Chapter 3

Innovative Oral Drug Delivery Technologies

The SR and CR system operate mechanistically with various ways of controlling drug release. The diffusion-controlled systems are based on gradual movement of the drug by means of a polymeric matrix or a membrane, and can release the drug over hours or even days. The dissolution-controlled systems make use of a special coated or matrix that dictates the rate of the drug dissolution to generate an expected and steady release profile. Osmotic pump systems work on the basis of osmotic pressure, which supplies the drug in a constant rate irrespective of the pH and motility of the gastrointestinal tract among other physiological parameters. These advanced systems allow the tight regulation of drug delivery, enhance pharmacokinetic character and assist in the improvement of therapeutic results.

3.1. Sustained-Release and Controlled-Release Systems

Oral pharmacotherapy is often prescribed to maintain therapeutic drug levels within a narrow margin in the blood over prolonged periods of time to produce optimal pharmacological effects and better patient outcomes. Traditional immediate-release (IR) preparations like standard tablets, capsules or syrups normally deliver the active pharmaceutical ingredient quickly following ingestion. Although this fast absorption may give rapid action, it frequently causes extreme fluctuations in plasma drug levels with sharp elevation and then the rapid fall. These fluctuations do not only impair the therapeutic efficacy but also pose the risk of adverse effects or even toxicity especially in the case of drugs with a narrow therapeutic index. Moreover, due to the many doses needed to maintain effective plasma concentrations the continuous dosing may place a considerable burden on patients which negatively affects the adherence and in the overall success of treatment.

In order to overcome these shortcomings, sustained-release (SR) and controlled-release (CR) drug delivery systems have been produced. These high-technology systems are specifically programmed to control the rate of release of the drug contained in the dosage form, and thus control more stable and predictable plasma concentrations over time. SR and CR equations eliminate sharp peaks and valleys, and thus make the drugs stay within a therapeutic range rather than be sub-therapeutic or toxic in their long-term properties. Not only does this controlled release increase pharmacological efficacy, but also indicates that a large number of daily dose does not require taking the medication, therefore, making treatment regimens easier and more convenient to patients and enhancing adherence. These advantages come especially in chronic disease management, where a constant exposure to drugs is the key to good disease management, e.g., hypertension, diabetes, and chronic long-term pains.

Outside of pharmacokinetics, the use of SR and CR formulations greatly improves the quality of life in patients. All these systems decrease the rate of drug dosing and decreasing the variability of drug levels increases the workload of the complicated medication regimens, reduce occurrences of missed medications, and increase the rates of adherence. Improved efficacy, safety and convenience are interconnected factors that are crucial in the contemporary oral drug delivery system, especially through sustained- and controlled-release systems. Combining pharmacological accuracy and a patient-centered architecture, these novel formulations can be considered a significant improvement compared to the traditional immediate release product and can enable a better CAM outcome, as well as patient satisfaction.

3.1.1.      Mechanisms of Drug Release

Various complex mechanisms can be used to obtain drug release by sustained-release (SR) and controlled-release (CR) systems to regulate the rate at which the active pharmaceutical ingredient (API) can be released into the gastrointestinal tract. The selection of the release mechanism comes about due to the physicochemical characteristics of the drug and the intended release profile as well as therapeutic needs. Knowledge on such mechanisms is important in developing oral dosage formulations that can sustain patient therapeutic responses at set plasma drug concentrations, enhance compliance to therapy, and optimize patient adherence.

One of the best-known mechanisms which could be employed is diffusion-controlled systems. In such systems, the drug is incorporated in a polymeric matrix or is covered by a rate-controlling membrane. The medication spreads slowly into the gastrointestinal fluids via the polymer or membrane. The release rate depends on factors like the size of the molecules in the drug, its solubility, the porosity of the polymer as well as the thickness of the barrier. Examples are matrix tablet based on hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC), or based on hydrophobic polymers such as ethylcellulose in which the drug is allowed to diffuse more slowly over an extended period of time to produce sustained therapeutic effects.

Figure 3: Drug delivery for prevention and treatment of oral infection

The systems that are dissolution-controlled are based on the rate at which a drug or its carrier dissolves within the gastrointestinal environment. To make the dissolution process slow, coating, filmed, or granule is used so that drug is released gradually. This method is especially efficient when the drugs are of high solubility but are rapidly absorbed, this method avoids a sharp increase in blood concentrations and also keeps the concentration in the blood over a long-duration of treatment.

Diffusion-Controlled Systems: In diffusion-controlled SR/CR systems, the drug is constrained within a polymeric matrix or it is covered by a polymer coating. The release is through diffusion of the drug molecules through the polymer barrier into the surrounding biological fluids. Increase in rate of drug release depends on various factors which include diffusion coefficient of a drug, thickness and composition of polymer layer, area of enface of dosage form that is exposed to dissolution medium. Examples of hydrophilic matrices include swelling when exposed to the gastrointestinal fluids forming a gel layer through which the drug diffuses gradually whereas the hydrophobic ones release the drug via a formation of micropores. Others are matrix tablets and coated beads in which diffusion offers a predictable and extended diffusion pattern of the drug.

Dissolution-Controlled Systems: The rate of drug release which is relevant in dissolution-controlled systems is determined chiefly by the rate of dissolution of the drug itself, or its delivery system, in gastrointestinal fluids. In this case the drug can be made in form of coated granules, pellets or/and tablets where each coating determines the rate of dissolution and the rate at which the drug is made available due to a dissolution rate. The release profile of the drug is determined by the thickness, solubility and composition of the coating and drug particle size. It is especially beneficial in drugs that are better delivered in a gradual manner to sustain plasma levels in the therapeutic range without experiencing rose and fall side effects.

Osmotic Systems: Osmotic-controlled release systems are systems which are elucidated by the concept of osmosis and which offer highly predictable and near-zero-order drug release. The core of these systems is usually a drug containing mixture of osmotic agents, behind which is covered by a semi-permeable membrane that has a small delivery orifice. The gastrointestinal water diffuses through the membrane to the central location, and creates an osmotic pressure that forces the drug solution/suspension to push out through the opening at a constant rate. The process does not depend on gastrointestinal pH, gastrointestinal motility, or food intake to a large extent, allowing it to be particularly beneficial in the situation when the patient needs to be kept at a constant plasma concentration of the drug. Examples are osmotic pump pills that retain steady release of some drug 12 or 24 hours or longer.

Together, the mechanisms of drug release in these drugs allow achieving SR and CR functions, which improve therapeutic effects, limit dosing frequency, and decrease changes in plasma drug concentration. Pharmaceutical scientists can design efficient oral dosage forms that are both effective and safe by making a proper choice of the right release mechanism depending on the physicochemical characteristics of the drug, intended pharmacokinetic, and patient requirements.

3.1.2.      Advantages and Limitations

The sustained- and controlled-release (SR/CR)-type of drug delivery systems has transformed the concept of oral dispensing of drugs by providing a long-lasting, predictable and more consistent spectrum of drug therapeutic activity relative to established immediate-release formulations. These systems also ensure stable plasma drug levels during prolonged durations, by tightly controlling the amount of the drug released into the gastrointestinal tract, which leads to changes in the levels, with unwanted sub-therapeutic or even toxic outcomes. Controlled release does not only increase the pharmacological effect of drugs but also greatly increases the convenience of a patient, reducing the rate of dosing, which is consequently a major advance towards adherence and overall treatment success.

Although SR/CR formulations have obvious benefits, the process has certain difficulties, which should be considered in the development of the drug. To develop such systems, there must be careful regulation of the delivery kinetics of the drug, which may depend on the drug pH, motility, enzyme activity, and variability in the patient. Also, complicated formulation methods, possible dumping of the doses, and cost efficiency of production are significant factors. It is subsequently prudent that polymers, excipients and release mechanisms are carefully selected to obtain the desired therapeutic profile as well as safeguard, safeguard and reproducible the final dose structure.

Ø  Advantages:

Decrease in Dosing Frequency: The first quality that can be pointed out associated with SR/CR systems is a decrease in the doses per day. Conventional once-a-day immediate dosage formulations may necessitate several doses per day to maintain therapeutic levels in the patient, a process which can be inconvenient and may cause missed dosages. SR/CR systems progressively release the drug over time thus enabling a single or two doses per day, which increase the compliance rate of patients, particularly when used in the chronic disease management of hypertension, diabetes, and arthritis.

Constant Plasma levels: The system will offer a more stable drug concentration in the blood as opposed to traditional ones which will normally induce peaks and troughs in plasma levels. Constant plasma levels will prevent sub-therapeutic exposure, which can decrease the efficacy, and toxic peaks, which can cause adverse events. Such regular drug exposure enhances the safety profile and gives it sustained pharmacological activity.

Enhanced Therapeutic Efficacy: SR/CR systems achieve this by ensuring having the best drug concentrations in the body over long durations, which increases the total therapeutic effect. It is especially significant with drugs with narrow therapeutic index and drugs that cannot be effective without a constant plasma concentration like anti-arrhythmic drugs or anti-convulsants. The expected release profile will see the patient get the desired pharmacological effect without variations that may undermine treatment results.

Ø  Limitations:

Dose Dumping Risk: It is one of the most serious issues with SR/CR formulations and the risk of dose dumping could occur as a result, meaning the total dose of the drug is discharged nearly immediately, as compared to gradual slow rates. This may happen either because of defects in formulation, mechanical stress or through interaction with food, which might lead to acute toxicity. Here, strict quality control, sound formulation design, and patient education are needed to reduce this risk.

The Nonalignment of SR/CR Systems: SR/CR systems are developed under complex formulation techniques as using those methods as matrix systems, coated pellets, or osmotic pumps. During these processes, it demands special equipment, high-grade materials, and proper optimization of release kinetics, all of which make production both more complex and expensive. Furthermore, maintaining a steady output of manufacturing batches is a major problem.

Patient Variability: SR/CR systems can be subject to patient factors regardless of their careful design. Difference in gastrointestinal motility, pH, food availability or underlying disease conditions may influence the release of the drug and its absorption. As an illustration, gastric emptying can delay or hasten the transit time in the intestine, therefore, altering the target release profile and allowing reduced efficacy or more side effects.

3.2. Mucoadhesive Systems and Gastroretentive Technologies

The problem of retention of the drug in the stomach or upper gastrointestinal (GI) tract is one of the continuing problems of oral drug delivery to make sure of maximum absorption. Traditional forms of oral dosage, including immediate release tablets or capsules are frequently absorbed quickly through the stomach especially when the patient is fasting. The effect of this quick emptying of the stomach can be not adequately absorbing drugs with short absorption indices or whose solubility in intestinal fluids is poor, or which are mainly absorbed in the proximal small intestine. This premature transit may be detrimental to the therapeutic effect, require regular dosing, and may lead to inconsistent response in patients.

In order to surmount these drawbacks, new formulation technologies, i.e., mucoadhesive systems and gastroretentive technologies, have been invented. Mucoadhesive systems involve using special polymers that can stick to the mucosa of the stomach or upper intestine and therefore increase the absorption of time of the drug at the most apt location. The bioadhesion enables the release of drugs to be locally released directly at the point of their absorption, thereby improving the local drug concentration and systemic bioavailability. The mucoadhesion processes are complex, which embraces the swelling of the polymer on exposure to gastrointestinal fluids, hydrogen binding to the mucin glycoproteins and the entrapment of the polymer within the mucus network. Mucoadhesive systems have the benefit of providing more predictable drug absorption by being in close contact with the absorptive mucosa, and this is particularly beneficial to drugs that have a short half-life or a small absorption window.

Gastroretentive technologies as opposed attempt to fix the dosage form physically in the stomach over long durations to avoid early emptying of the stomach. A number of strategies are used to accomplish this impact. To prevent peristaltic clearance, floating systems use low density compounds to keep the dosage particle airborne on gastric fluid. Expandable gadgets are designed to bloat or extend once ingested to be larger to slow transit through the pyloric sphincter. Bioadhesive tablets are based on the theory of mucoadhesion and gastric retention by directly binding onto the gastric mucosa in order to increase the gastric retention time of the drug. Such techniques are particularly useful with drugs whose absorption is preferentially localized to the stomach or proximal small intestine, short-acting drugs or drugs with a local therapeutic effect, e.g. eradication of Helicobacter pylori with antibiotics or management of gastric ulcers with drugs.

Mucoadhesive Polymers and Mechanisms

A divergence of the situation is the mucoadhesive drug delivery system, which is an innovative technology in oral drug formulation, aimed at optimizing drug uptake and therapeutic advantage through the advantages of the natural adhesive characteristics of selected polymers. These systems attach to the mucosal lining of a gastrointestinal (GI) tract, both stomach and small intestine thus increasing the residence time of the drug at the site of the major absorption. It would be particularly useful with drugs that have a small absorption window, find destabilization in distal areas of the GIT, or are insoluble, where an existing oral dosage form may bypass the GIT too fast to be effectively absorbed.

Adhesion of mucoadhesive polymers to the mucus layer takes place because of a complex of different molecular interactions. Hydrogen bonding between the polymer and glycoproteins in the mucus, electrostatic bonding because of charges on the polymer and mucin, van der Waals forces, and physical entanglement are helpful in bringing about the development of a stable bond. When the polymer touches the gastric or intestinal fluids, it usually swells thereby raising its surface area as well as enhancing its sticking to the mucosal surface. This swaging also helps in the regulated and slow discharge of drugs, as the active pharmaceutical ingredient (API) is released and dispensed gradually over a period, and not in a burst.

This drug accumulates in the absorption site resulting in high local concentration of the drug and the systemic bioavailability of the drug is heightened because with the accumulation, a larger percentage of the dose administered has a chance to cross the epithelial membrane. Mucoadhesive systems are especially beneficial to drugs with short biological half-lives, so that they do not have to be administered frequently, and unstable drugs in the distal GIT which then avoid degradation.

Typical mucoadhesion polymers are carbomers, chitosan, hydroxypropyl methylcellulose (HPMC) as well as polycarbophil. Every polymer has defined properties, i.e., the swelling capacity, mucoadhesive strength, biodegradability, and compatibility with individual drugs, and these properties can be optimized by individual formulations to achieve optimal results. As an example, chitosan, a cationic polymer which has a high propensity to stick to negatively charged mucosal lining, offers low adhesion to negatively charged surfaces and allows the Control Drug release/swelling.

Gastroretentive Approaches

Gastroretentive drug delivery systems (GRDDS) GRDDS are highly advanced oral dosage systems that are designed to extend the retention of the drug in the stomach and, as such, promote either a controlled or sustained release of a therapeutic drug and also ensure that the drug concentrations are maintained locally in the stomach or systemically in the bloodstream. Such systems are specifically very useful when dealing with drugs with limited absorption in the small intestine, are insoluble in intestinal fluids or even have a short biological half life and would otherwise require giving a large number of dosages. GRDDS can extend or increase the gastric residence time thereby improving drug absorption, bioavailability, decrease dose administration and therefore patient compliance, which is essential in long-term therapies and chronic diseases.

A number of new techniques have been invented in order to lead to successful gastric retention. One of the most popular methods is the floating systems. They are developed on a basis of low density coefficients or gas developing agents allowing the dosage to be suspended on the gastric juices. The buoyancy supports the system to withstand the normal peristaltic activity that characterises the stomach to make sure that the drug is released gradually and in a controlled manner over a long time. Bioadhesive pills unite the concept of mucoadhesion and gastroretention by integrating polymers that cling onto the gastric mucosa and increase the period of contact, and stabilize the concentrations of the drugs at the absorption area. Another advanced method is expandable devices which are meant to swell, unfold or expand when in contact with gastric juices to become bigger thus are not allowed to pass through the pyloric sphincter at that point. This process of mechanical retention delivers an extended gastric residence duration to improve drug release into the stomach and small intestine.

3.3. Use of Biodegradable Polymers in Oral Formulations

Original biodegradable polymers have become the backbone of the modern era of oral drug delivery, because of their incredible capacity to be broken down to non-toxic biocompatible products, including water, carbon dioxide and simple metabolites, in the gastrointestinal tract. These polymers serve as multipurpose vectors which not only transport drugs, but also enable controlled delivery of the drugs, enzyme and acidic resistance, as well as targeted delivery to certain regions of the intestines of specific areas in a few instances. Formulation scientists can closely adjust the pharmacokinetic profile of a drug by paying close attention to the means of selecting the polymer to use, with careful fashioning of which molecular weight, hydrophilicity, degradation rate, mechanical strength and stability affect the rate of the therapeutic effective concentration of a drug reaching the systemic circulation due to a careful choice.

One of the significant strengths of biodegradable polymers is their ability to give slow and controlled release of drugs. On loading a drug on a polymer, the drug will be delivered at a slow rate as the polymer decays leading to more time spent exposing the drug at the site of absorption. This slow absorption reduces the aspects of peaks and troughs of plasma drug concentrations seen with immediate-release preparations, decreases the number of doses and enhances the compliance of the patient, especially in chronic illnesses like diabetes, hypertension or pain medicine. Moreover, the labile and delicate molecules, such as peptides, proteins, nucleic acids, and less soluble drugs, can be safeguarded with biodegradable polymers and prevented to be destroyed under adverse conditions of the gastrointestinal tract: harsh gastric conditions, enzyme breakdown, and fast metabolism in the upper gastrointestinal tract. This shield increases the oral bioavailability and the percentage of dose given out is absorbed into the systemic circulation in an active form.

There are two broad areas of biodegradable polymers namely natural and synthetic. It also prefers natural polymers, including chitosan, alginate, gelatin and dextran, because of their intrinsic biocompatibility, low toxicity and occasionally inherent mucoadhesive behavior which may also increase the residence time of drugs in the gastrointestinal tract. They are broken down enzymatically into harmless metabolites, e.g. sugars or amino acids and are especially appropriate in sensitive molecules or pediatric and geriatric preparations. Artificial polymers such as poly (lactic-co-glycolic acid) (PLGA), polyplacetic acid (PLA), polycaprolactone (PCL) and polyglycolic acid (PGA) offer further stability of degradation rates and mechanical properties as well as drug release characteristics. These polymers may also be designed to degrade within hours, days or even weeks to provide precise temporal control of drug release and enable more complex delivery methods like pulsatile, site-specific or targeted intestinal release.

3.3.1.  Types of Biodegradable Polymers

The use of biodegradable polymers in oral delivery of drugs can be mainly divided into natural and synthetic types which provide different benefits depending on a specific treatment objective.

Some examples of natural polymers are chitosan, algae, gelatin, and dextran. These polymers are innately biocompatible, non-toxic and may be mucoadhesive and this means that the residence time of a drug in its absorption site in the gastrointestinal tract may be greatly extended. Their enzymatic degradability means that they are broken into harmful byproducts to the body- amino acids, sugars or oligosaccharides- that are easily metabolized or eliminated by the body and so, there is no build-up or toxicity. Moreover, natural polymers have the ability to bind with mucus layer of gastrointestinal lining which leads to increased retention of drugs, better solubility, and increased uptaking of poorly bioavailable drugs. Their safety profile and biodegradability in particular are especially appealing in sensitive groups of patients, e.g., pediatric or geriatric patients, or labile molecules (peptides and proteins).

Synthetic polymers, conversely, including polylactic acid (PLA), polyglycolic acid (PGA) and a copolymer poly(lactic-co-glycolic acid) (PLGA), are more flexible in designs of drug delivery systems, and offer more control. Formulation scientists can precisely control the rate of degradation, mechanical strength and the kinetics of drug release by manipulating polymer composition, molecular weight, or monomer content, whether in copolymer, monopolymers, etc. The ease of this tunability makes synthetic polymers particularly appropriate to sustained/targeted /controlled-release deliveries, as well as to safeguard sensitive drugs during enzymatic activity and extreme gastrointestinal environments. They can be designed to deliver the drug and sustain therapeutic plasma concentrations or deliver the drug to a particular region of the intestine, which allows them to achieve the best pharmacokinetic and pharmacodynamic characteristics.

Various factors are critical in the decision-making between natural and synthetic polymers based on the selected profile of drug release, stability of drug, targeted delivery of therapies to specific sites in the body and the consideration of patient safety. A mixture of both natural and synthetic polymers is utilized in most developed oral preparations to take advantage of the benefits of each: natural polymers have biocompatibility and mucoadhesive characteristics, whereas synthetic polymers can be tuned to degrade and exhibit mechanical properties. This synergistic solution enables very versatile delivery systems that can overcome the barriers, as well as enhance bioavailability, and therapeutic effects.

All together, biodegradable polymers have been found to be essential constituents of the contemporary oral drug delivery systems due to their versatility and functionality aspect. They are essential in coming up with formulations in drugs of poor solubility, which have short half-lives or highly gastrointestinal degradation to provide more effective, safer and accessible treatments to patients.

3.3.1.      Applications in Drug Delivery

Bio-degradable polymers are becoming a significant pillar of the contemporary delivery of drugs to the mouth due to incredible versatility and the capacity to greatly enhance treatment effectiveness. Controlled or sustained-release (CR/SR) formulations are among the most notable uses of such polymers in which the drug is incorporated as a polymeric network, which then decomposes in a predetermined duration. This is a regulated breakdown which enables the drug to be released steadily which ensures that the plasma levels remain constant over a period of time. CR/SR systems also minimize the occurrence of sub-therapeutic effect or toxicity by eliminating rapid rises and falls of the conventional immediate-release formulations, enhance treatment efficacy, and increase patient convenience. The lower dosage rate of these systems also enhances compliance especially in patients who have chronic illnesses like high blood pressure, diabetes or heart diseases and may thus require long term treatment.

Targeted intestinal delivery is another important use of biodegradable polymers to overcome the difficulty in drugs which are either unstable or destroyed during the acidic conditions of the stomach. Some drugs, especially peptides, proteins or acid labile small molecules can also be severely degraded prior to hitting the site of absorption; this reduces bioavailability. Formulations can deliver the active drug to the target location by either designing polymers that are resistant to gastric acid and degrade under certain conditions at a specific location in the intestines - such as pH-responding, or enzyme-sensitive polymers - or activating active drug with a signal of the target location. Examples of this approach include enteric-coated polymeric capsules, nanoparticles or tablets, so that acid-sensitive compounds are not destroyed by gastric acid during transit and are effectively released in the large or small intestine. Such a focused system is focused on maximizing therapeutic efficacy as well as reducing systemic side effects since the drug release is limited to the desired absorption site.

The biodegradable polymers are also important in increasing the bioavailability of poorly soluble or unstable drugs. Numerous therapeutic agents are low-water solubility or weak to enzymatic breakdown in the gastrointestinal tract and can have a profound negative effect on the absorption and therapeutic efficacy. Precise inclusion of these drugs into polymeric, nanoparticles or microparticles may enhance the solubility, offer an enzymatic barrier against degradation, or prevent chemical degradation, and ease their penetration over the intestinal epithelium. The polymer-based delivery systems are specifically beneficial when dealing with peptides, proteins, lipophilic small molecules and other problematic drug candidates, since they can be administered orally, a more favorable delivery method because it is convenient and patients tolerate it.

3.4. Nanotechnology in Oral Delivery

Nanotechnology has had important impact on oral drug delivery, with introduction of nanoscale of carriers that has the capability of increasing therapeutic effects, protecting labile drugs and also facilitating specific targeting in the gastrointestinal tract. Nanocarriers with a size range of 1-1000 nanometers have specific physicochemical characteristics including having a high surface area to volume proportion, adjustable surface chemistry, and the ability to carry both hydrophilic and hydrophobic molecules, which makes them very useful in defeating the barriers of conventional oral formulations.

Among the great benefits of nanocarrier, the enhancement of solubility and stability of poorly water-soluble drugs may be identified. Low aqueous solubility drugs are associated with unpredictable absorption and poor bioavailability. The potential to incorporate this information in nanoparticles, liposomes, solid lipid nanoparticles or polymeric nanocarriers provides enhanced solubility by increasing the surface area and rate of dissolution which results in more uniform plasma drug concentrations. Besides, encapsulation shields drugs against enzyme degradation and adverse intestinal gastric environments, which is particularly useful with peptides, proteins, and nucleic acids which are otherwise rapidly broken down in the gastrointestinal tract.

It can also be used to release drugs with targeted and controlled nanocarriers. Drugs can be released overtime by changing particle size, surface charge, polymer composition, and ligand functionalization until targeted to particular areas of the intestine or even particular cell types. As an illustration, pH-reactive nanoparticles are capable of being stored in a hydrochloric environment as the stomach and discharging their cargo in a neutral environment at the small intestine to maximize uptake. Likewise, mucoadhesive nanoparticles have the ability to fix to the intestine mucosa to extend residence time and increase uptake.

3.4.1.     Types of Nanocarriers

Nanocarriers are highly adaptable systems that are used to bolster oral drug absorption, shield labile drugs as well as obtainable controlled or focused delivery. There are many different types of nanocarriers that are popular both in pharmaceutical research and practice, and each possesses their distinctive structural and functional features that are effective in the task of drug delivery.

Liposomes refer to spherical vesicles made up of phospholipid bi-layers (4) and may contain hydrophilic and lipophilic drugs. Hydrophilic molecules are found in the aqueous core, whereas the lipophilic drugs are found in the lipid diaphragm. Liposomes offer resistance to enzyme breakdown in the gastrointestinal tract and decreases drugs breakdown by acidic stomach conditions. Moreover, their lipid structure enables them to combine with the intestinal cell membranes and increase drug absorption through transcellular processes. Surface ligands can be functionally attached to liposomes to offer targeted delivery or polymer modified liposomes can be used to extend gastrointestinal retention.

Solid Lipid Nanoparticles (SLNs): these nanoparticles are lipid core particles made of solid lipid and stabilized by surfactants or emulsifiers. The controlled and sustained release of the drug is possible because of the solid matrix which is more stable than the conventional emulsions. SLNs enhance solubilization of poorly water-soluble drugs, prevent gastric deterioration of the drug and promote uptake by the lymphatic system, which avoids first-pass metabolism. The low cost and biocompatibility of SLNs with their large-scale manufacturability make SLNs appealing as candidates in clinical applications.

3.4.2.     Benefits and Challenges

Nanocarriers are highly adaptable systems that are used to bolster oral drug absorption, shield labile drugs as well as obtainable controlled or focused delivery. There are many different types of nanocarriers that are popular both in pharmaceutical research and practice, and each possesses their distinctive structural and functional features that are effective in the task of drug delivery.

Liposomes refer to spherical vesicles made up of phospholipid bi-layers (4) and may contain hydrophilic and lipophilic drugs. Hydrophilic molecules are found in the aqueous core, whereas the lipophilic drugs are found in the lipid diaphragm. Liposomes offer resistance to enzyme breakdown in the gastrointestinal tract and decreases drugs breakdown by acidic stomach conditions. Moreover, their lipid structure enables them to combine with the intestinal cell membranes and increase drug absorption through transcellular processes. Surface ligands can be functionally attached to liposomes to offer targeted delivery or polymer modified liposomes can be used to extend gastrointestinal retention.

Solid Lipid Nanoparticles (SLNs): these nanoparticles are lipid core particles made of solid lipid and stabilized by surfactants or emulsifiers. The controlled and sustained release of the drug is possible because of the solid matrix which is more stable than the conventional emulsions. SLNs enhance solubilization of poorly water-soluble drugs, prevent gastric deterioration of the drug and promote uptake by the lymphatic system, which avoids first-pass metabolism. The low cost and biocompatibility of SLNs with their large-scale manufacturability make SLNs appealing as candidates in clinical applications.

Polymeric Nanoparticles are made out of biodegradable polymer like poly(lactic-co-glycolic acid) (PLGA), chitosan or polycaprolactone. The kinetics of drug release can be controlled accurately between immediate and sustained release, depending upon polymer composition, particle size and rate of degradation using these nanoparticles. Polymeric nanoparticles can be surface-modified to hit in intestinal receptors or transporters to increase cellular absorption and decreased systemic exposure to off-target tissues. The targeting advantage is especially useful in drugs with a small therapeutic index or to drugs that are to be applied locally in the intestine.

This group of nanocarriers has the consequence of enhancing oral drug delivery, protecting its active pharmaceutical ingredient, improving solubility, enhancing intestinal absorption, providing controlled release, and/or enabling targeted delivery that overall leads to improved therapy outcomes and patient adherence. The choice is based on the physicochemical nature of the drug, release profile required, as well as the clinical goals in mind.

3.5. Case Studies: Oral Delivery of Poorly Soluble Drugs

Ineffective water solubility still remains as one of the strongest obstacles in oral drug delivery as it has a direct impact on the rate of drug dissolution, as well as, its absorption by the small intestine and finally its therapeutic effect. Drugs should dissolve initially in the gastrointestinal liquids, before absorption across the intestinal epithelium may occur and poor solubility may result in low, unpredictable and haphazard bioavailability. This is a major issue with newly developed chemical entities, many of which occur as Biopharmaceutics Classification System (BCS) Class II drugs. These compounds are typified by low solubility in water, but high permeability through the membrane, i.e. whilst they can be easily absorbed in solution, can be extremely limiting to oral absorption as far as adequate dissolution in the GI tract is concerned. Lack of dealing with solubility problems may lead to variable plasma concentrations, impaired therapeutic performance, and an increased inter-patient variability.

In order to overcome them, pharmaceutical researchers have come up with numerous sophisticated formulation approaches to improve their solubility, stability, and bioavailability. One of the most popular methods is nanoparticle formulation, in which the drug is downsized to within the nanoscale, which causes a very high increase in surface area, and results in a rapid increase in the dissolution rates. Not only does it make the drugs more soluble but it also increases drug absorption in the gastrointestinal tract. Another useful method is solid dispersions whereby poorly soluble drugs are dispersed through hydrophilic carrier matrices, enhancing the loss of crystallinity, promoting wettability as well as rapid dissolution. Cyclodextrin complexation is another approach, and the drug molecule is incorporated into the hydrophobic cavity of the cyclodextrin which enhances aqueous solubility, enzyme protection as well as preserving stability in the GI environment. More often than not, these methods can also be used together such as nanoparticles incorporated into a solid dispersion which would maximize the solubility and absorption based on the physicochemical properties of the drug and therapeutic objectives.

3.5.1. Strategies for Enhancing Solubility

The problem of low water solubility is one of the major obstacle of oral drug delivery since it directly affects dissolution rate, intestine absorption and subsequent therapeutic effects of a specific drug. To curb this problem, a number of developed formulation techniques have been designed to help in promoting solubility and oral bioavailability to achieve good systemic probability of poorly water-soluble drugs. Nanoparticle formulation has been one of the most popular and universal options among them. The drug in this process is scaled down to the nanoscale size which is between 1 and 1000 nanometers. This extreme decrease in the size of the particles results in a large proportional expansion in the surface area/volume ratio, and, based on the NoyesWhitney equation will join the rate of dissolution. Enhanced dissolution in gastrointestinal fluids leads to quicker and more effective gastrointestinal absorption across the intestinal mucosa with subsequent higher and more consistent systemic concentrations of drug. In addition to downsizing, nanoparticles may also be surface-functionalized with polymer coatings, PEGylation or targeting ligands to improve stability, reduce early degradation, increase mucoadhesion and uptake in specific areas of the gastrointestinal tract to further optimize bioavailability.

The other notable approach is solid dispersions in which the drug that is poorly soluble is molecularly or amorphously dispersed in an aqueous polymer like polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC). The process improves drug wettability, crystallinity, and usually, remains the drug amorphous, which promotes faster dissolution and further absorption. Besides, labile drugs can be preserved in solid dispersions and not be damaged by acidic pH, enzymes or oxidation in the gastrointestinal tract. Solid dispersions offer a greater chance of attaining the therapeutic plasma concentrations by maintaining the presence of a large proportion of the drug in a readily absorbable form.

Another popular method, which is employed to increase solubility, stability, and biovailability, is cyclodextrin complexation. Cyclodextrins are cyclic oligosaccharides that have an outer hydrophilic and an inner hydrophobic cavity. Particularly insoluble or lipophilic drugs may give rise to creating an inclusion complex within the cavity of the cyclodextrin, which actually increases aqueous solubility and ensures that the drug is not susceptible of being degraded by chemicals or enzymes of gastrointestinal tract. The methodology is especially useful with drugs that may be exposed to hydrolysis, oxidation, or any other form of instability during GI tract.

3.5.2.  Examples of Successful Oral Formulations

Some of the ill-solubility drugs have been effectively created to be taken orally through the adoption of the complex methods of enhancing solubility, and this has shown remarkable effects of the formulation methods on clinical treatment. Curcumin is a naturally occurring polyphenolic agent that is highly affected by oral delivery because of its very low solubility in aqueous solutions, fast metabolism, and low stability in the gastrointestinal tract with high limitations. Traditional preparations of curcumin lead to low levels of systemic absorption limiting its clinical efficacy even with its pharmacological relevance. In order to overcome these, curcumin has been integrated into nanoparticle-based delivery systems and cyclodextrin inclusion complexes resulting in significant increases in its dissolute and rapid dissolution as well as stability. Nanoparticles expand the surface area during which dissolution may occur and could prevent acidosis of enzymes in the GI tract and cyclodextrins create hydrophilic pits around the lipophilic drug, which enhance solubility and reduce early metabolism. These high level formulations facilitate adequate absorption into the systemic circulation so that therapeutic plasma levels are obtained to produce effective clinical results.

Another drug that has been significantly impaired because of poor water solubility and extensive first-pass metabolism in the oral route administration is paclitaxel, which is a powerful chemotherapy drug used in the treatment of different types of cancers. When administered orally, paclitaxel is lowly soluble in gastrointestinal fluids, and results in intermittent absorption and reduction of the therapeutic plasma concentrations on sub-therapies. To overcome these barriers, advanced agencies of formulating including solid dispersions and nanocarrier-based delivery systems such as polymeric nanoparticles and lipid-based delivery systems have been used. The solid dispersions enhance the wettability, decreased crystallinity and the amorphous behavior of the drug to dissolve better. Nanocarriers on the other hand can help to counteract enzymatic dissolution of paclitaxel, aid its delivery through the intestinal epithelium and can be designed to target the delivery at the site where the drug is required hence enhancing bioavailability. These innovations enable the therapeutically relevant plasma concentrations of paclitaxel to be obtained by the oral administration of the drug as a safer and user-friendlier therapeutic approach compared with intravenous therapy.

The lipid-lowering agent fenofibrate that is applied in the control of hypertriglyceridemia and dyslipidemia is also a medication that faces big solubility issues. As a Class II drug according to the Biopharmaceutics Classification System (BCS), fenofibrate has a low water solubility and displays low absorption as well as unpredictable efficacy. In a bid to increase oral bioavailability there have been formulation strategies like micronization so that the particle size decreases to increase its surface area and dissolution rate and lipid based delivery systems that increase solubilization in the gastrointestinal fluids. The strategies will make sure that the plasma concentration of fenofibrate is kept at therapeutic levels at all times, eliminating inter-patient variability and improving clinical outcomes. The oral therapy is more effective and reliable as lipid-based systems do not degrade the drug, enhance the rate and extent of intestinal absorption, and make it more effective.

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