Typical pharmaceutical carriers, nanosized active agents, and delivery systems include dendrimers and nanoparticles with functionalized surface, antibody–drug conjugates, nanocrystals, nanoparticle albumin bound (nab) systems, lipid–polymer hybrid nanoparticles, liposomes, stealth liposomes, half-antibody functionalized ligand-targeted systems, micro-emulsions, nanosuspensions, emulsions, suspensions, oral-soluble strips, microcapsules, pellets, tablets, osmotic pumps, and encapsulated drug delivery systems in a capsule carrier. The latter seven delivery systems constitute greater than 80% of routinely used pharmaceuticals in current therapy.
According to the US Food and Drug Administration (FDA) and the US Pharmacopeia (USP), modified-release solid oral dosage forms encompass delayed/enteric-coated and extended-release drug products. Besides the delayed- and/or extended-release features, other newer types of oral modified-release products may include pulsatile-release, combination drugs (e.g., single dosage form containing immediate-release, enteric-coated, and/or extended-release components), targeted delivery (e.g., oral-mucosa, stomach, proximal intestine, distal intestine, and/or colon), or delivery systems that are based on the chronopharmacokinetics and interactions of drugs in the milieu of biologic rhythms from a clinical perspective and chronotherapeutics. These dosage forms can be designed to deliver drugs in a controlled and predictable manner over a prolonged time period or at a target location within the gastrointestinal (GI) tract to elicit the desired therapeutic effect. Moreover, development of such delivery systems having complicated features involved in their design has presented numerous challenges to the industry and regulatory authorities in ensuring pharmaceutical equivalence, bioequivalence, and therapeutic equivalence. Commonly used oral modified-release systems can be formulated as single-unit (e.g., tablet matrices, composites of layered tablets and compressed pellets) or multiple-unit dosage forms (e.g., based on encapsulation of pellets, spheres, granules, or multiparticulates). The relative merits of multiple unit dosage forms in terms of “release flexibility, increased bioavailability, predictable gastrointestinal transit time, less localized GI disturbances, more consistent blood levels, less intra or inter subject variability due to the food effects and greater product safety” over single-unit products are well established. In modified-release systems, the design of the dosage form allows for a specific drug delivery pattern so that the release rate becomes the rate-limiting step. This should be viewed in the context of existing parameters within the GI tract. For example, the two major rate-limiting factors to drug absorption are GI environment (e.g., pH, absorption site, and regional differences in drug permeability across GI mucosa, gut metabolism, and GI content) and transit rate of the dosage form. From a manufacturing point of view, irrespective of the type of the dosage form (single or multiple units), currently the utilization of hydrophilic matrices, mini-tablets, coated pellets or spheres, and osmotic systems is common and offers significant flexibility in pharmaceutical technology. In view of the many benefits offered by multiple-unit dosage forms, it is speculated that such systems are particularly useful in many chronic disease conditions and delivery of highly irritant and potent drugs for site-specific targeting within the GI tract and for delivery of non-steroidal anti-inflammatory drugs, colonic delivery of anticancer drugs, enzymes, peptides/proteins, and vaccines.
The purpose of this chapter is to highlight and describe potential uses of hard shell capsules as carriers for extended-release drug delivery systems that, by virtue of their design and popularity, satisfy features of an ideal technology platform for drug delivery and reliable pharmaceutical production. These features include the following:
Availability, types, and sizes of the capsule shells through different suppliers
Simplicity, flexibility and ease of production, low cost, and time efficient
Process familiarity and acquaintance with technology and equipment
Robust, manageable, quick changeover, transferability, suitable for worldwide manufacturing
Significant potential for innovation including multiple drug delivery options for modified release, targeted release, and delivery of drug combinations
The word capsule is derived from the Latin word Capsula, meaning “a small box or packet.”1,2 Therefore, hard shell capsules can be regarded as containers for delivery of formulated drug substances that are generally designed for oral administration, although non-oral products for rectal or vaginal administration are available. Capsules as a platform for delayed or controlled-release delivery offer numerous advantages and adaptabilities over tablets. They can readily accommodate a range of special excipients, formulations, and pre-fabricated systems to target specific regions of the GI tract including the following:
Powders, particulate systems, pellets, mini-tablets, coated particulates, or mixed coated beads with enteric coat or diffusion-controlled membrane
Multiple tablets, smaller hard or soft shell capsules, small drug wafers, or casted sheets containing drug
Enteric-coated systems with or without sustained release components
Various controlled-release forms
Drug combinations for targeting different regions of the GI tract for both local and systemic effects
Micronized or nanosized formulated drug(s) with pH-sensitive coatings for delivery to stomach, proximal intestine, distal intestine, or colon
Incompatible drugs where one drug in the form of a coated pellet, tablet, small soft shell capsule can be separated by placing it in a larger capsule before adding the second drug
Hard shell capsule sizes range from number 5, the smallest, to number 000, which is the largest, except for veterinary sizes. However, size number 00 generally is the largest size acceptable to patients. Hard shell capsules consist of two parts, cap and body piece. Generally, there are unique grooves or indentations molded into the cap and body portion to provide firm closure when fully engaged or fitted, which helps prevent the unintended separation of the filled capsules during shipping and handling.2 To assure strong closure, spot fusion “welding” of the cap and body piece together through direct thermal means, or application of ultrasonic energy, sealed banding, or liquid sealing can be applied. This further guarantees greater product stability by limiting oxygen and moisture penetration and also augments consumer safety by making the capsules tamper proof and difficult to open without producing noticeable damage to the dosage form and the shell’s integrity.
Two-piece hard shell capsules are commercially available and are manufactured from gelatin (animal derived) or hypromellose (hydroxypropylmethylcellulose [HPMC], plant derived) via the thermal gelation process.2,3 The HPMC capsules referred to as Vcaps Plus capsules or second-generation capsules are based on pure HPMC and generally dissolve similarly in different pH’s or ionic strengths and have a lower moisture content (4% to 9% w/w) relative to gelatin capsules (13% to 16% w/w). Unlike gelatin shells, which can undergo cross-linking in the presence of aldehyde groups and cause dissolution problems, the HPMC shells are stable and are not affected by the presence of aldehyde groups.
Modified-release drug delivery technologies, which include both enteric-coated systems and a variety of controlled-release solid dosage forms, including capsules, have evolved as a multidisciplinary science. For example, the extended-release Spansule capsule, containing a large number of coated and uncoated drug beads (i.e., coated spheres) to modify drug dissolution by controlling access of GI fluids to the drug through a coating barrier, was first introduced and patented in 1952, as shown in Figure 12.2.
A similar approach has been practiced since the 1950s, and today, there are dozens of modified-release capsule dosage forms using the same or similar principle that are commercially available. Some examples of modified-release hard shell capsules that have been FDA approved and are currently available in the marketplace are presented in Table 12.1. The list is not an exhaustive list of the available extended-release capsule products but rather an exemplary sample list that also includes fixed-dose combination products. Many of these products are marketed in different dose strengths for ease of clinical management of the disease conditions. For example, extended-release morphine sulfate (Kadian), listed in Table 12.1, has many different strengths with diversity in color(s), capsule size, and imprints in order to safely adjust the required dose for management of pain in patients having different pain thresholds and pain severity.
Calcium channel blocker
Pancreatic enzyme insufficiency
ER phenytoin sodium
Prevention and treatment of seizures
Management of exogenous obesity
Calcium channel blocker
Attention deficit hyperactivity disorder
Management of pain
Treatment of hypertension
Amphetamine, dextroamphetamine mixed salts
Attention deficit hyperactivity disorder
Calcium channel blocker
Treatment of erosive esophagitis
Treatment of duodenal ulcer
Irritable bowel syndrome with constipation
Aspirin/ER dipyridamole amlodipine besylate and benazepril HCl
Reduce the risk of stroke
Treatment of hypertension
Modified-release capsules encompass both enteric and extended-release products.
Note: Four selected modified-release capsule delivery systems representing different release mechanisms will be discussed in more detail in this text: Dilacor XR (multiple tablet matrices in capsule); Carbatrol extended release (diverse coated and uncoated multiparticulates in capsule); Prilosec delayed-release/enteric-coated pellets in capsule; and Linzess capsule containing drug-coated beads of a polypeptide for delivery to the distal intestine for topical effect via receptor binding in the intestine and colon.
A brief but comprehensive history of modified-release delivery systems and significance of their performance through either manipulation of the drug molecule itself or delivery types with specific release configurations is presented elsewhere.4 The groundbreaking theoretical developments of various scientists5–9 and others whose contributions allowed for a more rational understanding and application of basic principles to the design and development of an array of more sophisticated and multifaceted controlled-release systems should not be overlooked. Extended-release capsules are produced in such a way as to deliver their content upon oral administration either in the stomach or different regions of the GI tract for absorption over a few hours to about 12 to 24 h. Figure 12.3 shows various physiological constraints and GI environments that a modified-release capsule dosage form encounters upon oral administration.
The GI constraints should be considered in conjunction with characteristics and limitations described by way of the Biopharmaceutics Classification System (BCS), implemented in 1995 as a new approach to better predict oral drug absorption and adopted by the FDA.10,11 According to the BCS, drug substances are classified as follows:
Class I—High Permeability, High Solubility
Class II—High Permeability, Low Solubility
Class III—Low Permeability, High Solubility
Class IV—Low Permeability, Low Solubility
Furthermore, the class boundaries described above is based on the following premise:
A drug substance is considered highly soluble when the highest dose strength is soluble in <250 mL of water over a pH range of 1 to 7.5.
A drug substance is considered highly permeable when the extent of absorption in humans is determined to be >90% of an administered dose, based on mass balance or in comparison to an intravenous reference dose.
A drug product is considered to be rapidly dissolving when >85% of the labeled amount of drug substance dissolves within 30 min using USP apparatus I at 100 rpm or II at 50 rpm in a volume of ≤900 mL of buffer solutions.
The hard shell capsule itself, once in the desired GI environment/region, would dissolve fairly rapidly (10–30 min) and releases its content immediately (i.e., in the case of immediate release) for rapid absorption as opposed to modified-release systems such as controlled release or sustained release as shown in Figure 12.4.
When capsule dosage forms are designed for providing a particular release profile or sustained drug delivery, upon oral administration, it would deliver its content for further disintegration, dissolution, and release followed by absorption in various regions of the GI tract as shown in Figure 12.5.
FDA defines modified-release dosage forms as “dosage forms whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms, such as a solution or an immediate-release dosage form. Modified-release solid oral dosage forms include both delayed- and extended-release drug products.”12
The USP recognizes several types of modified-release systems including extended release, delayed release, or targeted release. However, expressions such as “prolonged-action,” “repeat-action,” “controlled-release,” “pulse-release,” “modified-release,” “ascending-release,” and “sustained-release” have also been used to describe such dosage forms. Although many of these terms have been used interchangeably, the terms “extended-release” and “modified-release” are used for Pharmacopeial purposes, and requirements for drug release typically are specified in the individual monographs [see general release standard USP 〈724〉 and 〈1088〉].13
The platform is highly flexible and lends itself to a variety of delivery system designs that could be complementary with different biopharmaceutical properties of the drug in relation to physiological constraints imposed by the GI tract. Ideally, the extended-release delivery system should provide release rate and duration of release that would match the necessary amount of drug in the blood for a specific duration of therapy. The modified-release capsule delivery platform permits for constant release (zero-order), variable release (pulsatile), delayed release, or extended drug release and absorption over a prolonged period after ingestion. Capsules can be enteric coated, or coated pellets/granules that resist releasing in the acidic environment of the stomach can be encapsulated. Enteric coating delays release of medicament until the capsule or its contents have passed through the stomach. Potential modified-release capsule delivery systems and sophisticated release rates and patterns that can be realized from manufacturing of different controlled-release capsule delivery designs are shown in Figures 12.6 and 12.7a and b.
Dissolution Rate of Drug from Drug Particles, Pellets, or from Various Modified-Release Formulations and Delivery Systems Encapsulated in a Capsule Shell as a Delivery Carrier
There are two major classes of dosage forms or drug delivery systems for oral administration:
Immediate-release solid dosage forms (orally disintegrating and immediate-release tablets and capsules)
Modified-/controlled-/sustained-release dosage forms
Drug release in vitro or in vivo from a conventional capsule is very similar to an immediate-release tablet dosage form except for a small lag time of less than 30 min for the capsule shell to dissolve. Release and subsequent bio-absorption are controlled by the physicochemical properties of the drug, its formulation, and the physiological conditions and constraints imposed by the GI tract. The release of a drug from these delivery systems is rapid and involves factors of dissolution and diffusion. The earliest work describing diffusion was by Fick in 1855. Fick’s first law of diffusion considers diffusion only under steady-state conditions.
where J is the diffusion current, D is the diffusion coefficient, and dc/dx is the concentration gradient assumed to be constant at steady state. However, as the concentration of drug changes with time, Fick’s second law of diffusion is used; hence, it considers non-steady-state conditions.
where dc/dt is the dissolution rate of the drug. Based on Fick’s second law of diffusion, Noyes and Whitney14 established a fundamental equation for dissolution. In its simplest form, the in vitro rate of solubility or dissolution rate of a drug substance is described by the Noyes–Whitney equation:
Under sink conditions, Cs >> Ct, and Equation 12.3 becomes
where dC/dt is the dissolution rate at time t, D is the diffusion rate constant, h is the thickness of the stagnant layer, S is the surface area of the dissolving solid, Cs is the concentration of the drug in the stagnant layer, and Ct is the concentration of the drug at time t in the bulk solution. Note that if the concentration in bulk solution is ≤15% of saturation solubility, “sink condition” prevails.
In an in vivo situation after dissolution, drug molecules move across a distance into a membrane and its membrane permeability depends on the velocity with which it moves. Apart from the role of transporters, channels, and carriers, a simplified absorption is described by Fick’s law of diffusion, which involves movement of the drug molecule from a region of high concentration to low concentration. Thus, the drug tends to move toward a region that we may regard as sink, which is passage through the epithelial membrane into blood circulation in accordance with the following equation:
where dC/dt is the rate of absorption, Pe is effective permeability, A is the surface area of the membrane, D is the diffusion coefficient of the drug molecule in water, CGI − CBlood is concentration gradient across the GI membrane, and h is membrane thickness. In Equation 12.5, it is assumed that the unstirred aqueous boundary layer next to the membrane does not significantly affect the total transport process. Therefore, it is important to note that many factors influence the dissolution rate of a drug both in vivo and in vitro, including physicochemical (i.e., particle size, molecular size, hydrophilicity/hydrophobicity, and crystallinity), physiological (i.e., presence of surfactants, GI motility, viscosity and volume of GI fluid, and pH), and in vitro factors (i.e., surfactants, stirring rate and hydrodynamics, viscosity, pH, and volume of medium).
Typically when immediate-release capsule dosage forms are administered orally, the capsule shell disintegrates within a few minutes (i.e., <15 min) and its content dissolves, and the dissolved drug is absorbed as shown in Figure 12.8.
Modified-release delivery from hard shell capsules may contain a variety of fabricated delivery systems. These include granules, powders, systems with different functional coatings such as enteric-coated, extended-, sustained-, controlled- (such as osmotic pump), and/or programmed-release systems including pulsatile or targeted-delivery systems and drug combinations, all of which can be placed in a capsule shell as a carrier for administration. It is also customary to coat hard shell capsules with polymers that prevent dissolution at low pH and can avert gastric degradation or release. Formulation methods vary and usually when needed allow for rapid release followed by slow release of the maintenance dose. All modified-release formulations employ a chemical, physical, or electrical constraint to deliver sustained release of the drug dose. In general, they can be divided into two major groups:
Matrix based systems—pellets, mini-matrices, or small tablets
Membrane diffusion-controlled systems—coated pellets, tablets, and osmotic pumps
Production of modified-release delivery systems is based on numerous formulation approaches, methodologies, and innovative methods, and they each have their own specific operating release-controlling mechanisms as shown in Figure 12.9.
Mathematical Models to Describe Release Kinetics from Extended-Release Capsules Containing Formulated Delivery Systems
Various mathematical models have been used to describe the rate of drug release from different types of encapsulated dosage forms and modified-release systems. For example, an analysis of drug diffusion from simple monolithic devices (i.e., cylinders or spheres representing small tablet matrix or an extruded and spheronized pellet type) designed for controlled release of drug has been described using exact solutions or reasonably accurate approximations.16,17 From experimental work, it is evident that, from such monolithic systems, initial amount of drug released (i.e., early time) is in accordance with the square root of time while release in a later stage follows an exponential decay with time (i.e., late time). Equations shown in Table 12.2 predict such drug release from an infinite system, assuming that the edge or end effects are inconsequential.17