Chapter 2

Oral Drug Delivery: Principles and Challenges

Drug delivery forms the basis of pharmaceutical sciences, which involves the design, formulation and administration of therapeutic agents to realize optimum effects as far as pharmacology is concerned. Effectiveness of any drug does not just lie in its pharmacodynamics and pharmacokinetics, but also in its capacity to reach the target site and at the appropriate time and concentration. The conventional dosage preparations, including tablets, capsules, syrups, injections, etc. have offered good solutions over the decades but they experience some difficulties including fluctuating absorption, first-pass metabolism, slow action, and uneven therapeutic responses. Current developments in the field of drug delivery seek to meet such constraints with new and emerging methods such as controlled and sustained-release, enteric coating, and nanoparticle-based drug delivery. These technologies are aimed at improving bioavailability, therapeutic efficacy, and patient compliance and reducing side effects and improving drug delivery, which is more precise, efficient, and more focused on the needs of a particular patient. This chapter offers a thorough summary of the basic concepts, administration locations, physiological and physicochemical principles influencing absorption, and contemporary formulation, which forms the basis of the elaboration of advanced drug delivery systems in later chapters.

2.1.Anatomy and Physiology of the Gastrointestinal Tract

The gastrointestinal (GI) tract is a complicated and highly specialized organ system, which is located between the anus and the mouth, the key location of nutrient digestion, absorption, and drug processing. In the event of oral drugs, the GI tract is the primary and the most important point of contact between the drug and the body where a cascade of physical, chemical, and enzyme activities define the final absorption, metabolism, and bioavailability of the drug. The presence of a dynamic environment, such as changes in pH, enzyme activity and mucus secretion and motility, is critical in determining how a drug dissolves, permeates through biological membranes, and gets into the systemic circulation. Learning the anatomy and physiology of GI tract is thus critical in designing effective oral dosage forms that are able to realize predictable and efficacious plasma drug concentrations.

Anatomically and functionally, the GIT is segmented into a number of parts with the stomach, small intestine and large intestine being the main parts engaged in drug absorption. All the segments play distinct roles in the pharmaceutical kinetics of orally administered drugs and their structural and functional attributes should be taken into consideration when formulating a drug.

Figure 2: Oral drug delivery system

The stomach acts as a storage and serves mainly as a storage area where the food and drugs are mechanically digested and the digestion process starts chemically. It has a pH of 1 to 3 making its environment highly acidic and thus can greatly affect the solubility and ionization of drugs. Weakly acidic drugs like aspirin are likely to be in their unionized form in the stomach and thus maximize their absorption but acid-labile drugs like penicillin, erythromycin and some drugs made of peptides may be destroyed and thus have reduced bioavailability. Another essential predictor of oral drug absorption is gastric emptying, or the transfer of the foodstuff of the stomach into the small intestine. The rate at which the action occurs may be delayed by delayed gastrointestinal emptying, which may depend on the amount of food intake, stress, or may depend on the physical properties of a dosage form, but may also be accelerated by rapid emptying.

The duodenum, jejunum, and ileum are the large intestine which is the primary location in drug absorption. Its structural changes such as villi and microvilli which constitute the brush border offer an enormous surface area of uptake of drugs. A relatively neutral pH (6 -7.5) also prevails in the small intestine, which is conducive to the solubility and permeability of most drugs, especially weak bases. Absorption mechanisms in this case are passive diffusion which is the most prevalent in the case of lipophilic and unionized compounds and active transport, facilitated diffusion, and the endocytosis of drugs that need carrier-mediated pathways. Also, there is the expression of diverse metabolic enzymes and transportation proteins in the small intestine: CYP3A4, P-glycoprotein, and esterases that may increase or decrease drug uptake. Such physiological characteristics enable the small intestine to be very efficient in terms of the rapidity as well as the extent of absorption in case the drug preparation is designed to suit these circumstances.

The large intestine or colon is less significant, but strategically located, especially when drugs have been designed in form of sustained or controlled-release. Despite the large intestine having fewer surface areas and a thicker mucosal barrier as compared to the small intestine, it has the advantage of more time to transverse through, where drugs meant to be absorbed slowly over the period can be absorbed. Also, the large intestine contains a high population of gut microbiota, which is capable of metabolizing some drugs and prodrugs, therefore, inactivating or activating them depending on the formulation strategy. Drug delivery to colon has been of interest in the treatment of local conditions including ulcerative colitis, Crohn’s disease and colorectal infections and in systemic delivery of drugs which are susceptible to enzymatic degradation in the upper gastrointestinal tract.

2.1.1.     Structure and Function of the Stomach

The stomach is a very important structure during the early stages of the processes of drug absorption, as it plays the role of reservoir as well as an intubatory chamber to the drugs administered orally. Structurally, it is a muscular structure in the form of a sac in between the esophagus and the small intestine, which is able to enlarge to fit the food and fluid ingested. It moves in rhythmic contracted motions referred to as peristaltic movements that assist in the operation of mixing of food and drugs into the secretions in the stomach to form a semi-liquid mixture termed chyme, which is released slowly to the small intestine.

At the physiological level, hydrochloric acid (HCl) and digestive enzymes, such as pepsin, are secreted into the stomach, so the stomach environment is very acidic (pH 1.53.5). This acidic environment has a dual part to play drug behavior. On the one hand, it increases the absorption and solubility of weakly basic drugs as it maintains them in an ionized and soluble state. Conversely, it may also result in degradation of acid labile drugs (e.g. penicillin, erythromycin and omeprazole) hence a diminished bioavailability. To curb this such drugs are usually formulated with enteric coatings or buffered systems that shield such drugs against gastric acid until their pH elevates to a more neutral value in the intestine.

Even though the surface area available in the stomach to facilitate absorption is small in comparison to that in the small intestine, stomach plays a crucial preparatory effect on drug disintegration and dissolution; two processes that determine the rate and the extent of drug absorption further along the digestive tract. One of the most significant factors influencing the oral drug bioavailability is the rate of gastric emptying, or the speed at which the stomach compartment is emptied into the small intestine. Quick removal of the gastric contents in the stomach aids in the faster absorption of drugs, whereas delayed emptying via fatty diets, individual drugs or stress may delay the absorption rates and block therapeutic action.

2.1.2.     Structure and Function of the Intestine

The convoluted intestine also comprising of the small and the large intestines is the central location of the absorption of drugs that are taken orally and thus, it is the main location where the medications are absorbed into the blood stream. The small intestine or the duodenum, jejunum and the ileum has a very specialized anatomical structure that is optimized to facilitate absorption. It has microvilli and villi on its inner lining, which are fingers that help in enlarging its surface area that can come into contact with the drug by a large margin, increasing its uptake. Besides this, the small intestine has a near-neutral pH (approximately 6 7. 5) environment and contains a large number of enzymes and transporter proteins, which both passively and actively absorb nutrients and pharmaceuticals hence.

Although the large intestine is less permeable and extensively covered in surface area than the small intestine, it also has a longer transit period and is beneficial as an absorption space to sustained- or controlled-release preparations. It is also favorable to some colon-delivering drug systems especially in the treatment of localized conditions like ulcerative colitis or Crohn disease.

In addition, the intestine has a rich blood supply and thus the speed with which drugs are absorbed in it is high causing immediate absorption of drugs in the hepatic portal system that carries it to the systemic circulation. Co-ordination of the motility, pH control, enzymatic activity, and structural characteristics all identify the degree, velocity, and constancy of drug uptake. The consequences of these physiological properties should warrant the development of oral dosages whose nature is likely to achieve the utmost bioavailability, predictable therapeutic and least interpatient variability.

The most important area of absorption is the small intestine which is divided into duodenum, jejunum and ileum. Its structure allows it to absorb a lot of surface area because of structural adaptations including villi, microvilli, and folds of Kerckring and therefore forming a massive absorptive interface. The gut mucosa supports almost neutral to slightly alkaline (6 7.5) pH which is a favorable condition of the dissolution and absorption of most weakly acid and weakly basic drugs. In addition, the small intestine has a lot of digestive enzymes and membrane transporters (P-glycoprotein and peptide transporter) that promote active and passive drug absorption.

Passive diffusion is still the single most common way of absorption, with lipid-soluble drugs absorption being facilitated by a concentration gradient across the intestinal membrane. However, some drugs, especially those that resemble nutrients or peptides, are carried out or actively taken up, that is, energy is necessary and a particular set of transport proteins. Intestinal motility, local blood circulation, and food are factors that can dramatically affect the rate of drug absorption in this area as well as its degree of absorption.

Although the large intestine (colon) is less permeable and has a smaller surface area, it also contributes to controlled-release drug delivery which is sustained and also controlled. It has a slower transit time, which permits extended contact of the drug with the absorptive mucosa and would hence be a desirable choice of formulation with an extended therapeutic action. As well, the large intestine contains a plentiful microflora that can enzymatically degrade particular drug vehicle which can be utilized to target the colon in cases of local disease, including ulcerative colitis and Crohn’s disease, and also in the treatment of colorectal cancer.

Simply put, the integrated activity of the stomach, small intestines and large intestines dictate the degree to which a drug is absorbed, and is made available in the systemic circulation. The pharmaceutical scientists can use this knowledge of the anatomy and physiology of the different segments of the intestine to come up with oral dosage forms which achieve the best bioavailability of the drug used, consistent pharmacological effects, and reduced interpersonal variation in the response to the drugs.

2.2. Factors Affecting Oral Drug Bioavailability

One of the pharmacokinetic parameters is oral bioavailability, which represents the ratio of the drug that was orally administered to reach the systemic circles in an unaltered and active form. It is basically a measure of the extent to which the dose that is given can be utilized to produce any given therapeutic effect. High oral bioavailability guarantees that the drug is directed to the target site to a sufficient concentration in comparison to low bioavailability which may impair efficacy or require excessive doses and even make some drugs inactive through administration by mouth.

Oral bioavailability depends on a number of factors. Physicochemical characteristics of the medicine, including solubility, permeability, lipophilicity, ionization (pKa), molecular size, and others are significant factors that help to define how easily the drug can dissolve in the gastrointestinal fluids, or cross the biological membranes. Poorly soluble drugs or those with undesired ionization at intestinal pH may have low bioavailability and therefore formulation options that include solubilization, salt complexation, or nanoparticles encapsulation should be considered to increase ease of absorption.

The effect of physiological factors of the gastrointestinal tract is influential also on the oral bioavailability. These are the gastric pH, gastric emptying charging, the intestinal motility, enzyme activities, concentration of bile salts and the presence of food or other medications. As an example, a growing fat meal has the potential to delay gastric emptying but has the potential to raise the lipophilic drugs and be better absorbed. On the other hand, fluctuations in intestinal outflow or enzyme activity may either speed up or slow down drug absorption, a fact which also plays a role in interindividual changes in the therapeutic response.

Lastly, formulation factors, such as dosage form, particle size, excipients, coating and release, may positively or negatively affect bioavailability. As an example, enteric coatings prevent degradation of acid-sensitive drugs in the stomach, and to sustain the plasma concentration of therapeutic levels of drugs, sustained-release preparations regulate the rate of absorption.

To sum it up, oral bioavailability can be considered the compound outcome of interacting complexities between drug characteristics, physiological status, and formulation design. These factors are important in which optimization is necessary to provide predictable absorption, steadfast plasma drugs, and dependable therapeutic efficacy. Oral bioavailability is also a central pillar in effective drug development and delivery, which is understood and controlled.

2.2.1.     Physicochemical Properties of the Drug

Physicochemical properties of any given drug constitute one of the most important determinants of the way a drug gets absorbed by mouth and general bioavailability. These properties determine the efficiency of the drug dissolved in gastrointestinal fluids, the intestinal epithelial crossing, and finally its subsequent entry into the active system through the active form. Inadequate optimization of physicochemical characteristics may result in the basis of subtherapeutic levels of drugs, unpredictable pharmacokinetics and inconsistent treatment, despite the inherent pharmacological effectiveness of the individual drug. These properties include solubility, pKa, molecular size and lipophilicity; they are known to be the most active in determining the pharmacokinetic properties of a drug and determine the formulation strategy.

The most basic condition of drug absorption into the body is arguably solubility. A drug should be able to dissolve in the aqueous environment of the gastrointestinal tract and then it could interrelate with the absorptive surfaces of the small intestine. Poorly soluble drugs tend to exhibit low or unpredictable bioavailability due to their low water solubility leading to irregular bioavailability and hence, bad therapeutic response. Pharmaceutical scientists use various strategies of formulations to tackle this challenge. As an example, the solubility of weak acids or bases can be enhanced by salt formation, whereas micronization and particle size can enhance the amount of surface area that can dissolve. It is further possible to use surfactants or solubilizing agents to increase the wettability and dissolution rates of drugs. Also, carriers developed by nanotechnology such as nanoparticles, nanocrystals, and liposomes allow poorly soluble drugs to be effectively administered in a dispersed or encapsulated state to enhance their solubility and absorption. All these strategies are intended to be used such that there is sufficient fraction of the orally given dose that will be bioavailable and thus increase therapeutic efficacy.

Another important variable of drug absorption is the pKa of the drug i.e. the ionization constant. The drugs exist in equilibrium with both ionized and unionized states, and such a balance is a strong factor of the pH of the environment. Subsequently, unionized form of a drug is more lipophilic which enables it to bypass lipid filled membranes with ease which are present in intestinal epithelial cells. The pK a of the drug vis-a-vis that of the local gastrointestinal pH therefore becomes the main determinant of the locus and effectiveness of absorption. An example is weakly acidic drugs like aspirin and ibuprofen mostly being absorbed in an acidic stomach and weakly basic drugs like ampicillin being absorbed more effectively in the near-neutral pH conditions of the small intestine. Knowledge of this relationship can be used to advantage formulation scientists to optimize drug design, e.g., by designing prodrugs that can alter ionization characteristics to improve their absorption at the desired location.

2.2.2.     Physiological Factors

Physiological states of the gastrointestinal (GI) tract are very critical towards the oral bioavailability of drugs. These are conditions that affect the rate, extent, and consistency of the absorption of drugs into the systemic circulation and thus they are very important factors when developing and optimizing the drug preparations via the oral route. Such crucial physiological variables are gastric emptying rate, intestinal motility, pH changes, enzymatic activities, bile release, inbound foodstuffs, and first-pass metabolism. Proper knowledge of these variables will enable the pharmaceutical scientists to predict the possible absorption problems and to shape dosage delivery methods that will optimize treatment responsiveness and reduce interpatient differences.

One of the greatest determinants of oral drug absorption is the rate at which the drug gets emptied into the stomach. It controls the speed with which a drug is absorbed by the small intestine which is the main site of absorption, where the dissolution process starts after it leaves the stomach. Slows in gastric emptying, such as that which follows high-fat food intakes, in dysfunctions such as gastroparesis, or when other drugs which slow gastric motility are used concomitantly, can dramatically delay the development of drug activity. Alternatively, the rapid gastric emptying may result in a rapid drug delivery to the intestine, which enhances the rate of absorption and results on a rapid occurrence of a therapeutic response. Certain formulations like gastroretentive systems are particularly aimed to extend the gastric residence time and enhance absorption of drugs that are absorbed in the stomach or higher part of the small intestine.

The intestinal motility is also of critical importance in determining the drug absorption since it determines the contact time of the drug with the absorptive surfaces. A very abnormal intestinal transit rate can decrease the absorption rate since the drug lacks enough time to diffuse across the intestinal mucosa. Reduced motility, conversely, may increase time to contact with the epithelium, which may increase uptake. Moreover, the normal intestinal contractions promote the mixing of the drug with the digestive fluids that lead to uniform distribution of the drug along the mucosal surface as well as more uniform absorption. Enteric-coated or sustained-release tablets are the most common example of modified-release formulations that utilize motility patterns to produce a long and predictable course of drug release.

Another significant factor that determines oral bioavailability is the pH gradient along the GI tract. Local pH is very important in determining drug solubility and ionization thereby, determining whether the drug will be able to cross lipid membranes or not. Although it is difficult to quantify this phenomenon, weakly acidic drugs (aspirin and non-steroidal anti-inflammatory drugs) are better absorbed in the acidic environment (pH 1.53.5) of the stomach, and weakly basic drugs (ampicillin or metoprolol) are better absorbed in the near-neutral slightly more distinct alkaline pH (67.5) of the small intestine. Changes in GI pH due to disease conditions, other concomitant drugs or dietary intake can thus cause significant changes in the share of the drug in its unionized, membrane-permeable form, and can result in differing efficacy of absorption and systemic exposure.

The effect of oral drug bioavailability is also significantly influenced by enzyme activity in the GI tract. Drugs may be degraded by hydrolytic enzymes, proteases as well as metabolic enzymes which are found in the intestinal lumen and mucosa before they are absorbed. An example is the insulin, or vasopressin, which enzyme hydrolysis is most likely to cause and extremely decreases both the oral bioavailability of peptide and protein drugs. Methods that include enzyme inhibitors, enteric coating, and nanoparticles encapsulation are one of the common mechanisms used to make sure drugs are not broken down by enzymes and make sure that a therapeutically effective portion of the drug gets into the bloodstream.

2.3.First-Pass Metabolism and Enzymatic Barriers

Oral drugs have to overcome a number of biological and metabolic barriers before they are converted into an active form and localized into the systemic circulation. The most important of these obstacles is first-pass metabolism, sometimes called presystemic metabolism. This mechanism takes place mainly in the liver, but the intestinal wall is more or less a contributory factor. In the process of first-pass metabolism, some of the taken drug is subjected to an enzyme conversion to produce inactive metabolites before it enters the bloodstream. This could lead to a significant decrease in systemic availability of the active drug potentially undermining therapeutic efficacy when not addressed when developing a formulation. Propranol, morphine, and nitroglycerin are familiar examples of drugs with high first-pass rates, and frequently high oral doses or alternative routes of administration are needed to attain the desirable plasma levels of these drugs.

Besides hepatic metabolism, other challenge to oral delivery is enzyme degradation in the gastrointestinal tract. Prone drugs, including peptides, proteins, and other heat sensitive ones, can be broken down by digestive enzymes, including peptidases, proteases and esterases, prior to absorption. Considering the example of orally administered insulin and vasopressin, virtually all of them are broken down in the GI tract, and therefore, they are absorbed minimally into the system. Due to this enzyme-mediated degradation, and the initial metabolism on first pass by the liver, this is very protective to oral delivery, especially of drugs with low inherent stability or with high vulnerability to enzymatic activity.

In order to overcome such metabolic and enzymatic problems, contemporary pharmaceutical methods utilize numerous formulation methods and chemical reactions. Prodrug design may alter temporarily the drug molecule so as to prevent enzyme degradation or first-pass metabolism. Enteric coatings shield drugs that are unstable to acids or enzymes in the stomach and release in the more neutral level of the small intestines. The inhibitors of enzymes may be used alongside to decrease the speed of presystemic metabolism, and new drug delivery systems, including nanoparticles, liposomes, and polymeric carriers, may be used to wrap the drug, increasing its stability, aiding absorption, and permitting controlled release.

With the combination of these methods, the pharmaceutical scientists will be able to reduce presystemic loss, improve oral bioavailability, ensure predictable plasma levels of medicines and eventually regulate the best therapeutic response. Profound knowledge of not only hepatic metabolism but also intestinal enzymatic activity will thus be imperative in the rational development of effective oral drug delivery systems.

2.3.1.     Hepatic First-Pass Effect

This is because the hepatic first-pass effect is a significant determinant of oral drug bioavailability that defines the high metabolism of a drug in the liver after absorption through the gastrointestinal tract but before entering the systemic circulation. When the drug is absorbed through the intestinal mucosa, it is transported to the hepatic portal vein and straight into the liver. In this case, the drug is chemically altered by a variety of metabolizing enzymes, such as the members of the cytochrome P450 (CYP450) family, esterases, transferases, and others, depending on the multiple processes, including oxidation, reduction, or conjugation.

This pre-systemic metabolism has the potential to significantly lower the unchanged medication concentration entering the systemic circulation, and hence reducing the therapeutic efficacy. Propranol, lidocaine, morphine, are all famous examples of the drugs whose hepatic first-pass metabolism is extensive and makes the oral bioavailability much lower than the one observed in parenteral assay.

First-pass metabolism, in the liver, is different in magnitude depending on a number of factors such as enzyme activity in the liver, hepatic blood flow, and affinity of the drug in enzymes metabolism. This effect may be further affected by variations in individual patients, age, genetic polymorphism, and diseases states.

In order to overcome or reduce the first-pass effect, pharmaceutical scientists are making use of all sorts of approaches. Prodrug design changes the active drug to metabolically stable precursor and is activated when the drug enters the system. To minimize metabolic degradation, enzyme inhibitors can be co-administered and other routes of delivery like transdermal, intravenous or sublingual are administered to bypass the liver to enhance systemic availability. These methods are essential in improving oral bioavailability, attainment of predictable plasma drug levels, and optimal therapeutic results.

2.3.2.     Intestinal Enzymatic Degradation

The intestinal mucosa is also important in the presystemic drug loss after oral administration besides hepatic clearance. A vast amortioselective range of metabolic enzymes including CYP3A4, esterases, peptidases, and glucuronidases are facilitated on the epithelial lining of the small intestine and are capable of metabolizing drugs before they are even delivered to the liver. This enzyme activity acts as a kind of natural protective barrier, stopping possibly harmful or xenobiotic components to be introduced into the systemic blood circulation. Nevertheless, it is the same defense mechanism which may unintentionally damage drugs that are therapeutically useful and lower their bioavailability to a level that impairs their effect.

A good example of such phenomenon is witnessed with the use of peptide-based drugs, including insulin, vasopressin, and some growth factors, which are greatly sensitive to proteolytic activity within the intestinal lumen. The activity of these enzymes is very fast in breaking peptide bonds, which leads to degradation of the drug molecules and the absorption through the oral route will be virtually zero. Likewise, small lipid soluble drugs can be influenced too; transit drugs via the gut intestines are metabolised by intestinal CYP450 enzyme, specifically CYP3A4 isoform, reducing the proportion of active drug which enters the systemic circulation before the liver undergoes a first-pass metabolism. Some examples of these are anticancer drugs, immunosuppressants, and steroids which, as a result of intestinal metabolism, exhibit decreased oral bioavailability.

In order to counter these shortcomings, the current pharmaceutical research has come up with new formulation techniques that provide protection to drugs against enzyme damages in the gastro-intestinal tract. One of such methods is enteric coatings, which provides a pH sensitive environment, adversaries which protect untimely exposure to gastric and intestinal enzymes and allows the drug to be absorbed at the necessary level of location. Co-administration of enzyme inhibitors may suppress temporary postponement of metabolic activity in the gut and therefore increase the proportion of the active drug to be absorbed. Moreover, the more complex nanocarrier-mediated delivery systems, e.g. liposomes, polymeric nanoparticles and solid lipid nanoparticles, physically entrap the drug, which increases the stability, solubility and permeability of the drug. Also, these systems can be used to deliver to specific regions of the intestine, and this increases the residence time and increases the efficiency of absorption.

Through these approaches, the pharmaceutical scientists are able to greatly reduce the presystemic enzymatic barrier, and, therefore, higher percentage of the drug given will be able to enter the systemic circulation in its active form. Not only is this better oral bioavailability, but there is also an increased therapeutic efficacy, lower dose requirement and less variability in patient response and, as a result, safer and more reliable oral drug therapy.

2.4.  Advantages and Limitations of Oral Delivery

Orally delivered drugs are the most preferred and commonly taken path when administering drugs in modern therapeutics. It is done orally, in which case the drug is absorbed through the gastrointestinal (GI) tract mainly in the systemic circulation. This is the most preferred route in clinical use because it is convenient, non-invasive, and easy to self-administration and, consequently, is applicable to a wide variety of patients including those of childhood, adulthood and the elderly. Oral administration also allows flexibility in relation to both acute treatments when fast acting of the treatment is needed and the long term treatment where repeating or prolonged dose is advantageous.

The use of oral delivery of drugs takes its popularity due to a number of benefits. It enhances a sense of compliance in a patient, because taking a pill or a capsule is usually not painful or complicated as compared to injections or other methods that can be invasive. It also provides flexibility in terms of formulations, immediate-release, sustained release, enteric coated as well as combination dosage forms, providing the opportunity to tailor it to the therapeutic requirements. Moreover, it was able to be delivered orally, manufactured inexpensively and it is also easy to store and be transported in contrast to parenteral formulations.

Nevertheless, regardless of its rampant use, oral drug delivery has considerable challenges that may influence the drug absorption, bioavailability, and therapeutic outcome. Variability in absorption is one of the major problems that can be caused by a difference in gastric emptying, intestinal motility, a food presence, which causes inconsistent plasma drug concentrations. Also due to enzyme activity drugs can degrade in the GI tract especially the enzyme peptide or protein based therapeutics which restrict their stability and the quantity of drug that can be absorbed. Furthermore, hepatic and intestinal mucosa first-pass metabolism can cause a major change within the proportion of active form of drug that may enter systemic circulation particularly in the instances of extremely vulnerable compounds, i.e., to hepatic or intestinal enzyme actions.

In order to circumvent these difficulties, pharmaceutical scientists have come up with improved formulation and delivery strategies. Such methods include enteric coating, sustained-release systems, nanocarriers, and prodrug, which aim at preventing drug degradation, enhancing solubility, absorption, and avoiding or circumventing first-pass metabolism. Through a judicious combination of the physiological and physicochemical considerations that govern the oral drug delivery picking, effective oral dosage forms may be perfected that make the most of the therapeutic effect, reduce variability, and enhance patient outcome.

2.4.1.      Benefits: Convenience, Non-invasiveness, and Patient Compliance

Among the major benefits of oral drug delivery, its unsurpassed convenience is the one that is of crucial importance in the general acceptance of the route at a large scale in clinical practice. Oral route enables the patients to administer the drugs easily without skills, medical attention or use of sterile materials. This aspect is especially useful regarding outpatient care, home-based treatment, and long-term treatments since the contact with healthcare specialists may be insufficient. Tablets, capsules, syrups and suspensions are more practical as oral dosage forms are very easy to administer and also simple to prepare, package, store and even transportation since they can be distributed by such ways on a large scale in healthcare systems around the world.

Orally administered drugs are also non-invasive, which makes them even more attractive. Oral delivery, in contrast to parenteral routes, including intravenous, intramuscular, or subcutaneous injections, does not use needles, which makes the procedure less painful to patients, less likely to cause infections, and less likely to result in adverse effects, such as the damage of surrounding tissues. This is particularly useful in pediatrics and geriatrics and to patients with chronic therapy who need frequent dosing in the long term. Psychologically, patients tend to swallow a pill or a liquid than engage in invasive treatment, which enhances adherence and acceptability in the administration of a regimen.

The other key benefit of oral delivery is the fact that it leads to improvement of patient compliance. The ease, non-invasiveness, and convenience of oral medication usage into the day to day activities of the patients is highly likely to sustain the propensity of the patients adhering to the dosing schedules of the medications that are supposed to be taken. Enhanced compliance is directly applied into enhanced treatment outputs, lowering chances of failure or advancement of treatment. Besides, different drug release technologies can be designed with oral preparations, which makes it possible to have flexibility in the dosing strategies. Quick-acting preparations can be used instead of other types to offer fast effects when required, but controlled-release, sustained-release, or enteric-coated preparations will offer the benefit of stable plasma drug concentrations over a long duration, reduced variability, and enhanced overall effectiveness.

Moreover, combination therapies can be administered orally, thus improving the effectiveness of treatment and decreasing the number of pills the patients on complicated regimes need to take. It would also allow the chance of taste-masked or flavored preparations, which are better accepted, especially by children. All these factors combine to make oral drug delivery one of the most user-friendly, convenient, and widespread approaches to delivering medications, as the backbone of the current-day pharmacotherapy, and one of the primary factors in the success of the acute and chronic treatment regimen.

2.4.2.      Limitations: Variable Absorption, First-Pass Metabolism, and Delayed Onset

Although it is used widely with many benefits, oral drug delivery is not applicable in all situations of drugs and therapy. Variable absorption is one of the major issues, and it may result in inconsistent plasma drug concentrations and unpredictable treatment results. Various physiological and external factors such as gaseous pH, intestinal motility, eating, stomach gas and intestinal food interacting with other drugs, predispose absorption variability. As an illustration, certain drugs are better soluble and absorbed under acidic conditions of the stomach but others are fragile and decompose under acidic conditions. Likewise, food may either decrease or strengthen absorption dissimilarly to drug physicochemical characteristics thus introducing additional variation in bioavailability.

The second constraint of oral delivery is a first-pass metabolism interference. Once the drug is absorbed by the gastrointestinal tract it moves into the hepatic portal circulation and through the liver where metabolic enzymes, including the cytochrome P450 isoforms, can chemically alter or break down a large part of the biological reagent before entering the systemic circulation. This presystemic metabolism may significantly decrease bioavailability whereby larger doses are needed to attain the desired therapeutic effect, or alternative methods of delivery should be developed, e.g., sublingual, transdermal, and parenteral to achieve the same desired therapeutic effect.

Also, latent effect is a severe issue with respect to oral drugs, especially when it comes to emergency cases or acute care. Oral drugs, in contrast to intravenous administration, which avails the drug immediately in the blood stream, have to first disintegrate, dissolve, and be absorbed in the GI tract before they reach the effective plasma concentrations. Such time lag renders oral administration less appropriate to those conditions that demand fast pharmacological action, as in severe pain, myocardial infarction, or even acute allergic reactions.

On the whole, the mentioned limitations of oral drug delivery, such as fluctuating absorption rates, the first-pass effect, and delayed activation of action promote the latter approach to careful consideration of the peculiarities of drugs, patient requirements, and goals of therapy. In some cases, different routes of administration can be more suitable especially in some drugs or clinical conditions which will necessitate quick, dependable and effective treatments.

2.5. Patient Compliance and Formulation Requirements

Medication adherence, also known as patient compliance is the foundation of effective oral drug administration and as significant as the pharmacological effects of the drug upon which therapeutic results is to be achieved. There is no single medication, no matter how powerful and well designed it may be, without making its effect on the patient, when he or she does not adhere to the prescription set by the doctor. Inadequate compliance may lead to under effective plasma concentration, shortening effectiveness and increasing length of sickness. There are certain cases when treatment failure, disease aggravation, or severe complications can be observed due to the inconsistency of dosing especially in chronic diseases such as hypertension, diabetes, or cardiovascular diseases.

There is also wider public health implications with non-compliance. As an example, the inconsistent use of antibiotics or antiviral agents may favor the development of drug-resistant pathogen, making treatment more complex and reducing the possibilities of future treatment methods. In a similar fashion, inappropriate adherence to the use of drugs including epilepsy or HIV may result in the development of the disease and even lethal outcomes.

The factors that affect patient adherence include; patient dosage schedules, dosing frequency, side effects, flavours, and the physical attributes of dosage form (size, texture or ability to swallow). Also, psychological, societal and economic aspects including forgetfulness, lack of education on the treatment or financial limitations may further undermine adherence.

In order to manage these issues, pharmaceutical researchers and nurses target the design of formulations on the basis of patient-centered approaches and learning methods. Tactics like sustained- or controlled-release formulations, taste-masking, easy dosing schedules and easy-to-use dosage forms are aimed at enhancing compliance. In addition to that, the proper use of medications can be strengthened by patient counseling, reminders, and digital tools of adherence.

In short, compliance in patients is a key factor of therapeutic performance, which connects pharmacological performance to actual performance. By identifying and managing the factors that affect adherence, the formulators and clinicians will get the most out of oral drug therapy against what risks can be done due to poor or less adherence.

2.5.1.     Role of Taste, Size, and Dosage Form in Compliance

Organoleptic characteristics of a medication which include its flavor, aroma and feel are determinants of patients adhering to the medication, especially among the geriatric and pediatric groups. Drugs without a pleasant or sweet taste may deter regular intake that translates to omission of doses, intermittent intake and ultimately, the drug is losing its effectiveness as a treatment tool. To counter such difficulties, pharmaceutical scientists use diverse formulation methods including flavor masking, coating methods and microencapsulations that can make oral drugs less unacceptable to the patients.

Besides the taste, the size and shape of pills or capsules would also play an important role in the willingness and capability of patients to consume medication. Big or massive pills cause specific challenges to children, older people, and dysphagic (i.e. troubled with swallowing) patients. It increases the ease of administration and increases adherence by creating formulations that are easy to swallow like smaller smooth-coated pills, orally disintegrating tablets (ODTs), and liquid formulations that a patient can swallow without difficulty and without exerting much effort.

Dosage form also has an impact on the compliance and convenience. Alternatives to the traditional tablets are single-dose sachets, chewable pills and effervescent preparations, which are easy to administer and more acceptable by users. This is necessary more so in chronic diseases, which may include hypertension, diabetes, or cardiovascular diseases, where prolonged treatment is needed. Doses that lower the dosage schedule, cause few side effects and increase ease of administration can radically boost adherence so that patients obtain the desired therapeutic effects regularly.

In general, the consideration of organoleptic features, the shape of tablets, and the choice of dosage should be regarded as a central issue in pharmaceutics today, and it directly affects the adherence of the patient to the use of these drugs and the overall therapy. The taste, smell, touch, and feel of the drug are its organoleptic properties that have the potential to significantly impact the patient’s intention to religiously take drugs, especially among pediatric and geriatric groups. Unpleasant, bitter or irritating preparations can deter compliance leading to missing injections, non-optimal effects of treatment or even treatment failure. Pharmaceutical scientists will use the methods that include flavor masking, coating, microencapsulation as well as taste-modifying excipients in order to make oral medication much more palatable and friendlier to patients.

Besides that, even the physical appearance of tablets and capsules such as size, shape, hardness and disintegration are important too. Tablets with a size bigger than 10 mm or difficulty swallowing may become a challenge among patients with swallowing problems or chronically out of shape illnesses that may need the use of long-term medicine. Easy administration through the development of orodispersible tablets, mini-tablets, chew able formulations, and liquid dosage forms has increased the acceptability and compliance among various patients with dissimilarities.

2.5.2.     Strategies for Enhanced Oral Formulation (Sustained-Release, Enteric Coating, Nanoparticles)

In order to enhance patient compliance and therapeutic efficiency, there has been a growing focus on the laboratory drugs delivery technology in the contemporary pharmaceutical research. In comparison with the traditional dosage forms that release the drug instantly, these innovative systems are supposed to regulate the rate, the timing, and the place at which the drug will be released to ensure that the active pharmaceutical ingredient will reach the target site of action at the optimum concentration. These technologies reduce the low and high levels of conventional dosing by preserving the steady plasma levels of drugs that in turn mitigate the side effects of drugs in addition to improving the safety of drugs.

Among the developments is the sustained- or controlled-release formulation, where a drug is released slowly over some duration of time. This decreases the number of doses taken each day such as increased doses to one dose per day, hence it becomes easy to stick to the treatment schedule. There is also the positive aspect of controlled-release systems which offer more predictable pharmacokinetics, resulting in improved therapeutic outcomes and reduced complications with regard to varying concentrations of drug.

A targeted drug delivery is another critical strategy in which the drug is targeted to a specific tissue, organ or even the cell location. This enhances the therapeutic activity of the site of action with minimal side-effects on the body system and hence increases patient compliance. Some of the methods of achieving the targeting can be nanoparticles, liposomes, polymeric carriers and ligand-receptor mediated delivery systems.

Enteric coating is another strategy, which shields acid-sensitive drugs against degradation in the stomach and liberates them in the more neutral environment of the small bowel. These are mainly useful when dealing with drugs that are susceptible to gastric pH or drugs that are supposed to be absorbed into the intestines.

Together, these advanced formulation technologies not only boost therapeutic performance but also go a long way in enhancing patient convenience, adherence and quality of life immensely. Modern drug delivery systems are an illustration of the incorporation of the concept of precision medicine into the daily therapeutic context by focusing on the two causes, pharmacological and behavioral.

A method that has been used the most in this field is the sustained- or controlled-release formulation. As opposed to the traditional immediate-release dosage forms which release the drug load at once, sustained-release system enables the drug to be delivered slowly within a long duration. There are several positives with this design: it allows the dosing frequency to be lower and in many instances, once a day rather than several times a day, it is extremely beneficial to an individual receiving a chronic therapy. Sustained-release formulations eliminate the peaks and troughs of constant dosage regimens which cause adverse effects and lead to variations in therapeutic consistency by the maintenance of consistent plasma drug concentrations. These instances are long-acting pills containing cardiovascular drugs or long-acting pill-like analgesics.

Enteric coating is another important form of oral drug formulation method whose purpose is to protect drugs against the harsh acidic conditions of the stomach or the gastric irritation. Enteric coating refers to PH responsive polymers that will not be dissolved in the stomach but will dissolve in the relatively neutral small intestinal pH. This makes sure that the active drug is deposited in the most advantageous location of absorption which improves bioavailability and efficacy. Enteric coating is particularly, however not exclusively, necessary with acid-unstable drugs like omeprazole, which otherwise would be broken down in gastric acid, or with drugs which can be discomforting in the gut, like nonsteroidal anti-inflammatory drugs (NSAIDs).

Along with these traditional approaches, nanoparticle-based drugs delivery systems are an innovative breakthrough on the fronts of oral pharmacotherapy. Nanoparticles have the capability of enhancing solubility, stability as well as bioavailability especially to drugs that do not dissolve readily in water. They have small size and high surface area which enables their enhanced absorption by gastrointestinal tract. In addition, nanoparticles may be designed to be delivered specifically to a tissue or cell type with high therapeutic effect and reduced exposure to the host system and side effects. Liposomes, polymeric nanoparticles, and solid lipid nanoparticles are some of the techniques to which precise delivery of drugs, reduced dosing frequency, and enhanced adherence in patients are increasingly being carried out.

All of these modern formulation approaches, including sustained-release or controlled-release systems, enteric coatings, and nanoparticle delivery, point to the continuing efforts of the pharmaceutical industry in terms of precision, efficiency, and patient-centered design. The new improved systems as opposed to the traditional dosage forms, which do not slow down clarifying the hours when the drugs are released and in most cases, randomizes them, the new improved systems are strategically designed, allowing the active ingredient to be delivered to its target site in the body at the most appropriate concentration. Such control does not only achieve better therapeutic performance due to the maximization of efficacy and reduction of toxicity, but it also causes less spikes in plasma drug concentrations, this has also been found to cause side effects or poor treatment response.

 REFERENCES

1.     Alqahtani, M. S., Kazi, M., Alsenaidy, M. A., & Ahmad, M. Z. (2021). Advances in oral drug delivery. Frontiers in pharmacology, 12, 618411.

2.     Alshawwa, S. Z., Kassem, A. A., Farid, R. M., Mostafa, S. K., & Labib, G. S. (2022). Nanocarrier drug delivery systems: characterization, limitations, future perspectives and implementation of artificial intelligence. Pharmaceutics, 14(4), 883.

3.     Amidon, S., Brown, J. E., & Dave, V. S. (2015). Colon-targeted oral drug delivery systems: design trends and approaches. Aaps Pharmscitech, 16(4), 731-741.

4.     Buya, A. B., Beloqui, A., Memvanga, P. B., & Préat, V. (2020). Self-nano-emulsifying drug-delivery systems: From the development to the current applications and challenges in oral drug delivery. Pharmaceutics, 12(12), 1194.

5.     Ezike, T. C., Okpala, U. S., Onoja, U. L., Nwike, C. P., Ezeako, E. C., Okpara, O. J., ... & Nwanguma, B. C. (2023). Advances in drug delivery systems, challenges and future directions. Heliyon, 9(6).

6.     Florek, J., Caillard, R., & Kleitz, F. (2017). Evaluation of mesoporous silica nanoparticles for oral drug delivery–current status and perspective of MSNs drug carriers. Nanoscale, 9(40), 15252-15277.

7.     Homayun, B., Lin, X., & Choi, H. J. (2019). Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics, 11(3), 129.

8.     Ita, K. (2017). Dissolving microneedles for transdermal drug delivery: Advances and challenges. Biomedicine & Pharmacotherapy, 93, 1116-1127.

9.     Jain, K. K. (2019). An overview of drug delivery systems. Drug delivery systems, 1-54.

10.  Keller, L. A., Merkel, O., & Popp, A. (2022). Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug delivery and translational research, 12(4), 735-757.

11.  Liu, L., Yao, W., Rao, Y., Lu, X., & Gao, J. (2017). pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms. Drug Delivery, 24(1), 569-581.

12.  Lou, J., Duan, H., Qin, Q., Teng, Z., Gan, F., Zhou, X., & Zhou, X. (2023). Advances in oral drug delivery systems: challenges and opportunities. Pharmaceutics, 15(2), 484.

13.  Mandal, U. K., Chatterjee, B., & Senjoti, F. G. (2016). Gastro-retentive drug delivery systems and their in vivo success: A recent update. Asian journal of pharmaceutical sciences, 11(5), 575-584.

14.  Newman, S. P. (2017). Drug delivery to the lungs: challenges and opportunities. Therapeutic delivery, 8(8), 647-661.

15.  Reinholz, J., Landfester, K., & Mailänder, V. (2018). The challenges of oral drug delivery via nanocarriers. Drug delivery, 25(1), 1694-1705.

16.  Singh, N., Joshi, A., Toor, A. P., & Verma, G. (2017). Drug delivery: advancements and challenges. In Nanostructures for drug delivery (pp. 865-886). Elsevier.

17.  Tewabe, A., Abate, A., Tamrie, M., Seyfu, A., & Abdela Siraj, E. (2021). Targeted drug delivery—from magic bullet to nanomedicine: principles, challenges, and future perspectives. Journal of Multidisciplinary Healthcare, 1711-1724.

18.  Vargason, A. M., Anselmo, A. C., & Mitragotri, S. (2021). The evolution of commercial drug delivery technologies. Nature biomedical engineering, 5(9), 951-967.

19.  Viswanathan, P., Muralidaran, Y., & Ragavan, G. (2017). Challenges in oral drug delivery: A nano-based strategy to overcome. In Nanostructures for oral medicine (pp. 173-201). Elsevier.

20.  Wang, B., Hu, L., & Siahaan, T. J. (Eds.). (2016). Drug delivery: principles and applications. John Wiley & Sons.