the stomach and duodenum but may not be so in the rest of the small and large intestines. (Marrianne, 2015). Each epithelial cell is f irmly joined to the next cell thereby creating a joint known as "tight junction" between adjacent cells.
Following the dif f usion of drug molecule through the mucus membrane barrier, it encounters the epithelium as another barrier, (Laf f leur; Bernkop-Schnürch, 2013 Aulton (2002) noted that the tight junction constitutes a natural barrier to par cellular absorption of large molecular size drugs. Similarly, the absorptive apical cell membrane of the columnar cell appears to behave, with respect to nutrient and drug, like lipoidal membrane penetrated periodically by sub microscopic aqueous-f illed channels or pores. The predominantly lipoidal membranes act as absorption barriers to aqueous drug molecules while the aqueous pores allow only molecules of selected molecular sizes to pass through. The membrane, theref ore, acts as passage sieve to both hydrophilic and lipophilic compounds. Luo et al. (2021), postulated that the transcellular transport is mostly restricted to molecules that comply with Lipinski's rule of five and which are lipophilic in nature. On the other hand, the tight junctions (paracellular transport route) allow the passage of hydrophilic molecules of molecular weight not more than 1000g/mol. The paracellular route (tight junction), theref ore, constitutes an absorption barrier to hydrophobic/lipophilic and large molecular weight drugs while the lipoidal cell membrane act as absorption barriers to hydrophilic drug molecules.

Efflux system barriers
Ef f lux systems ref er to a group of transporter gene proteins that are f ound in the cell membranes of many tissues and organs especially the intestine, liver, kidney, and the lungs, (Srivalli & Lakshmi, 2012. They inhibit the natural process of drug transport across the cell membranes. These gene proteins belong to the class known as adenosine triphosphate (ATP) binding cassette (ABC) super f amily with f amily members such as, the permeability glycoprotein (P-gp) also known as ABCB1; bile salt export pump (BSEP) or ABCB11; the multidrug resistance proteins (MRP1-6) or ABCC 1-6 and the breast cancer resistance proteins (BCRP) or ABCG 2. (Kuar et al., (2015). Members of this super f amily utilize adenosine triphosphate (ATP) to generate energy enabling them to pump substrate drugs back against their concentration gradients (f rom the enterocyte membrane back to the intestinal lumen (Shugarts & Benet, 2009). Their action limits the quantity of drugs that eventually enter the circulatory and/or the lymphatic system.

Unstirred water layer barrier
The unstirred water layer (UWL) ref ers to an aqueous dif f usion layer just adjacent to the intestinal membrane. This layer exerts some resistance against passive permeation of molecules into the epithelial membranes and drug dif f usion across the mucous membrane (Wilson & Dietschy (1972). An exp erimental investigation on absorption across the unstirred water layer and brush boarder of the rat jejunum concluded that the uptake of polar bile was limited solely by membrane permeation while the mucosal uptake of less polar bile was signif icantly limited by the unstirred water layer. The report also claimed that the permeation retarding ef f ect of the UWL was more pronounced f or micellar solutions than f or f ree monomers (Thomson, 1980).

Gastrointestinal fluid pH absorption barrier
The pH of the intraluminal f luid varies widely along the length of the GIT, generally lying between 1.0 -3.0 within the stomach, about 6 in the duodenum, between 6 -7.4 in the small intestine and between 7.5 and 8.0 within the ileum and rectal regions. (Evans et al., 1998). These variations in pH values inf luence the ionization statues of dissolved drugs ((Brunton et al., 2018). The ionization levels equally determine the population of the charged and uncharged species of ingested drug molecules at any given region of the GIT. This, in turn, inf luences the membrane permeation of drugs. For a drug to be absorbed, it must be present in the f orm of an aqueous solution at the site of absorption. (Kalepu & Nekkant, 2015). This implies that dissolution medium that f acilitates ionization of a drug will cause poor membrane permeation and poor absorption of the drug through the adjacent biological membranes. Most drugs are either weakly acidic (polar) like aspirin and phenobarbitone or weakly basic. Weakly acidic drugs exist in unionized (neutral) state in the gastric f luid (with acidic pH) and hence exhibit good absorption in the stomach while weakly basic drugs ionize in the same region and exhibit poor absorption there. Since drugs are absorbed in their unionized f orms, the absorption of weakly acidic drugs in the gastric segment of the GIT is enhanced while absorption of weakly basic drugs is impeded by the prevailing low pH environment. To the contrary, weakly acidic drugs undergo signif icant ionization in the high pH (basic) intestinal f luid and as such exhibit poor absorption as against weakly basic drugs that remain unionized in the intestinal f luid. (Kalepu & Nekkant, 2015). The pH condition of a specif ic GIT region may, theref ore, constitute absorption barrier f or some drugs. The pH environment of various sections of the GIT may also pose serious challenge to the stability of the administered drug such that a greater portion of both the intact and ionized drug is not absorbed. The acidic condition of the gastric f luid can cause denaturation and/or degradation of drugs while bile salts of the small intestine can distabilize biological products (Khonsary et al., 2017& Luo et al., 2021 First pass metabolism barrier. First pass metabolism ref ers to the metabolism or biotransf ormation of orally administered drugs that take place bef ore the drug gets into the systemic circulation. The main sites of such pre-systemic metabolism are the intestine and the liver. First pass metabolism reduces the quantity of f ree active molecules that get into the systemic circulation. (Engman 2003). Bioavailability is described as the f raction of orally administered drug that reaches the systemic circulation in intact f orm. The relationship between bioavailability and f irst pass metabolisms has been expressed by Thorn, (2012)) as; where, F represents drug's total bioavailability, f abs is the total quantity of drug absorbed by the intestinal enterocyts, EG represents gastric extraction or quantity of drug metabolized in the intestine and EH is the quantity metabolized in the liver bef ore entering the circulatory system. Any change in (1-EG) or (1-EH) af f ects the bioavailability (F). Liver enzymes involved in hepatic f irst metabolism are, the cytochrome P450 (CYP450) and the uridine diphosphate glucuronosyltransf erase (UGT) f amilies of enzymes. Some drugs that are substrates of various permeability glycoprotein (Pg-p) enzymes are shown in Table 1. (Brown, 2010). ketoconazole, Atovastatin, lovastatin, azithromyc in, clarithromycin, benzodiazepimes, calcium channel blockers, protease inhibitors .

Gastric emptying rate
The rate at which the stomach empties its digestive product to the intestine through the pyloric sphincter may f acilitate or constitute absorption barrier to orally administered drugs. The small intestine is the major absorption site of the GIT. Fast emptying of digestive product containing a drug will deliver such drug f aster to the absorption sites of the small intestine thereby f ast-tracking absorption. The reverse is true f or slow emptying rate. Prescott (1974) reported that, f or drugs that are rapidly absorbed, gastric emptying time is the absorption rate limiting step He also noted that, on the contrary, slow gastric emptying rate has the potential of retaining drugs longer in the stomach, slowing drug absorption and subjecting it to possible gastric enzyme and acid degradation. The impact of gastric emptying rate on absorption theref ore depends partly on the nature of the drug.

Pathological conditions and surgery
Many pathological conditions occurring locally within the GIT or elsewhere in the body can alter the physiological f unctions of the organ in a way that can disrupt its normal drug absorbing activities. For instance, pain can alter gastrointestinal blood perf usion, motility, enzyme secretion and membrane permeability in a way that reduces its capacity f or drug absorption, (Konturek Similarly surgical partial resections on both stomach or intestine or even colons perf ormed in the treatment of diseases like peptic ulcer disease, malignancies, inf lammatory bowel disease and other GIT pathologies can af f ect drug absorption ostensibly due to reduction in absorption surf ace areas and other pathological changes, (Titus et al. 2013;Hua et al., 2015;Hatton et al., 2018;Kyietys, 1999 andThompson et al. 1998).
Ef f inger et al. (2018) have reviewed the impact of some gastrointestinal disease states including irritable bowel syndrome (IBS), inf lammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease on oral drug absorption and the implications f or f ormulation design. They concluded that drug absorption via the oral route is adversely af f ected by these disease conditions.

Food effects and drugdrug interaction
The ef f ect of f ood on drug absorption has been widely reported showing that the inf luence of food is related to both drug f ormulation and the type of f ood. These ef f ects present as decreased gastric emptying time, change in intestinal pH, change in intestinal f luid viscosity, increase in secretion of digestive enzymes and emulsif ying endogenous bile (Kostewicz et al. 2002. These changes af fect drug absorption in various ways. The beagle dog pentagastrin model has become the standard approach f or studying the ef f ect of f ood on drug absorption (Zhang et al., 2018). This model can establish and extrapolate the ef f ect of f ood on drug absorption f rom pharmaceutical f ormulations (Zane et al. 2014). For instance, presence of f atty f ood enhances the absorption of BCS class II drugs (Chatterjee et al. 2016) whereas the absorption of some oral penicilins is inhibited by the presence of antacids.
In like manner, drugs can af f ect the absorption and bioavailability of other drugs by altering the physiological state of the GIT, f orming complexes with other drugs or by outright competitive antagonism. Laxatives can cause a reduction in the absorption of co administered drugs by reducing the GIT retention times of such drugs. Many antacids are also known to reduce the absorption of the tetracyclines by f orming insoluble complexes just as proton pump inhibitors can af f ect release of drugs f rom f ormulations that depend on specif ic GIT pH f or drug release (Brunton et al., 2018;Lahner et al. 2009). Some potent antibiotics can destroy the GIT f lora and result in poor absorption of some other drugs (Sartor, 2010, as cited in Hua, S. (2020).

Age related drug absorption barriers
Many physiological and anatomic f unctions of the GIT like intestinal motility, gastric acid secretion, length of the GIT, gastric emptying time, enzyme secretion and microbial f lora are af f ected by age. In children and the elderly, these f unctions are of ten sub optimal and as such drug absorption, bioavailability and metabolism are negatively af f ected, (van den Anker, 2018). Reduced gastrointestinal motility and/or slow gastric emptying time have implication in delayed delivery of drugs to absorptive sites in the GIT. Similarly, age related alteration in the intestinal f lora which aid drug metabolism may undermine absorption in the children, the elderly and other underdeveloped persons. Jones, (2020) specif ically noted that "inf ants with congenital atretic bowel or surgically removed bowel or who have jejunal f eeding tubes may have specif ic absorptive def ects depending on the length of bowel lost or bypassed and the location of the lost segment." Advancing age is associated with alteration in many physiological f unctions including gastrointestinal perf ormances. Gastric pH and gastric emptying time have been reported to be signif icantly altered in the elderly, (Russell et al., 1993;Russell et al., 1994;Vertzoni et al., 2020b). Apart f rom these two parameters, variation in gastrointestinal absorption is very likely due to multimorbidity and polypharmacy which are common among the geriatrics (Mojaverian et al., 1988;Moore et al., 1983;Stillhart et al., 2020).

Strategies for improving gastrointestinal absorption of orally administered drugs
Most of the strategies deployed to enhance gastrointestinal absorption of drugs target, (i) increase in the GIT f luid solubility of poorly watersoluble drugs, (ii) promotion of drug membrane permeability and (iii) creating drug f orms, carriers and devices that are capable of overcoming drug absorption and delivery challenges. Dissolution in the GIT f luid is a prerequisite f or drug absorption through the GIT membrane, distribution in the circulating blood (which is aqueous in nature) and eventual accumulation of the drug at the site of pharmacological action (Dhillon et al., 2014). The lymphatic system plays comparatively lesser roles in this regard. For the purposes of pharmaceutical f ormulation, a drug is said to be highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over pH range of 1 to 7.5 (Savjani et al., 2012). Drugs which f all into the British Pharmacopoeial grouping of sparingly soluble, slightly soluble, very slightly soluble, and practically insoluble may, f or the purposes of f ormulation design, be generally described as poorly water-soluble drugs (PWSD). The most widely reported techniques f or increasing drug aqueous solubility include use of particle size technologies, use of lipid-based systems, cosolvents and surf actant systems, salt f ormation and use of delivery carriers like liposomes, niosomes, cyclodextrins, micelles and other similar nanodevices. Some other techniques involving molecular structural manipulations like co-crystal habit modif ication, polymorphism and amorphous solid dispersion have also been employed. These various strategies employed f or improving drug solubility, absorption and systemic bioavailability are discussed below.

Use of particle technologies
In Pharmaceutics, the term 'particle technologies' is used to describe various techniques f or size and morphology manipulations employed to modify the physicochemical, micromeritic and biopharmaceutical characteristics of drug particles. Common particle technologies involve particle size reduction (micronization, and nanosization), engineered particle size control using cryogenic spray technique and crystal growth habit modif ication.

Micronization and nanosization
Micronization is the process of reducing coarse drug particles to an ultraf ine powder with mean particle size in the range of 2 -5 µm and only a very little f raction of the particles lying below 1µm size (Khadka et al., 2014). Like other particle reduction processes, micronization results in increase in the particle surf ace areato -volume ratio and subsequent increase in the dissolution rate. Particle size reduction equally reduces particle thickness and solvent dif f usion part length thereby increasing rate of drug passage f rom the particle to the dissolution media in accordance with the Norye-Withney dissolution theory, (Smita et al., 2015).
It has, however been argued that a decrease in particle size has relatively little ef f ect on the solubility of a drug substance since as such reduction does not alter the solid-state properties of the particles (Khadka et al., 2014). However, Williams et al (2013) in their work concluded that particle size reduction indeed increases kinetic solubility of poorly soluble drugs by increasing the solutesolvent interaction surf ace areas. Nanosization involves the reduction of particles to nanoscale sizes which f all within the range of 1-100 nanometers (Kalepu & Nekkant, 2015). Apart f rom physical size reduction, nano properties can also be conf erred on a drug material by embedding or conjugating the drug to a nanocarrier (Dhiman. 2006). Nanosizing dramatically conf ers on drug substances many pharmacokinetic characteristics that are clearly distinct f rom those of their bulk o r macro counterparts. In addition to having larger surf ace areas nanomaterials acquire other attributes like, enhanced electrical, optical, thermal, and other physicochemical characteristics which can be exploited in designing products with enhanced solubility, absorption, and bioavailability. Wanigasekara & Witharana. 2016).

Crystal habit modification (co-crystal and polymorphism)
Crystal engineering also known as crystal habit modif ication can lead to co-crystallization or polymorphism. The deliberate objective of crystal habit modif ication is to design and control the molecular packing within a crystal structure with the intention of generating a new solid crystal that exhibit some desired characteristics such as altered shapes and sizes, increased surf ace area, new crystal packing arrangement, increased solubility, and other similar f eatures (Joshi, 2020). If a crystal engineering process leads to the f ormation of one or more crystalline solids that dif f er only in the molecular arrangement the process is known as polymorphism and the products are called polymorphs. Co-crystals, on the other hand result f rom a molecular complex f ormed between a drug molecule and a crystal f ormer leading to change in the original lattice arrangement (Williams et al., 2013). Either of these modif ications can create new molecular entity with enhanced pharmacokinetic properties. Bucovec et al. (2016) investigated the ef f ect of crystal habit on the dissolution behaviour of simvastatin crystals and its relationship to crystallization solvent properties. The researchers reported that dif f erent crystal morphology types of simvastatin resulting f rom crystal isolation using dif ferent solvents exhibited dif f erent dissolution rates in the same dissolution medium. They associated this dif f erence with dif f erences in sizes, shapes, and wettability of dif f erent crystal lattice structures. They reported a signif icant increase in the dissolution rate of the re-crystallized drug sample in a buf f er medium.

Salt formation and pH adjustment technique.
Salt Formation and pH adjustment are both f orms of chemical modif ication that can improve the aqueous solubility and gastrointestinal absorption of poorly water-soluble drugs. The ionized f orms of drugs are generally more soluble in polar solvents like water than their neutral base f orms. This has been explained to be because the af f inity of ionized species f or water is more than that of the unionized species. (Williams, et al., 2013). Any chemical modif ication (pH adjustment or salt f ormation) that results in increased molecular ionization will likely enhance the aqueous solubility of the drug of interest. Most drugs are either ionizable weak acids or weak bases in which ionization is a major f actor f or solubilization. The extent of solubilization may also be dependent on the pH of the solution and the pKa (ionization constant) of the drug molecules. Weakly acidic drugs are more soluble at pH ≥ pKa while weakly basic drugs are soluble at pH ≤ pKa (Kalepu, et al., 2015), For solid dosage f orms, salt f ormation play the same role since the salt f orms undergo easier ionization in aqueous media than the pure base.

Use of solid dispersion systems
Solid dispersion describes a dosage f ormulation in which a drug in solid f orm is unif ormly distributed (dispersed) in another solid material (dispersion matrix) with the intent of improving the solubility or other delivery f eatures of the dispersed drug. Lipids are widely used as matrix materials. Unif orm dispersions can be achieved using various techniques such as, mechanical blending, hot melt f usion, hot melt extrusion and solvent evaporation methods. Popular matrix materials include, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulphate (SLS), Plasdone-S630, Tween 80 and many other polymers (Savjani et al., 2012). Solid dispersion of diclofenac potassium in hydroxypropylmethyl cellulose (HPMC) has been successf ully used not only to improve the aqueous solubility of the drug but also to sustain the release f or up to 14 h. (Omeh, 2009). Studies have established dif f erent mechanisms by which solid dispersions enhance the aqueous dissolution of poorly water-soluble drugs to include reduction in ef f ective particle size, improvement in particle surf ace wetting and elimination of the impact of lattice energy via stabilization of drugs in amorphous state (Williams, et al., 2013).

Strategies for oral delivery of proteins peptides and other biologics
A plethora of strategies f or saf e delivery of organic therapeutics that are subject of gastrointestinal tract enzyme degradation have been developed and some are already patented or commercialized. Momoh et al., (2020) successf ully f ormulated snail mucin-based microemulsion f or oral delivery of insulin. The researchers reported an enhanced capsulation ef f iciency of 70 %, sustained drug release of over 12 h and blood glucose reduction over a period ˃ 8 h in rat model. Another per oral protein delivery approach involves the use of protease enzyme inhibitors. Some tested inhibitors include aprotinin, soybean trypsin inhibitors, camostat mesilate and chromostatin (Muheem, et al., 2016) all which were used to inhibit the ef fect of protein degradative enzymes like the peptidases. Agarwal & Khan (2001) reported the use of chicken and duck ovomucoids as enzyme inhibitors to of f er 100% protection against the degradative action of intestinal trypsin and αchymotrypsin.
Many recent works have also reported the use of permeation enhancers to f acilitate passage of proteins and other large molecular weight compounds though the epithelial membranes (Brayden & Mrsny, 2011). Permeation enhancers increase transcellular membrane transport by modif ying the tight junctions of the epithelial cells and the paracellular transport by epithelial membrane perturbation, Zonula occludens toxin (ZOT) (Salama et al., 2006), chitosan (Prego et al., 2005), thiolate polymers (Bernkop-Schnurch,2005) and Pg-p. Surf actants have also been used to modif y the integrity of the gastro absorption membranes f or enhanced drug absorption, (Muheem et al., 2016)

Use of carrier systems
Although most popular f or delivery of parenteral f ormulations, novel lipid, polymeric and other novel carrier systems such as liposomes, niosomes, microspheres, emulsion systems, nanoparticles and a host of others are being widely studied for oral delivery of medications. These carriers not only increase the gastrointestinal solubility and absorption of poorly water-soluble drugs but also protect the drugs f rom harsh gastrointestinal conditions perpetrated by various enzymes and biological chemicals. They also serve as ef f ective devices f or drug targeting, sustained release, and stimulus response devises. Successf ul f ormulation of breadf ruit seed oil-based self -emulsif ying drug delivery system f or the enhancement of the bioavailability of two non-steroidal antinf lammatory drugs -aceclof enac and ibuprofen has been reported with improvement in the solubility, drug release prof iles and other pharmacokinetic parameters (Omeh, R, University of Nigeria, Nsukka, Nigeria. Ph.D. thesis). Versicular systems like liposomes, bilosomes, micelles and microcapsules have been used to embed sensitive drugs and biomolecules for targeting ef f ects or protection against opsonisation, phagocytosis and gastroenzyme degrading ef f ects. Gastro-mucoadhessive carriers have also been suggested to improve drug residence time and reduce clearance time thereby increasing drug absorption and bioavailability.

Use of physical methods
One of the latest novel approaches to gastrointestinal drug absorption enhancement involves techniques based on physical interactions and manipulations of the GIT membrane using magnetic, mechanical, and acoustic energies to improve drug permeability across the GI mucosa (Luo et al. 2021). Application of such energies to the cell membrane through some f aily complex procedures has been reported to be capable of disrupting the tight columnar epithelial packing (Trepat et al., 2007, as cited in Luo et al. 2021 thereby increasing both paracellular and transcellular transport of drugs (A.-L. 2019).

Gastroretentive approaches
Formulation of dosage f orms in a way that delays their transit time through the stomach and other parts of the GIT has also been exploited f or the enhancement of drug absorption and local ef f ects. Floating f ormulations that exhibited three-f old f loating time increase of albendazole tablets on gastrointestinal f luids have been successf ully designed (Omeh, R. Enugu State University of Science and Technology, Nigeriaaccepted manuscript). Sunoqrot et al. (2017) equally sort to overcome the problem of rapid clearance of some model drugs f rom the stomach by incorporating some mucoadhesive components into some nanoparticulate f ormulations while Sharma et al, (2018) used high density systems to delay transit of iron nanoparticles-based f ormulation through the stomach. A f ew researchers have reported promising drug delivery results with regards to gastric retention and/or mucoadhesion in both invitro and in vivo experiments (Hua, 2020).

Use of nanoparticles for oral delivery of biological products
Nanoparticles have been successf ully used in novel ways f or both local and systemic delivery of drugs that otherwise were not possible because of the ef f ects of gastrointestinal tract bioactive chemicals, poor GIT membrane permeability and ef f ects of phagocytic enzymes. Many researchers have, however, reported improved absorption of drugs in the small intestine f rom nanoparticle loaded f ormulations and attributed this to the enhanced mucosal membrane permeation by the nano sized particles (Ahmad et al., 2018;Prajapati et al., 2018). Rapid uptake of nanoparticles by the microf old cells (M-cells) of the Peyer's patches in the small intestine has also been exploited f or the delivery of biological products and oral vaccines. The M-cells act as both protective biological carriers and antigenic targeting moieties for therapeutic compounds (Yu et al., 2019);Managuli et al.,2018). Such systems have been f ound to be very strategic in oral delivery of vaccines. The Mcells may also promote pref erential passive lymphatic targeting resulting in improved systemic delivery of some drugs

Other oral drug delivery enhancement techniques
Other technologies that have shown potential for improving oral drug delivery include, among others, f ast-dispersing tablets, three-dimensional Printing (3DP) and electrostatic coating technologies. These are aimed at modif ying the physicochemical and pharmacokinetic properties of drugs to improve their systemic and local delivery. Fast dispersing tablets promote rapid disintegration of tablets and quick release of drugs f or systemic absorption. Electrostatic coating which involves the spraying of dry charged powder on tablet surf aces provides superior surf ace protection f or active ingredients against gastric acid and enzyme degradation (Yang et al., 2016).
The 3D printing technology is unique for combination therapies and patient specific treatment solutions (Tsintavi et al., 2020).

CONCLUSION
A lot of research activities had been and are still being undertaken to elucidate the physiological and anatomical f eatures of the gastrointestinal tract that either enhance or impede ef f ective oral systemic delivery of many pharmacologically active and clinically important drugs. Many reviewed reports show that these strategies range f rom f ormulation design, molecular modif ication, and gastrointestinal membrane perturbation, all which have shown great potentials f or overcoming poor gastrointestinal absorption of many drugs. The f uture of oral drug delivery may be conf ronted with increasing poor drug solubility and suboptimal membrane permeation arising f rom the deployment of sophisticated drug discovery technologies like high throughput screening (HTS), combinatorial chemistry and others which are associated with synthesis of large molecular weight, structurally complex and non-polar hydrophilic new drug entities (Szymański et al., 2012;Guram et al., 2015) Nanotechnology, gastrointestinal membrane alterations and 3D technologies are likely to play signif icant roles as solutions to evolving per oral route drug delivery challenges.
(2014). Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution, and bioavailability. Asian