Controlled Drug Delivery Systems: Current Status and Future Directions
Dosage Form Composition
Every dosage form combines a drug/active pharmaceutical ingredient (API) with non-drug components called excipients/additives (Figure 1). APIs are the actual chemical components that treat diseases [2].
Need for a Dosage Form
Drug delivery systems (DDS) are preferred because direct clinical use of APIs is rare due to several reasons:
API handling and accurate dosing can be difficult for very potent drugs (e.g., low mg and µg doses) [3].
Administration of drugs into body cavities (rectal, vaginal) can be impractical and they can be degraded at the site of administration (e.g., low pH in the stomach) and may cause local irritations or injury when the drug concentration is high at the site of administration [3].
Some APIs are sensitive to the environment and can benefit from reduced exposure to environmental factors (light, moisture, temperature, and pH), or they need chemical stabilization due to inherent chemical instability.
APIs mostly have unpleasant organoleptic qualities (taste, smell, and compliance), which reduce patient compliance [2].
Hence, APIs are always formulated along with excipients.
Excipients/Additives
Excipients/Additives are used:
To give a particular structure and shape to the formulation.
To increase stability.
To mask the bitter taste and increase palatability.
To bulk up formulations that contain very potent active ingredients.
To allow for convenient and accurate dosage.
To aid in the handling of the active substance.
To aid in the manufacturing process [4].
In addition, excipients enhance bioavailability and improve the overall safety or function of the dosage form during storage or in use with enhanced patient acceptability [5].
Excipients
One or more of the excipients generally utilized in formulations include: coloring agents, suspending agents, binding agents, solvents, and lubricants, perfumes, sweetening agents, flavoring agents, solubilizing agents, and antioxidants [4].
A filler is included to increase the size of the tablet (e.g., lactose) as often the amount of "active ingredient" is so small that the dosage form would be too tiny to handle without filler.
Binders are added to hold the tablet together after it has been compressed and prevent the breakdown into separate pieces (e.g., starch, HPMC, etc.) [6].
Disintegrants help the dosage form to break down into small fragments after ingestion, which allows the medicine to dissolve and be absorbed by the body, so it can act more rapidly [6].
The glidants prevent lump formation by reducing the friction between particles and improving the flowability of the tablet granules or powder.
Anti-adherents stop the powder from sticking to the machines during manufacturing.
Lubricants ensure the smooth surface of the dosage form by reducing the friction between the walls of the tablets and the die cavity during ejection.
Flavoring agents help to mask the unpleasant odor, and colorants are added to aid in recognition and aesthetics [7].
Biopharmaceutics Classification System (BCS) Classification of Drugs
The Biopharmaceutics Classification System classifies drugs into four types based on their permeability (intestinal) and solubility (Figure 2) [8].
Class I: High permeability and high solubility; well absorbed; absorption rate is greater than excretion (e.g., metoprolol, paracetamol, etc.).
Class II: High permeability but low solubility; bioavailability is restricted by their rate of solvation (e.g., glibenclamide, aceclofenac, etc.).
Class III: Low permeability but high solubility where the drug solvates quickly; nevertheless, absorption is limited by the rate of permeation. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied (e.g., cimetidine).
Class IV: Low permeability and low solubility; poorly absorbed through the intestine; thus, they have poor bioavailability with high variability (e.g., Bifonazole) [8].
Different Routes of Drug Administration
Dosage forms can be administered through different routes based on the target site, duration of treatment, and the physicochemical attributes of the drug [9]. The most common dosage forms comprise tablets, capsules, pills, ointments, syrups, and injections. Various routes of drug administration are tabulated in Table 1 and Figure 3.
The preferred route of drug administration depends on three main factors: the part of the body being treated, the way the drug works within the body, and the solubility and permeability of the drug. For example, certain drugs are prone to destruction by stomach acids after oral administration, resulting in poor bioavailability. Hence, they need to be given by the parenteral route instead. Intravenous administration of drugs gives 100% bioavailability [9].
Classification of Dosage Forms
The dosage forms are classified based on the route of administration, the origin of the compound (natural/synthetic), and the physical form of the final delivery systems (Figure 4).
Classification of Solid Dosage Forms
Solid dosage forms are further classified into two main categories based on the type of dose, i.e., unit dose and bulk dose.
(a) Unit dose: Each dose is fixed and formulated as a separate dosage form, and the patient needs to take a single unit of a specific dose at a time. Examples of unit dosage forms include tablets, capsules, pills, lozenges, chewable tablets, effervescent tablets, and dry powder inhalation in metered-dose containers.
(b) Bulk dose: As the name itself says, it is a bulk solid powder where the individual dose is not formulated (Figure 5) [10,11]. Dose dumping is a major problem with bulk powders. However, bulk powders are generally used as dressing powder for surgical and injury wounds. Examples of bulk dosage forms include insufflation powder, dressing powder, etc. [10].
Tablets
A tablet is a solid unit dosage form manufactured by compression and wet/dry granulation into different shapes (round, oval, or square shape). For efficient tableting, binders, glidants, and lubricants are often added as excipients. To enhance the easy breakdown of tablets in the digestive tract, disintegrants are added. The tablet coating with pigments, sweeteners, and flavoring agents helps to mask the taste of other ingredients and makes the tablet smoother and easier to swallow. Tablet coating also offers environmental protection and extends the shelf life [10,12].
Sublingual and Buccal tablets are also solid unit dosage forms administered by placing them under the tongue and between the gum and cheek, respectively. Advantages of sublingual/buccal delivery systems include:
The medications dissolve rapidly and are absorbed through the mucous membranes of the mouth into the systemic circulation.
This avoids the acid and enzymatic environment of the stomach and the drug-metabolizing enzymes of the liver [10,12].
Effervescent tablets are designed to evolve carbon dioxide when in contact with water and disintegrate within a few minutes. These are uncoated tablets consisting of acids (citric or tartaric acid) and carbonates or bicarbonates which react rapidly in water and release carbon dioxide. They are intended to be either dispersed or dissolved in water before intake to offer very rapid tablet dispersion and dissolution and release of the drug. It tastes similar to a carbonated drink (e.g., antacids).
Chewable tablets are chewed before swallowing. They are designed for administration to deliver the drug by mastication. They are very useful for children and the elderly (e.g., vitamin products) [10,12].
Capsules, Lozenges, Pills, and Granules
A capsule is a unit solid dosage form where the drug components are enclosed in a soluble shell. Capsules help to mask the unpleasant taste of their contents, and the drug has limited interaction with the excipients. Capsules are classified into two types: Hard-shelled capsules, which are used to encapsulate dry, powdered components, and soft-shelled capsules, principally used for hydrophobic drugs and oily active substances that are suspended or dissolved in oil.
Lozenges are chewable solid unit dosage forms, where the drug is loaded in a caramel base made up of sugar and gum; the latter provides cohesiveness and strength to the lozenge and enables slow release of the drug. Lozenges are traditionally used for local slow release of demulcents, anesthetics, and cough remedies in the mouth/pharynx.
Pills are solid unit dosage forms made by compressing API with adhesives and other excipients into rounded masses for oral administration.
Granules are solid, dry aggregates provided as a single-dose in sachets which can either be placed on the tongue and consumed with water or dissolved in water before taking (Figure 6h). Effervescent granules evolve carbon dioxide similar to effervescent tablets when added to water.
Bulk Solid Dosage Forms
Bulk Powders are multidose formulations comprising loose, solid, and dry particles of variable fineness. One or more active ingredients are present with or without excipients, and, if needed, coloring and flavoring agents are added. These are packed in wide-mouthed, airtight, bulk containers made of glass or plastic and are intended for either internal or external administration. There are two kinds of bulk powders intended for internal use.
Bulk powders are often limited by inaccurate dosage, since the patient measures each dose varyingly. Hence, they are usually formulated with non-potent drugs such as laxatives, antacids, purgatives, etc. The powder is then typically dispersed in water or dissolved before taking.
Divided powders are a single-dose of powder (for example, a small sachet) with more accurate control on dosage than bulk powder [10].
Semisolid Dosage Forms
Semisolid dosage forms are of semisolid consistency, intended to be applied onto skin/mucous membranes (nasal, vaginal or rectal cavities) for therapeutic, protective, or cosmetic applications. Semisolid dosage forms include ointments, creams, gel/jelly, lotions, pastes, suppositories, and transdermal patches (Figure 7 and Table 2) [13].
Semisolid dosage forms are used externally and locally at the target site, which reduces the probability of side effects. It is convenient for unconscious patients or patients who have difficulty in oral administration. It is a suitable dosage form for bitter drugs and more stable than liquid dosage forms [14].
Ointments
Ointments are oil-based semisolid formulations where the base is usually anhydrous and immiscible with skin secretions. These are made of less than 20% water and volatile substances, and more than 50% of hydrocarbons (waxes or polyols) as the vehicle, due to which retention time for ointments is high and spread-ability is less. Hence, ointments may be used as emollients or to apply suspended or soluble drugs to the smaller portions of skin for a longer duration [14,15].
Creams
Creams are relatively soft, easy to spread, semisolid dosage forms which often contain more than 20% water and volatile substances and less than 50% hydrocarbons (waxes or polyols) as the base for the drugs. Cream bases are emulsions that are classified into two types: Oil-in-water (O/W) creams and water-in-oil (W/O) creams.
Oil-in-water (O/W) creams are comprised of small oil globules dispersed in a continuous aqueous phase stabilized by surfactants [15]. Oil-in-water creams are more cosmetically tolerable as they are less greasy and simply washed off using water.
Water-in-oil (W/O) creams are comprised of small droplets of water dispersed in a continuous oily phase. Hydrophobic drugs can easily be incorporated into W/O creams and are also more moisturizing than O/W creams as they offer an oily barrier to prevent moisture loss from the outermost layer of the skin, the stratum corneum [14].
Gels (Jellies) and Lotions
Gels are semisolid systems in which the liquid phase is confined in a 3D polymeric matrix (made up of natural or synthetic gums) with a high degree of physical or chemical cross-linking [16]. They are used in medicine, in cosmetics, for lubricating purposes, and also as a drug carrier for spermicides used in the vagina [14].
A lotion is an aqueous fluid preparation for external use without friction. They are applied to the skin directly or poured on a suitable dressing and covered with a waterproof dressing to reduce evaporation [14].
Pastes
A paste is basically an ointment with a high percentage of insoluble solids added. A large amount of particulate matter stiffens the system. As compared to the ointment, paste has lower permeability, lower maceration, and lower heat. When applied to the skin, they form a good protective barrier [15]. The solids they contain can absorb and therefore neutralize certain harmful chemicals before they reach the skin. Like the ointment, the paste forms a complete film that is relatively impermeable to water [16]. Unlike the ointment, the film is opaque, so it can be used as an effective sunscreen. Since the fluid hydrocarbon fraction is absorbed by the particles, the paste is less greasy [14].
Transdermal Patches
A transdermal patch or skin patch is an adhesive drug patch placed on the skin to deliver a specific dose of drug into the blood through the skin. For patients who cannot take oral dosage forms or oral medications that cause intolerable side effects, the use of transdermal patches is strongly recommended as a treatment option [17]. However, this is not an appropriate method to control acute pain or clinical situations that require rapid titration of the drug.
The transdermal patch is made up of a backing film, which is the outermost layer of the patch and provides protection for the drug components. The second layer consists of a drug contained in a film or adhesive. The membrane is a thin film that controls the diffusion rate of the drug from the patch to the skin. The adhesive layer helps the patch adhere to the skin [18]. As a functional layer or outer lining, the film-coated tape is directly integrated into the patch design. The release liner protects the sticky side of the patch which is going to be in contact with the skin and is removed before applying the patch to the skin [19].
Transdermal patches are classified into four types based on the drug loading type: Matrix, reservoir, multilaminate, and drug-in-adhesive. The first type is a single-layer/multi-layer drug-in-adhesive transdermal patch, in which the drug is directly incorporated into the adhesive; the second type has a separate drug-containing layer, which is considered to be a drug reservoir; the third, called matrix transdermal patches, has a drug layer comprising a semisolid matrix containing a drug solution or suspension; and the fourth one is multilaminate having different layers of drugs (Figure 8).
The molecular weight of the drug should be less than 500 Daltons to formulate as a transdermal patch. The drug should be sufficiently lipophilic for easy permeation through the skin. The dosage of the drug depends on the duration for which the patch is worn. The first commercially available patch was scopolamine for motion sickness [20].
Suppositories
A suppository is a small, round or cone-shaped semisolid dosage form that is inserted into a body orifice (rectum, vagina) where it dissolves or melts to release the drug and exert local or systemic therapeutic effects. Suppositories are made up of natural fat (cocoa butter) or polyethylene glycol (Carbowax) and glycerol as main excipients. They are exclusively intended to be introduced in the anus and show a rapid onset of action since the rectum is highly vascularized; besides, they bypass the hepatic first-pass metabolism [14,22].
Liquid Dosage Forms
Liquid dosage forms are pourable pharmaceutical formulations comprising of API and excipients either dissolved or dispersed in a suitable solvent/s. These are intended to offer a fast therapeutic response in people with trouble swallowing solid dosage forms. Liquid dosage forms are available as ready-to-use liquids or dry powders for reconstitution. These can be administered by oral (syrups, suspensions, etc.) and/or parenteral (injectable, ophthalmic, nasal, otic and topical) routes. Oral liquids are generally nonsterile, while the parenteral liquid dosage forms are offered as sterile and non-sterile formulations (Figure 9). Liquid dosage forms are classified based on the number of phases present into two types: Monophasic (solutions) and biphasic (suspensions and emulsions) [23].
Oral solutions are monophasic clear liquids for oral use comprising one or more active ingredients dissolved in a suitable solvent system [24].
Oral emulsions are biphasic liquids for oral use where the drug is present in an oil-in-water emulsion either in single or dual phases [25].
Oral suspensions are biphasic liquid dosage forms for oral use comprising one or more APIs suspended in a suitable solvent. They tend to sediment with time; nevertheless, they can be readily re-dispersed by shaking into a uniform suspension that remains appropriately stable to allow the accurate dose to be delivered [24].
Syrup is a concentrated aqueous sugar solution, usually sucrose, in which APIs are dissolved. Flavored syrups are suitable to mask the unpleasant taste of drugs [25].
Elixir is a monophasic clear liquid for oral use for administering potent or nauseous drugs by adding pleasant flavors. The vehicle comprises a high amount of ethanol or sucrose along with antimicrobial preservatives to enhance the stability of the formulation [25].
Linctuses are viscous oral liquids made of a high amount of syrup and glycerol which have a demulcent effect on the membranes of the throat and are used for cough relief. These are taken in smaller doses (<5 ml) and undiluted to prolong the demulcent action [26].
Oral drops are either solutions, suspensions, or emulsions that are administered in very small volumes (<1 ml) into the eyes, nose, or ears [27].
Gargles are concentrated aqueous solutions that need to be diluted with warm water before use to wash the mouth and throat by holding the liquid in the throat and agitate it by the air from the lungs [28].
Mouthwashes are similar to gargles but are used to maintain food oral hygiene and also to prevent infections in the mouth [23,28].
Pharmacokinetics of Drug Delivery Systems
Pharmacokinetics is the movement of drugs into, through, and out of the body—the time course of drug absorption, distribution, metabolism, and excretion. In simple terms, it is what the body does to a drug [29]. A schematic illustration of pharmacokinetics is represented in Figure 10.
Absorption
Absorption is the movement of a drug from its site of administration to the bloodstream. The rate and extent of drug absorption depend on several factors, such as route of administration, physicochemical properties of the drug, type of formulation, and drug–food interactions [30,31]. The fraction or amount of drug (in active form) that reaches the target site through the systemic circulation is called bioavailability. Intravenous administration of the drug offers 100% bioavailability as the dosage form is directly administered into the bloodstream. Oral dosage forms suffer from poor bioavailability due to incomplete absorption and the hepatic first-pass effect which metabolizes the drug in the liver, rendering it less active or inactive. Absorption of the drug through the plasma membrane occurs by either passive transport or active transport [30].
(a) Passive Transport involves the movement of the drug across the cell membrane from the high drug concentration region (such as the gastrointestinal tract) to the low drug concentration region (such as blood). This is a passive process, and no energy is required, and the rate of drug diffusion is directly proportional to the concentration gradient [32]. Other factors influencing passive transport include the physicochemical properties of the drug, such as its lipid solubility, molecular size, degree of ionization, and the absorptive surface area available to the drug [30].
(b) Active transport requires energy to facilitate the transport of drug molecules against a concentration gradient, which usually occurs at specific sites in the small intestine. The majority of drugs that are absorbed via active transport share a similar structure with endogenous substances such as ions, vitamins, sugars, and amino acids [30,33].
Distribution
Distribution is a reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the body (for example, fat, muscle, and brain tissue). Drug distribution governs the amount of drug reaching target sites as compared to the rest of the body and thus plays an important role in drug efficacy and toxicity. Various factors affecting drug distribution include blood flow, lipophilicity, and molecular size of the drug, and binding affinity of the drug with plasma proteins [36,37]. For example, a drug with a high protein-binding affinity (e.g., warfarin) possesses a very little amount of free drug in the target site to exert a desired therapeutic response. Warfarin drug, due to strong protein binding efficacy, can replace any other drug bound to plasma proteins and allow it to be free to show the therapeutic response [30]. Additionally, there are anatomical barriers found in certain organs like the blood–brain barrier, preventing certain drugs from going into brain tissue (Figure 12). Drugs with high lipophilicity, smaller size, and low molecular weight can cross the blood–brain barrier [29].
Metabolism
The metabolism of drugs (in the gut wall and liver) into inactive or less active components before being absorbed into the systemic circulation. The concentration of a drug, especially after oral administration, is significantly reduced before reaching the bloodstream [37,38]. It is the fraction of drug that is lost during absorption, and cytochrome P450 (CYP450) enzymes of the liver are accountable for the metabolism or biotransformation of about 70–80% of the drugs in clinical use [30].
Excretion
The removal of unchanged drugs or their metabolites from the body is called drug excretion [39]. There are many different routes of excretion, including urine, bile, sweat, saliva, tears, milk, and stool [30].
Bioavailability
This is the fraction or percentage of administered drug absorbed into the systemic circulation. Drugs with high hepatic metabolism and faster excretion have low bioavailability. The sub-therapeutic dose is present at the target site and results in low efficacy. Hence, for low bioavailable drugs, high dosage is needed. Drugs that are absorbed via the Gastro-Intestinal Tract (GIT) are circulated to the liver first via the hepatic portal vein. The liver then acts as a filter (CYP enzymes metabolize). Only part of the drug is reached systemically. The greater the first pass effect, the lesser the bioavailability. The IV route offers 100% bioavailability [40,41].
Biological Half-Life (t_{1/2})
Elimination half-life or Biological half-life (t{1/2}) is the time at which the mass of an unchanged drug becomes half (50%) of the initial concentration. Simply, t{1/2} refers to how long it takes for half of the administered dose to be metabolized and eliminated from the bloodstream [42]. The half-life of a drug can be determined using the following equations:
t{1/2} = (0.7 Vd)/Cl where Vd is the volume of distribution and Cl is clearance. t{1/2} = 0.693/Kt where Kt is the Elimination rate constant.
Drugs with a short biological half-life need frequent dosing to achieve a therapeutic response for a longer duration. The goal is to maintain the therapeutic blood level over extended periods, for which the drug must enter the systemic circulation approximately at the same rate at which it is eliminated. Elimination of a drug varies due to factors like age, weight, other medications taken, other medical conditions present, kidney function, liver function, etc. Therefore, the half-life is used as a guide or an estimate of how long it may take for the drug to be removed from the body [41].
Drug Release Kinetics Basic Concepts
The drug release profile is generally expressed as a plot of plasma-drug concentration versus time.
In the plot shown in Figure 16, two important concentration levels are shown: The minimum effective concentration, below which the drug is ineffective, and the toxic concentration, above which undesirable side effects occur. Maintenance of drug concentration at any instance between minimum effective concentration to minimum toxic concentration is critical for safety and therapeutic effectiveness [42]. Drug release kinetics is said to be zero-order kinetics when a constant amount of drug is eliminated per unit time but the rate is independent of the concentration of the drug. Zero-order DDS has the potential to overcome the issues faced by immediate-release and first-order systems by releasing the drug at a constant rate, thereby maintaining drug concentrations within the therapeutic window for an extended period [43,44].
Minimum effective concentration (MEC): The lowest level of concentration of drug in the body that shows the desired therapeutic effect [45].
Zero-order release: Zero-order kinetics is described when a constant amount of drug is eliminated per unit time but the rate is independent of the concentration of the drug [45].
First-order release: The drug release rate is directly proportional to the concentration gradient and is a function of the amount of drug remaining in the dosage form [45].
Sustained release: This is designed to achieve slow release of a drug over an extended period after administration of a single dose [45].
Therapeutic Index (TI) and Therapeutic Window
The therapeutic index (TI; also referred to as the therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. A therapeutic window or safety window refers to the range of doses that optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side effects or toxicity [45].
TI is calculated from the ratio of the dose of a drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g., toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g., efficacious dose in 50% of subjects, ED50) (Figure 17) [46].
Conventional vs. Controlled Drug Delivery Systems
Conventional DDS (tablets, capsules, syrups, etc.) get eliminated from the body very quickly, and the dose is not well maintained within the therapeutic window. After taking a single conventional dose, the drug metabolizes very quickly, and the drug level increases, immediately followed by an exponential decrease. The time frame may not be long enough to produce a significant therapeutic effect and result in a sub-therapeutic response. Figure 18 illustrates the plasma drug fluctuations in conventional DDS. Hence, to maintain the plasma drug concentration above the minimum effective concentration (MEC) and below the toxic concentration, multiple approaches have been sought. Administering multiple doses at regular intervals of time might seem to be an alternative to a single dose, but the former results in fluctuations in plasma drug levels and often reaches below effective levels and above toxic levels. Taking several doses within a day results in poor patient compliance. Another approach is by administering a single dose greater than the required dose, which leads to adverse effects other than the effects intended by the drug (Figure 18). Hence, controlled release DDS is required to maintain the plasma drug levels at a constant rate within the therapeutic window and offer the desired therapeutic effect for a longer duration of time. [43].
Sustained-release drug delivery systems achieve the slow release of a drug over an extended period after administration of a single dose.
Controlled Drug Delivery Systems
This is the drug delivery system in which a constant level of a drug is maintained in the blood and tissue for an extended period. Pharmacokinetics (PK) curves of plasma concentration of a drug versus time for two types of delivery systems, conventional and controlled, are represented in Figure 20. In a conventional delivery system, there is a typical bolus PK for multiple dosing with oral tablets or injections, where the drug level fluctuates above and below the minimum effective concentration. The controlled delivery system, on the other hand, shows zero-order PK with just a single dose of controlled drug delivery from a specific formulation or device. The drug levels are maintained constantly within the therapeutic window [47].
Controlled DDS maintains drug plasma levels constantly by releasing the definite dose of the drug at each time point for a pre-determined duration. This helps in reducing the dose and dosing frequency and improves patient compliance. Lesser drug exposure to the biological environment reduces drug toxicity and adverse effects. The overall efficacy of the dosage form is augmented [43]. The medical rationale behind controlled DDS is schematically represented in Figure 21.
Design Considerations of Controlled Release Drug Delivery Systems
In designing a controlled release drug delivery system, various factors and parameters need to be considered; Figure 22 briefly illustrated the design considerations. The parameters are broadly classified as formulation-related and drug-related. Under formulation-related parameters, the biomaterial properties, route of administration, pharmacokinetics, and stability enhancement are the major factors. In addition, the drug-related parameters include drug binding efficiency with plasma proteins and the ability of the drug to cross biological barriers, and regulatory aspects are also the foremost criteria in designing the dosage form [43].
Biomaterial properties such as biocompatibility, surface chemistry, hydrophilicity, degradation, mechanical, and rheological properties need to be studied. In addition, the behavior of the biomaterials at various pH and temperatures also needs to be assessed. The routes of drug administration are critical for choosing the suitable biomaterial and designing the dosage form. For instance, rectal administration needs the melting point of the biomaterial to be at or above 37 °C, or it is soluble at that pH so that the drug gets released. For certain drugs which are not stable in harsh conditions, including peptides, proteins, genes (DNA), growth factors, and colloidal/non-colloidal particles, the stability enhancement should be done while designing the controlled release carrier. This can be achieved by incorporating the particular drugs in specialized carrier systems [48].
Targeting the drug to the site wherever the intended pharmacological activity is needed is of utmost importance to prevent the unwanted drug effects on other organs. This could be achieved by antibody tagging, attaching ligands, and localized delivery. The biological barriers are a hindrance to targeting drug delivery to certain areas, including the brain, bone, and testicles. Drugs formulated with permeation enhancers and nanocarriers are the alternatives that can cross the barriers and deliver the drug to the target site [49].
Suitable animal models need to be established for each kind of delivery system to get the best in vitro in vivo co-relationship (IVIVC). This helps to bridge the gap between in vivo animal studies and the clinical study results [50].
Classification of Controlled Release Drug Delivery Systems
Controlled release drug delivery systems are classified based on the mechanism of drug release from the dosage form into dissolution-controlled, diffusion-controlled, water penetration-controlled (osmotic pressure-controlled and swelling-controlled), chemically controlled, and nanoparticle-based systems [51].
Dissolution Controlled Drug Delivery Systems
In dissolution-controlled release systems, drugs are either coated with or encapsulated within slowly dissolving polymeric membranes (reservoir systems) or matrices (monolithic systems), respectively (Figure 23). In reservoir systems, drugs are protected inside polymeric membranes with low solubility. Most of the conventional immediate-release tablets, pills, and effervescent tablets are dissolution-controlled systems, where the rate-limiting step is dissolution [52].
Diffusion-Controlled Drug Delivery Systems
In diffusion-controlled release systems, drugs are trapped in and released via diffusion through inert water-insoluble polymeric membranes (reservoir systems) or polymeric matrices (monolithic systems). These are classified into membrane control reservoir systems and monolithic matrix systems (Figure 24). The drug release is governed by Fick’s laws of diffusion. The rate-limiting step in diffusion-controlled systems is the diffusion of drugs [53,54].
Fick’s first law of diffusion (Equation (1)) states that the molar flux (J) due to diffusion is proportional to the concentration gradient (dc/dx). Fick’s second law (Equation (2)) states that the rate of change of concentration of the solution at a point in space is proportional to the second derivative of concentration with space. It gives deals with changes in concentration gradient with time at any distance. The drug release which obeys Fick’s law is said to be Fickian diffusion, while those which do not obey are considered as non-Fickian or anomalous diffusion [53].
Fick’s first law: J∝ frac{dc}{dx} or J = D frac{dc}{dx} (1)
Fick’s second law: frac{dc}{dt} = D frac{d^2c}{dx^2} (2)
Where:
dc = change in concentration of drug (g/cm3)
dx = change in distance (cm)
D = diffusion constant (cm2/s)
J = flux (cm-2 s-1)
dt = change in time (s).
Diffusion-controlled systems are classified into membrane-controlled and monolithic or matrix systems. In membrane-controlled systems, the drug is contained in the core as a reservoir and is covered by a thin polymeric membrane. The membrane could be either porous or non-porous. The release of drugs is by diffusion through the membrane, and the rate of release is governed by membrane thickness, porosity, and physicochemical characteristics of drugs (partition coefficient, molecular size and diffusivity, protein binding, and dosage). Common methods to fabricate membrane-controlled reservoir systems include encapsulation and press coating of tablets [53].
In monolithic or matrix-controlled delivery systems, the drug is either dissolved or dispersed homogeneously throughout the polymer matrix. The drug release is through diffusion when the outside layer that is exposed to the solution gets dissolved first, allowing drugs to diffuse out of the matrix. In monolithic systems where a drug is dissolved, drugs are loaded below the solubility limit. As the size of the matrix decreases, the drug released decreases. Here, the drug release is non-zero order, i.e., rate of absorption ≠ rate of elimination. In monolithic systems where the drugs are dispersed in the polymer matrix, drugs are loaded above the solubility limit [53].
Water Penetration-Controlled Drug Delivery Systems
These are classified as osmotic pressure-controlled drug delivery systems and swelling-controlled drug delivery systems. The rate control is dependent on water penetration into the system.
Osmotic Controlled Drug Delivery Systems
Osmotic drug delivery uses osmotic pressure for the controlled delivery of drugs by using osmogens. Osmosis refers to the process of movement of solvent from a lower concentration of solute towards a higher concentration of solute across the semipermeable membrane. Osmotic pressure is the pressure exerted by the flow of water through a semipermeable membrane separating two solutions with different concentrations of solute. These systems can be used for both routes of administration, i.e., oral and injectables [55].
Basic components of osmotic DDS include the drug which itself may act as osmogen; otherwise, osmogenic salt can be added to the formulation. A semipermeable membrane with sufficient wet strength and water permeability that is biocompatible and rigid in withstanding the pressure within the device is needed. Apart from that, an outer coating material that is permeable to water but impermeable to solute can be used. Polymers such as cellulose acetate, cellulose triacetate, and ethyl celluloses are commonly used in osmotic drug delivery systems. The advantages of osmotic-controlled delivery systems include increased efficacy of the drug, controlled drug delivery, and reduced dosing frequency [56].
A simple osmotic delivery system is a pump made up of two compartments separated by a moving partition. Compartment one is filled with an osmotic agent covered by a semi-permeable membrane. Compartment 2 is covered by a hard rigid shell with a delivery orifice [56].
Swelling-Controlled Drug Delivery Systems
In swelling-controlled drug delivery systems, the drug is dispersed or dissolved in the hydrophilic polymer when in a glassy (hard and rigid) state. In an aqueous solution, water penetrates the matrix, and the glass transition temperature of the polymer is lowered below ambient temperature. This makes the matrix swollen and rubbery, which results in slow drug diffusion out of the swollen rubbery polymer
Dosage Form Composition
Every dosage form combines a drug/API with excipients (Figure 1). APIs treat diseases [2].
Need for a Dosage Form
DDS are preferred because direct API use is rare:
API handling and accurate dosing can be difficult for potent drugs [3].
Administration into body cavities can be impractical; APIs can degrade or cause local irritations [3].
Some APIs are sensitive to the environment (light, moisture, temperature, pH) or chemically unstable.
APIs often have unpleasant qualities (taste, smell), reducing patient compliance [2].
Hence, APIs are formulated with excipients.
Excipients/Additives
Excipients/Additives are used:
To give structure and shape.
To increase stability.
To mask taste and increase palatability.
To bulk up potent formulations.
To allow convenient, accurate dosage.
To aid in handling.
To aid in manufacturing [4].
Additionally, excipients enhance bioavailability and improve safety/function [5].
Excipients
Common excipients include coloring, suspending, binding, solvents, lubricants, perfumes, sweetening, flavoring, solubilizing, and antioxidants [4].
Fillers increase tablet size (e.g., lactose).
Binders hold the tablet together (e.g., starch, HPMC) [6].
Disintegrants help the tablet break down (allowing faster absorption) [6].
Glidants prevent lump formation.
Anti-adherents stop powder from sticking to machines.
Lubricants ensure smooth tablet surfaces.
Flavoring agents mask odor, and colorants aid recognition [7].
Biopharmaceutics Classification System (BCS) Classification of Drugs
BCS classifies drugs based on permeability and solubility (Figure 2) [8].
Class I: High permeability, high solubility (e.g., metoprolol, paracetamol).
Class II: High permeability, low solubility (e.g., glibenclamide, aceclofenac).
Class III: Low permeability, high solubility (e.g., cimetidine).
Class IV: Low permeability, low solubility (e.g., Bifonazole) [8].
Different Routes of Drug Administration
Dosage forms are administered via various routes based on the target site, treatment duration, and drug attributes [9]. Common forms: tablets, capsules, ointments, syrups, injections (Table 1, Figure 3).
Route depends on the body part, drug action, and drug solubility/permeability. Some drugs require parenteral routes to avoid stomach acid destruction. IV administration = 100% bioavailability [9].
Classification of Dosage Forms
Dosage forms are classified by administration route, origin, and physical form (Figure 4).
Classification of Solid Dosage Forms
Solid forms: unit dose and bulk dose.
(a) Unit dose: Fixed dose, separate unit (e.g., tablets, capsules, lozenges).
(b) Bulk dose: Bulk powder, dose not pre-divided (Figure 5) [10,11]. Dose dumping is a risk. Used as dressing powder (e.g., insufflation powder) [10].
Tablets
Solid unit dosage form made by compression. Excipients: binders, glidants, lubricants, disintegrants. Coating masks taste and protects (e.g. pigments, sweeteners, flavoring agents) [10,12].
Sublingual/Buccal tablets: Dissolve under tongue/in cheek. Advantages: rapid absorption, avoids stomach acid and liver enzymes [10,12].
Effervescent tablets: Generate CO_2 in water, disintegrate rapidly. (e.g., antacids).
Chewable tablets: For mastication (e.g., vitamins) [10,12].
Capsules, Lozenges, Pills, and Granules
Capsule: Drug in a soluble shell. Masks taste. Types: hard-shelled (dry powders) and soft-shelled (hydrophobic drugs in oil).
Lozenges: Chewable, slow release (e.g., cough remedies).
Pills: Rounded masses of API and excipients.
Granules: Single-dose sachets, consumed with water (Figure 6h). Effervescent granules release CO_2.
Bulk Solid Dosage Forms
Bulk Powders: Multidose, loose particles. Limited by inaccurate dosing, used for non-potent drugs (e.g., laxatives). Dispersed or dissolved before taking.
Divided powders: Single-dose sachets for better dosage control [10].
Semisolid Dosage Forms
Semisolids: Applied to skin/membranes (nasal, vaginal, rectal) for therapeutic, protective, or cosmetic uses (Figure 7, Table 2) [13].
Semisolids are external/local, reducing side effects. Suitable for unconscious patients and bitter drugs. More stable than liquids [14].
Ointments
Oil-based, anhydrous, immiscible with skin secretions. High retention time, low spreadability. Used as emollients or to apply drugs to small skin areas [14,15].
Creams
Soft, spreadable emulsions. Types: O/W and W/O.
Oil-in-water (O/W) creams: Oil in aqueous phase, stabilized by surfactants [15]. Less greasy.
Water-in-oil (W/O) creams: Water in oily phase. Good for hydrophobic drugs, more moisturizing [14].
Gels (Jellies) and Lotions
Gels: Liquid in a 3D polymeric matrix [16]. Used in medicine, cosmetics, lubricants.
Lotion: Aqueous fluid for external use [14].
Pastes
Ointment with high insoluble solids. Protective barrier [15]. Absorbs chemicals, opaque (sunscreen) [14,16].
Transdermal Patches
Adhesive patch for drug delivery through skin [17]. For patients who cannot take oral doses.
Components: backing film, drug layer, membrane, adhesive layer, release liner [18,19].
Types: Matrix, reservoir, multilaminate, drug-in-adhesive (Figure 8).
Criteria: MW < 500 Daltons, lipophilic. Scopolamine was the first patch [20].
Suppositories
Semisolid, inserted into body orifice (rectum, vagina). Melts to release drug. Bases: cocoa butter or polyethylene glycol. Bypasses hepatic first-pass metabolism [14,22].
Liquid Dosage Forms
Pourable, APIs dissolved or dispersed in solvent [23]. Fast therapeutic response. Forms: ready-to-use or dry powders for reconstitution. Routes: oral, parenteral. Types: monophasic (solutions) and biphasic (suspensions and emulsions) [23].
Oral solutions: API in a solvent [24].
Oral emulsions: Oil-in-water [25].
Oral suspensions: API suspended in solvent [24].
Syrup: Concentrated sugar solution [25].
Elixir: Clear liquid with ethanol or sucrose [25].
Linctuses: Viscous liquids for cough relief [26].
Oral drops: Solutions, suspensions, or emulsions for eyes, nose, or ears [27].
Gargles: Concentrated solutions, diluted with water [28].
Mouthwashes: Similar to gargles [23,28].
Pharmacokinetics of Drug Delivery Systems
Pharmacokinetics: Drug movement into, through, and out of the body (Figure 10) [29].
Absorption
Drug movement from administration site to bloodstream. Factors: route, drug properties, formulation, drug–food interactions [30,31]. Bioavailability: drug amount reaching target site. IV = 100% bioavailability. Oral forms have poor bioavailability due to incomplete absorption and first-pass effect. Transport: passive or active [30].
Passive Transport: From high to low concentration, no energy needed [32]. Influenced by drug properties (lipid solubility, size, ionization) [30].
Active transport: Requires energy, against gradient [30,33].
Distribution
Reversible transfer between blood and tissues. Affects drug amount reaching target sites [36,37]. Factors: blood flow, lipophilicity, drug size, protein binding [36,37]. High protein-binding reduces free drug. Anatomical barriers (blood–brain barrier) limit drug entry to brain (Figure 12) [29].
Metabolism
Drug metabolism into inactive forms in gut wall and liver [37,38]. Reduces drug concentration before bloodstream [37,38]. CYP450 enzymes metabolize 70–80% of drugs [30].
Excretion
Removal of drugs or metabolites [39]. Routes: urine, bile, sweat, saliva, tears, milk, stool [30].
Bioavailability
Fraction of drug absorbed into circulation. High hepatic metabolism = low bioavailability. IV route = 100% bioavailability [40,41].
Biological Half-Life (t_{1/2})
Time for unchanged drug mass to halve [42].
t{1/2} = (0.7 Vd)/Cl; t{1/2} = 0.693/Kt.
Short half-life drugs need frequent dosing [41].
Drug Release Kinetics Basic Concepts
Drug release profile: plasma-drug concentration vs. time.
Therapeutic window: between minimum effective concentration and toxic concentration [42].
Minimum effective concentration (MEC): Concentration for therapeutic effect [45].
Zero-order release: Constant amount released per time unit [45].
First-order release: Rate proportional to concentration [45].
Sustained release: Slow release over time [45].
Therapeutic Index (TI) and Therapeutic Window
TI: Safety measure. Ratio of toxic dose to effective dose (Figure 17) [46].
Conventional vs. Controlled Drug Delivery Systems
Conventional DDS are quickly eliminated; dose not maintained. Controlled release needed to maintain levels [43].
Controlled Drug Delivery Systems
Maintains constant drug level via controlled release (Figure 20) [47].
Reduces dose frequency and toxicity [43].
Design Considerations of Controlled Release Drug Delivery Systems
Factors: formulation-related and drug-related (Figure 22) [43].
Classification of Controlled Release Drug Delivery Systems
Based on release mechanism: dissolution, diffusion, water penetration, chemically controlled, and nanoparticle-based [51].
Dissolution Controlled Drug Delivery Systems
Drugs coated or encapsulated in dissolving membranes or matrices (Figure 23) [52].
Diffusion-Controlled Drug Delivery Systems
Drugs trapped in and released via diffusion through inert membranes or matrices (Figure 24). Governed by Fick’s laws [53,54].
Fick’s first law: $$J = D \frac{dc}{