Most conventional [immediate release] oral drug products, such as tablets and capsules, are formulated to release the active drug immediately after oral administration. In the formulation of conventional drug products, no deliberate effort is made to modify the drug release rate. Immediate-release products generally result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. In the case of conventional oral products containing prodrugs, the pharmacodynamic activity may be slow due to conversion to the active drug by hepatic or intestinal metabolism or by chemical hydrolysis. Alternatively, conventional oral products containing poorly soluble [lipophilic drugs], drug absorption may be gradual due to slow dissolution in or selective absorption across the GI tract, also resulting in a delayed onset time.
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The pattern of drug release from modified-release [MR] dosage forms is deliberately changed from that of a conventional [immediate-release] dosage formulation to achieve a desired therapeutic objective or better patient compliance. Types of MR drug products include delayed release [eg, enteric coated], extended release [ER], and orally disintegrating tablets [ODT].
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The term modified-release drug product is used to describe products that alter the timing and/or the rate of release of the drug substance. A modified-release dosage form is a formulation in which the 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 solutions, ointments, or promptly dissolving dosage forms. Several types of modified-release oral drug products are recognized:
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Extended-release drug products. A dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release [conventional] dosage form. Examples of extended-release dosage forms include controlled-release, sustained-release, and long-acting drug products.
Delayed-release drug products. A dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration. An initial portion may be released promptly after administration. Enteric-coated dosage forms are common delayed-release products [eg, enteric-coated aspririn and other NSAID products].
Targeted-release drug products. A dosage form that releases drug at or near the intended physiologic site of action [see Chapter 18]. Targeted-release dosage forms may have either immediate- or extended-release characteristics.
Orally disintegrating tablets [ODT]. ODT have been developed to disintegrate rapidly in the saliva after oral administration. ODT may be used without the addition of water. The drug is dispersed in saliva and swallowed with little or no water.
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The term controlled-release drug product was previously used to describe various types of oral extended-release-rate dosage forms, including sustained-release, sustained-action, prolonged-action, long-action, slow-release, and programmed drug delivery. Other terms, such as ER, SR, XL, XR, and CD, are also used to indicate an extended-release drug product. Retarded release is an older term for a slow release drug product. Many of these terms for modified-release drug products were introduced by drug companies to reflect either a special design for an extended-release drug product or for use in marketing.
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Modified-release drug products are designed for different routes of administration based on the physicochemical, pharmacodynamic, and pharmacokinetic properties of the drug and on the properties of the materials used in the dosage form [Table 17-1]. Several different terms are now defined to describe the available types of modified-release drug products based on the drug release characteristics of the products.
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Table Graphic Jump Location
Table 17-1 Modified Drug Delivery Products
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Table 17-1 Modified Drug Delivery ProductsRoute of AdministrationDrug ProductExamplesCommentsOral drug productsExtended releaseDiltiazem HCl extended releaseOnce-a-day dosing.Delayed releaseDiclofenac sodium delayed-releaseEnteric-coated tablet for drug delivery into small intestine.Delayed [targeted] drug releaseMesalamine delayed-releaseCoated for drug release in terminal ileum.Oral mucosal drug deliveryOral transmucosal fentanyl citrateFentanyl citrate is in the form of a flavored sugar lozenge that dissolves slowly in the mouth.Oral soluble filmOndansetronThe film is placed top of the tongue. Film will dissolve in 4 to 20 seconds.Orally disintegrating tablets [ODT]AripiprazoleODT is placed on the tongue. Tablet disintegration occurs rapidly in saliva.Transdermal drug delivery systemsTransdermal therapeutic system [TTS]Clonidine transdermal therapeutic systemClonidine TTS is applied every 7 days to intact skin on the upper arm or chest.Iontophoretic drug deliverySmall electric current moves charged molecules across the skin.Ophthalmic drug deliveryInsertControlled-release pilocarpineElliptically shaped insert designed for continuous release of pilocarpine following placement in the cul-de-sac of the eye.Intravaginal drug deliveryInsertDinoprostone vaginal insertHydrogel pouch containing prostaglandin within a polyester retrieval system.Parenteral drug deliveryIntramuscular drug productsDepot injectionsLyophylized microspheres containing leuprolide acetate for depot suspension.Water-immiscible injections [eg, oil]Medroxyprogesterone acetate [Depo-Provera].Subcutaneous drug productsControlled-release insulinBasulin is a controlled-release, recombinant human insulin delivered by nanoparticulate technology.Targeted delivery systemsIV injectionDaunorubicin citrate liposome injectionLiposomal preparation to maximize the selectivity of daunorubicin for solid tumors in situ.ImplantsBrain tumorPolifeprosan 20 with carmustine implant [Gliadel wafer]Implant designed to deliver carmustine directly into the surgical cavity when a brain tumor is resected.Intravitreal implantFluocinolone acetonide intravitreal implantSterile implant designed to release fluocinolone acetonide locally to the posterior segment of the eye.
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Examples of Modified-Release Oral Dosage Forms
++The pharmaceutical industry uses various terms to describe modified-release drug products. New and novel drug delivery systems are being developed by the pharmaceutical industry to alter the drug release profile, which in turn, results in a unique plasma drug concentration versus time profile and pharmacodynamic effect. In many cases, the industry will patent the novel drug delivery system, the resulting drug release profile and the plasma drug concentration versus time profile. Due to the proliferation of these modified-release dosage forms, the following terms are general discriptions and should not be considered definitive.
++An enteric-coated tablet is an example of a delayed-release type of modified-release dosage form designed to release drug in the small intestine. For example, aspirin irritates the gastric mucosal cells of the stomach. An enteric coating on the aspirin tablet prevents the tablet from dissolving and releasing its contents at the low pH in the stomach. The coating and the tablet later dissolve and release the drug in the higher pH of the duodenum, where the drug is rapidly absorbed with less irritation to the mucosal cells. Mesalamine [5-aminosalicylic acid] tablets [Asacol, Proctor & Gamble] is a delayed-release tablet coated with an acrylic-based resin that delays the release of mesalamine until it reaches the terminal ileum and colon. Mesalamine tablets could also be considered a targeted-release dosage form.
++A repeat-action tablet is a type of modified-release drug product that is designed to release one dose of drug initially, followed by a second dose of drug at a later time. A prolonged-action drug product is designed to release the drug slowly and to provide a continuous supply of drug over an extended period. The prolonged-action drug product prevents very rapid absorption of the drug, which could result in extremely high peak plasma drug concentration. Most prolonged-release products extend the duration of action but do not release drug at a constant rate. A prolonged-action tablet is similar to a first-order-release product except that the peak is delayed differently. A prolonged-action tablet typically results in peak and trough drug levels in the body. The product releases drug without matching the rate of drug elimination, resulting in uneven plasma drug levels in the body.
++A sustained-release drug product can be designed to deliver an initial therapeutic dose of the drug [loading dose], followed by a slower and constant release of drug. The purpose of a loading dose is to provide immediate or fast drug release to quickly provide therapeutic drug concentrations in the plasma. The rate of release of the maintenance dose is designed so that the amount of drug loss from the body by elimination is constantly replaced. With the sustained-release product, a constant plasma drug concentration is maintained with minimal fluctuations. Figure 17-1 shows the dissolution rate of three sustained-release products without loading dose. The plasma concentrations resulting from the sustained-release products are shown in Fig. 17-2.
++Figure 17-1Graphic Jump Location
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Drug dissolution rates of three different extended-release products in vitro.
++Figure 17-2Graphic Jump Location
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Simulated plasma–drug concentrations resulting from three different sustained-release products in Fig. 17-1.
++Various terms for extended-release drug products often imply that drug release is at a constant or zero-order drug release rate. However, many of these drug products release the drug at a first-order rate. Some modified-release drug products are formulated with materials that are more soluble at a specific pH, and the product may release the drug depending on the pH of a particular region of the gastrointestinal [GI] tract. Ideally, an extended-release drug product should release the drug at a constant rate, independent of the pH, the ionic content and other contents within the entire segment of the gastrointestinal tract.
++An extended-release dosage form with zero- or first-order drug absorption is compared to drug absorption from a conventional dosage form given in multiple doses in Figs. 17-3 and 17-4, respectively. Drug absorption from conventional [immediate-release] dosage forms generally follows first-order drug absorption.
++Figure 17-3Graphic Jump Location
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Plasma level of a drug from a conventional tablet containing 50 mg of drug given at 0, 4, and 8 hours [A] compared to a single 150-mg drug dose given in an extended-release dosage form [B]. The drug absorption rate constant from each drug product is first order. The drug is 100% bioavailable and the elimination half-life is constant.
++Figure 17-4Graphic Jump Location
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Bioavailability of a drug from an immediate-release tablet containing 50 mg of drug given at 0, 4, and 8 hours compared to a single 150-mg drug dose given in an extended-release dosage form. The drug absorption rate constant from the immediate-release drug product is first order, whereas the drug absorption rate constant from the extended-release drug product is zero order. The drug is 100% bioavailable and the elimination half-life is constant.
++Frequently Asked Questions
- What is the difference between extended release, delayed release, sustained release, modified release, and controlled release?
- Why does the drug bioavailability from some conventional, immediate-release drug products resemble an extended-release drug product?
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Biopharmaceutic Factors
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Modified-release drug product should produce a pharmacokinetic profile that provides the desired therapeutic efficacy and minimizes adverse events. In the case of delayed-release drug products, the enteric coating minimizes gastric irritation of the drug in the stomach. The major objective of extended-release drug products is to achieve a prolonged therapeutic effect while minimizing unwanted side effects due to fluctuating plasma drug concentrations.
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Ideally, the extended-release [ER] drug product should release the drug at a constant or zero-order rate. As the drug is released from the drug product, the drug is rapidly absorbed, and the drug absorption rate should follow zero-order kinetics similar to an intravenous drug infusion. The drug product is designed so that the rate of systemic drug absorption is limited by the rate of drug release from the drug delivery system. Unfortunately, most ER drug products that release a drug by zero-order kinetics in vitro do not demonstrate zero-order drug absorption, in vivo. The lack of zero-order drug absorption from these ER drug products after oral administration may be due to a number of unpredictable events happening in the gastrointestinal tract during drug absorption.
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The ER oral drug products remain in the GI tract longer than conventional, immediate-release drug products intended for rapid absorption. Thus, drug release from an ER drug product is more affected by the anatomy and physiology of the gastrointestinal tract, gastrointestinal transit, pH, and its contents compared to an immediate-release oral drug product. The physiologic characteristics of the GI tract, such as variations in pH, blood flow, GI motility, presence of food, enzymes, bacteria, etc, affects the position of the extended-release drug product within the GI tract and may affect the drug release rate from the product. In some cases, there may be a specific absorption site or location within the GI tract in which the extended-release drug product should release the drug. This specific drug absorption site or location within the GI tract is referred to as an absorption window. The absorption window is the optimum site for drug absorption. If drug is not released and available for absorption within the absorption window, the extended release tablet moves further distally in the GI tract and incomplete drug absorption may occur.
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Stomach
++The stomach is a “mixing and secreting” organ, where food is mixed with digestive juices and emptied periodically into the small intestine. However, the movement of food or drug product in the stomach and small intestine is very different depending on the physiologic state. In the presence of food, the stomach is in the digestive phase; in the absence of food, the stomach is in the interdigestive phase [Chapter 13]. During the digestive phase, food particles or solids larger than 2 mm are retained in the stomach, whereas smaller particles are emptied through the pyloric sphincter at a first-order rate depending on the content and size of the meals. During the interdigestive phase, the stomach rests for a period of up to 30 to 40 minutes, coordinated with an equal resting period in the small intestine. Peristaltic contractions then occur, which end with strong housekeeper contractions that move everything in the stomach through to the small intestine. Similarly, large particles in the small intestine are moved along only in the housekeeper contraction period.
++A drug may remain for several hours in the stomach if it is administered during the digestive phase. Fatty material, nutrients, and osmolality may further extend the time the drug stays in the stomach. When the drug is administered during the interdigestive phase, the drug may be swept along rapidly into the small intestine. Dissolution of drugs in the stomach may also be affected by the presence or absence of food. When food is present, HCl is secreted and the pH is about 1 to 2. Although some food and nutrients can neutralize the acid and raise stomach pH, the fasting pH of the stomach is about 3 to 5. The drug release rates from some extended-release drug products are affected by food. For example, an older extended-release drug product, Theo-24 [theophylline, anhydrous] extended-release capsule, releases drug at a higher rate in the presence of food compared to fasting conditions [Chapter 13]. This more rapid drug release rate appeared to be related to food in the GI tract, a change in pH, the stomach-emptying rate, or a food interaction affecting the extended-release formulation. After the introduction of Theo-24, food effect studies were initiated on all new drug products. A longer time of retention in the stomach may expose the drug to stronger agitation in the acid environment. The stomach has been described as having “jet mixing” action, which sends mixture at up to 50 mm Hg pressure toward the pyloric sphincter, causing it to open and periodically release chyme to the small intestine.
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Small Intestine and Transit Time
++The small intestine is about 10 to 14 ft in length. The duodenum is sterile, while the terminal part of the small intestine that connects the cecum contains some bacteria. The proximal part of the small intestine has a pH of about 6, because of neutralization of acid by bicarbonates secreted into the lumen by the duodenal mucosa and the pancreas. The small intestine provides an enormous surface area for drug absorption because of the presence of microvilli. The small-intestine transit time of a solid preparation has been concluded to be about 3 hours or less in 95% of the population [Hofmann et al, 1983]. Transit time for meals from mouth to cecum [beginning of large intestine] has been reviewed by Shareef et al [2003]. Various investigators have used the lactulose hydrogen test, which measures the appearance of hydrogen in a patient's breath, to estimate transit time. Lactulose is metabolized rapidly by bacteria in the large intestine, yielding hydrogen that is exhaled. Hydrogen is normally absent in a person's breath. These results and the use of gamma-scintigraphy studies confirm a relatively short GI transit time from mouth to cecum of 4 to 6 hours.
++This transit time interval was concluded to be too short for extended-release dosage forms that last up to 12 hours, unless the drug is to be absorbed in the colon. The colon has little fluid and the abundance of bacteria may make drug absorption erratic and incomplete. The transit time for pellets has been studied in both disintegrating and nondisintegrating forms using both insoluble and soluble radiopaques. Most of the insoluble pellets were released from the capsule within 15 minutes. Scattering of pellets was seen in the stomach and along the entire length of the small intestine at 3 hours. At 12 hours most of the pellets were in the ascending colon, and at 24 hours the pellets were all in the descending colon, ready to enter the rectum. With the disintegrating pellets, there was more scattering of the pellets along the GI tract. The pellets also varied widely in their rate of disintegration in vivo [Galeone et al, 1981].
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Large Intestine
++The large intestine is about 4 to 5 ft long. It consists of the cecum, the ascending and descending colons, and eventually ends at the rectum. Little fluid is in the colon, and drug transit is slow. Not much is known about drug absorption in this area, although unabsorbed drug that reaches this region may be metabolized by bacteria. Incompletely absorbed antibiotics may affect the normal flora of the bacteria. The rectum has a pH of about 6.8 to 7.0 and contains more fluid compared to the colon. Drugs are absorbed rapidly when administered as rectal preparations. However, the transit rate through the rectum is affected by the rate of defecation. Presumably, drugs formulated for 24 hours' duration must remain in this region to be absorbed.
++Several extended-release and delayed-release drug products, such as mesalamine delayed-release tablets [Asacol], are formulated to take advantage of the physiologic conditions of the GI tract [Shareef et al, 2003]. Enteric-coated beads have been found to release drug over 8 hours when taken with food, because of the gradual emptying of the beads into the small intestine. Specially formulated “floating tablets” that remain in the top of the stomach have been used to extend the residence time of the product in the stomach. None of these methods, however, is consistent enough to perform reliably for potent medications. More experimental research is needed in this area.
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Dosage Form Selection
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The properties of the drug and required dosage are important in formulating an extended-release product. For example, a drug with low aqueous solubility generally should not be formulated into a nondisintegrating tablet, because the risk of incomplete drug dissolution is high. Instead, a drug with low solubility at neutral pH should be formulated, so that most of the drug is released before it reaches the colon, since the lack of fluid in the colon may make complete dissolution difficult. Erosion tablets are more reliable for these drugs because the entire tablet eventually dissolves.
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A drug that is highly water soluble in the acid pH in the stomach but very insoluble at intestinal pH may be very difficult to formulate into an ER drug product. An ER drug product with too much coating protection may result in low drug bioavailability, while too little coating protection may result in rapid drug release or dose dumping in the stomach. A moderate extension of duration with enteric-coated beads may be possible. However, the risk of erratic performance is higher than with a conventional dosage form. The osmotic type of controlled drug release system may be more suitable for this type of drug.
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With most single-unit dosage forms, there is a risk of erratic performance due to variable stomach emptying and GI transit time. Selection of a pellet or bead dosage form may minimize the risk of erratic stomach emptying, because pellets are usually scattered soon after ingestion. Disintegrating tablets have the same advantages because they break up into small particles soon after ingestion.
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Advantages and Disadvantages of Extended-Release Products
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ER drug products offer several important advantages over immediate-release dosage forms of the same drug. Extended release allows for sustained therapeutic blood levels of the drug; sustained blood levels provide for a prolonged and consistent clinical response in the patient. Moreover, if the drug input rate is constant, the blood levels should not fluctuate between a maximum and minimum compared to a multiple-dose regimen with an immediate-release drug product [Chapter 8]. Highly fluctuating blood concentrations of drug may produce unwanted side effects in the patient if the drug level is too high, or may fail to exert the proper therapeutic effect if the drug level is too low. Another advantage of extended release is patient convenience, which leads to better patient compliance. For example, if the patient needs to take the medication only once daily, he or she will not have to remember to take additional doses at specified times during the day. Furthermore, because the dosage interval is longer, the patient's sleep may not be interrupted to take another drug dose. With longer therapeutic drug concentrations, the patient awakes without having subtherapeutic drug levels. The patient may also derive an economic benefit in using an extended-release drug product. A single dose of an extended-release product may cost less than an equivalent drug dose given several times a day in rapid-release tablets. For patients under nursing care, the cost of nursing time required to administer medication is decreased if only one drug dose is given to the patient each day.
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For some drugs with long elimination half-lives, such as chlorpheniramine, the inherent duration of pharmacologic activity is long. Minimal fluctuations in blood concentrations of these drugs are observed after multiple doses are administered. Therefore, there is no rationale for extended-release formulations of these drugs. However, such drug products are marketed with the justification that extended-release products minimize toxicity, decrease adverse reactions, and provide patients with more convenience and, thus, better compliance. In contrast, drugs with very short half-lives need to be given at frequent dosing intervals to maintain therapeutic efficacy. For drugs with very short elimination half-lives, an extended-release drug product maintains the efficacy over a longer duration.
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There are also a number of disadvantages in using extended-release medication. If the patient suffers from an adverse drug reaction or accidentally becomes intoxicated, the removal of drug from the system is more difficult with an extended-release drug product. Orally administered extended-release drug products may yield erratic or variable drug absorption as a result of various drug interactions with the contents of the GI tract and changes in GI motility. The formulation of extended-release drug products may not be practical for drugs that are usually given in large doses [eg, 500 mg] in conventional dosage forms. Because the extended-release drug product may contain two or more times the dose given at more frequent intervals, the size of the extended-release drug product may have to be quite large, too large for the patient to swallow easily.
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The extended-release dosage form contains the equivalent of two or more drug doses given in a conventional dosage form. Therefore, failure of the extended-release dosage form may lead to dose dumping. Dose dumping is defined either as the release of more than the intended fraction of drug or as the release of drug at a greater rate than the customary amount of drug per dosage interval, such that potentially adverse plasma levels may be reached [Dighe and Adams, 1988; Skelly and Barr, 1987]. With delayed release or enteric drug products, two possible problems may occur if the enteric coating is poorly formulated. First, the enteric coating may become degraded in the stomach, allowing for early release of the drug, possibly causing irritation to the gastric mucosal lining. Second, the enteric coating may fail to dissolve at the proper site, and therefore the tablet may be lost prior to drug release, resulting in incomplete absorption.
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In recent years, pharmaceutical manufacturers have made new extended-release drug products of branded drugs that are losing patent protection. Although these extended-release drug products may have some of the advantages stated above, the cost of the medication may be much higher than that of the generic drug in a conventional drug product given several times a day.
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Kinetics of Extended-Release Dosage Forms
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The amount of drug required in an extended-release dosage form to provide a sustained drug level in the body is determined by the pharmacokinetics of the drug, the desired therapeutic level of the drug, and the intended duration of action. In general, the total dose required [Dtot] is the sum of the maintenance dose [Dm] and the initial dose [DI] released immediately to provide a therapeutic blood level.
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In practice, Dm [mg] is released over a period of time and is equal to the product of td [the duration of drug release] and the zero-order rate kr0 [mg/h]. Therefore, Equation 17.1 can be expressed as
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Ideally, the maintenance dose [Dm] is released after DI has produced a blood level equal to the therapeutic drug level [Cp]. However, due to the limits of formulations, Dm actually starts to release at t = 0. Therefore, DI may be reduced from the calculated amount to avoid “topping.”
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Equation 17.3 describes the total dose of drug needed, with tp representing the time needed to reach peak drug concentration after the initial dose.
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For a drug that follows a one-compartment open model, the rate of elimination [R] needed to maintain the drug at a therapeutic level [Cp] is
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where kr0 must be equal to R in order to provide a stable blood level of the drug. Equation 17.4 provides an estimation of the release rate [kr0] required in the formulation. Equation 17.4 may also be written as
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where ClT is the clearance of the drug. In designing an extended-release product, DI would be the loading dose that would raise the drug concentration in the body to Cp, and the total dose needed to maintain therapeutic concentration in the body would be simply
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For many sustained-release drug products, there is no built-in loading dose [ie, DI = 0]. The dose needed to maintain a therapeutic concentration for τ hours is
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where τ is the dosing interval.
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Example
What dose is needed to maintain a therapeutic concentration of 10 μg/mL for 12 hours in a sustained-release product? [a] Assume that t1/2 for the drug is 3.46 hours and VD is 10 L. [b] Assume that t1/2 of the drug is 1.73 hours and VD is 5 L.
From Equation 17.7,
From Equation 17.8,
In this example, the amount of drug needed in a sustained-release product to maintain therapeutic drug concentration is dependent on both VD and the elimination half-life. In part b of the example, although the elimination half-life is shorter, the volume of distribution is also smaller. If the volume of distribution is constant, then the amount of drug needed to maintain Cp is dependent simply on the elimination half-life.
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Table 17-2 shows the influence of t1/2 on the amount of drug needed for an extended-release drug product. Table 17-2 was constructed by assuming that the drug has a desired serum concentration of 5 μg/mL and an apparent volume of distribution of 20,000 mL. The release rate needed to achieve the desired concentration, R decreases as the elimination half-life increases. Because elimination is slower for a drug with a long half-life, the input rate should be slower. The total amount of drug needed in the extended-release drug product is dependent on both the release rate R and the desired duration of activity for the drug. For a drug with an elimination half-life of 4 hours and a release rate of 17.3 mg/h, the extended-release product must contain 207.6 mg to provide a duration of activity of 12 hours. The bulk weight of the extended-release product will be greater than this amount, due to the presence of excipients needed in the formulation. The values in Table 17-2 show that, in order to achieve a long duration of activity [≥12 hours] for a drug with a very short half-life [1–2 hours], the extended-release drug product becomes quite large and impractical for most patients to swallow.
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Table Graphic Jump Location
Table 17-2 Release Rates for Extended-Release Drug Products as a Function of Elimination Half-Lifea
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Table 17-2 Release Rates for Extended-Release Drug Products as a Function of Elimination Half-LifeaTotal [mg] to Achieve Durationt1/2 [h]k [h–1]R [mg/h]6 h8 h12 h24 h10.69369.3415.8554.4831.6166320.34734.7208.2277.6416.4832.840.17317.3103.8138.4207.6415.260.11611.669.692.8139.2278.480.08668.6652.069.3103.9207.8100.06936.9341.655.483.2166.3120.05775.7734.646.269.2138.5
aAssume Cdesired is 5 μg/mL and the VD is 20,000 mL; R = kVDCp: no immediate-release dose.
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Pharmacokinetic Simulation of Extended-Release Products
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The plasma drug concentration profiles of many extended-release products fit an oral one-compartment model assuming first-order absorption and elimination. Compared to an immediate-release product, the extended-release product typically shows a smaller absorption rate constant, because of the slower absorption of the extended-release product. The time for peak concentration [tmax] is usually longer [Fig. 17-5], and the peak drug concentration [Cmax] is reduced. If the drug is properly formulated, the area under the plasma drug concentration curve should be the same. Parameters such as Cmax, tmax, and area under the curve [AUC] conveniently show how successfully the extended-release product performs in vivo. For example, a product with a tmax of 3 hours would not be very satisfactory if the product is intended to last 12 hours. Similarly, an excessively high Cmax is a sign of dose dumping due to inadequate formulation. The pharmacokinetic analysis of single- and multiple-dose plasma data has been used by regulatory agencies to evaluate many sustained-release products. The analysis is practical because many products can be fitted to this model even though the drug is not released in a first-order manner. The limitation of this type of analysis is that the absorption rate constant may not relate to the rate of drug dissolution in vivo. If the drug strictly follows zero-order release and absorption, the model may not fit the data.
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Figure 17-5Graphic Jump Location
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Plasma drug concentration of a sustained-release and a regular-release product. Note the difference of peak time and peak concentration of the two products.
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Various other models have been used to simulate plasma drug levels of extended-release products [Welling, 1983]. The plasma drug levels from a zero-order, extended-release drug product may be simulated with Equation 17.8.
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where R = rate of drug release [mg/min], Cp = plasma drug concentration, k = overall elimination constant, and VD = volume of distribution. In the absence of a loading dose, the drug level in the body rises slowly to a plateau with minimum fluctuations [Fig. 17-6]. This simulation assumes that [1] rapid drug release occurs without delay, [2] perfect zero-order release and absorption of the drug takes place, and [3] the drug is given exactly every 12 hours. In practice, the above assumptions are not precise, and fluctuations in drug level do occur.
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Figure 17-6Graphic Jump Location
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Simulated plasma drug level of a extended-release product administered every 12 hours. The plasma level shows a smooth rise to steady-state level with no fluctuations.
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When a sustained-release drug product with a loading dose [rapid release] and a zero-order maintenance dose is given, the resulting plasma drug concentrations are described by
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where Di = immediate-release [loading dose] dose and Ds = maintenance dose [zero-order]. This expression is the sum of the oral absorption equation [first part] and the intravenous infusion equation [second part].
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Extended-Release Drug Product with Immediate-Release Component
++Extended-release drug products may be formulated with or without an immediate release loading dose. Extended-release drug products that are given to patients in daily multiple doses to maintain steady state therapeutic drug concentrations do not need a built-in loading dose when given subsequent doses. Pharmacokinetic models have been proposed for extended-release drug products that have a rapid first-order drug release component and a slow zero-order release maintenance dose component. This model assumes a long elimination t1/2 in which drug accumulation occurs until steady-state is attained. The model predicts spiking peaks due to the loading dose component when the extended-release drug product is given continuously in multiple doses. In this model, a rapid-release loading dose along with the extended-release drug dose given in a daily multiple dose regimen introduces more drug into the body than is necessary. This is observed by a “topping” effect.
++When a loading dose is necessary, a rapid- or immediate-release drug product may be given separately as a loading dose to initially bring the patient's plasma drug level to the desired therapeutic level. In certain clinical situations, an extended-release drug product with an immediate-release component along with a controlled-release core can provide a specific pharmacokinetic profile that provides rapid onset and prolonged plasma drug concentrations that relates to the time course for the desired pharmadynamic activity. For these extended-release drug products with initial immediate-release components, the active drug must have a relatively short elimination t1/2 so that the drug does not accumulate between dosing.
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Clinical Examples
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Methylphenidate HCl Extended-Release Tablets [Concerta®]
++Methylphenidate HCl is a CNS [central nervous system] stimulant indicated for the treatment of attention deficit hyperactivity disorder [ADHD] and is often used in children 6 years of age and older. Methylphenidate is readily absorbed after oral administration and has an elimination t1/2 of about 3.5 hours. Methylphenidate HCl extended-release tablets [Concerta] have an osmotically active controlled release core with an immediate-release drug overcoat. After oral administration of Concerta, the plasma methylphenidate concentration increases rapidly reaching an initial maximum at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours after which a gradual decrease begins. Mean tmax occurs between 6 to 10 hours. When the patient takes this product in the morning, the patient receives an initial loading dose followed by a maintenance dose that is eliminated by the evening when the patient wants to go to sleep. Due to the short elimination t1/2, the drug does not accumulate.
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Zolpidem Tartrate Extended-Release Tablets [Ambien CR]
++Zolpidem tartrate extended-release tablets are indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Zolpidem has a mean elimination t1/2 of 2.5 hours. Zolpidem tartrate extended-release tablets exhibits biphasic absorption characteristics, which results in rapid initial absorption from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides extended plasma concentrations beyond 3 hours after administration.1 Patients who use this product have a more rapid onset of sleep due to the initial dose and are able to maintain sleep due to the maintenance dose. Due to the short elimination t1/2, the drug does not accumulate.
++1Approved label for Ambien CR, April 2010.
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Types of Extended-Release Products
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The pharmaceutical industry has been developing newer modified-release drug products at a very rapid pace. Many of these modified-release drug products have patented drug delivery systems. This chapter provides an overview of some of the more widely used methods for the manufacture of modified drug products.
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The extended-release drug product is designed to contain a drug dose which will release drug at a desired rate over a specified period of time. As discussed previously, the extended-release drug product may also contain an immediate-release component. The general approaches to manufacturing an extended-release drug product include the use of a matrix structure in which the drug is suspended or dissolved, the use of a rate-controlling membrane through which the drug diffuses, or a combination of both. None of the extended-release drug products works by a single drug-release mechanism. Most extended-release products release drug by a combination of processes involving drug dissolution, permeation, erosion, and diffusion. The single most important factor is water permeation into the drug product, without which none of the product release mechanisms would operate. Controlling the rate of water influx into the product generally dictates the rate at which the drug dissolves in the gastrointestinal tract. Once the drug is dissolved, the rate of drug diffusion may be further controlled to a desirable rate. Table 17-3 describes some common extended-release product examples and the mechanisms for controlling drug release. Table 17-4 lists the composition for some drugs.
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Table 17-3 Examples of Oral Modified-Release Drug Products
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Table 17-3 Examples of Oral Modified-Release Drug ProductsTypeTrade NameRationaleExtended-Release Drug ProductsErosion tabletConstant-TTheophyllineTenuate DospanDiethylpropion HCl dispersed in hydrophilic matrixTedral SACombination product with a slow-erosion component [theophylline, ephedrine HCl] and an initial-release component theophylline, ephedrine HCl, phenobarbital]Waxy matrix tabletKaon CISlow release of potassium chloride to reduce GI irritationCoated pellets in capsuleOrnade spansuleCombination phenylpropanolamine HCl and chlorpheniramine with initial-and extended-release componentPellets in tabletTheo-DurTheophyllineLeachingFerro-Gradumet [Abbott]Ferrous sulfate in a porous plastic matrix that is excreted in the stool; slow release of iron decreases GI irritationDesoxyn gradumet tablet [Abbott]Methamphetamine methylacrylate methylmethacrylate copolymer, povidone, magnesium stearate; the plastic matrix is porousCoated ion exchangeTussionexCation ion-exchange resin complex of hydrocodone and phenyltoloxamineFlotation–diffusionValreleaseDiazapamOsmotic deliveryAcutrimPhenylpropanolamine HCl [Oros delivery system]Procardia-XLGITS—Gastrointestinal therapeutic system with NaCl-driven [osmotic pressure] delivery system for nifedipineMicroencapsulationBayer timed-releaseAspirinNitrospanMicroencapsulated nitroglycerinMicro-K ExtencapsPotassium chloride microencapsulated particlesDelayed-release drug productsdiclofenac sodium enteric-coated tabletsEnteric coating dissolves at pH >5 for release of drug in duodenummesalamine] delayed-release tabletsDelayed-release tablets are coated with acrylic based resin, Eudragit S [methacrylic acid copolymer B, NF], which dissolves at pH 7 or greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colonOrally disintegrating tables
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Table 17-4 Composition and Examples of Some Modified-Release Products
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Table 17-4 Composition and Examples of Some Modified-Release ProductsK-Tab [Abbott]750 mg or 10 mEq of potassium chloride in a film-coated matrix tablet. The matrix may be excreted intact, but the active ingredient is released slowly without upsetting the GI tract.Inert ingredients: Cellulosic polymers, castor oil, colloidal silicon dioxide, polyvinyl acetate, paraffin. The product is listed as a waxy/polymer matrix tablet for release over 8–10 h.Toprol-XL tablets [Astra]Contains metoprolol succinate for sustained release in pellets, providing stable beta-blockade over 24 h with one daily dose. Exercise tachycardia was less pronounced compared to immediate-release preparation. Each pellet separately releases the intended amount of medication.Inert ingredients: Paraffin, PEG, povidone, acetyltributyl citrate, starch, silicon dioxide, and magnesium stearate.Quinglute Dura tablets [Berlex]Contains 320 mg quinidine gluconate in a prolonged-action matrix tablet lasting 8–12 h and provides PVC protection.Inert ingredients: Starch, confectioner's sugar and magnesium stearate.Brontil Slow-Release capsules [Carnrick]Phendimetrazine tartrate 105 mg sustained pellet in capsule. Slow Fe tablets [Ciba]Slow-release iron preparation [OTC medication] with 160 mg ferrous sulfate for iron deficiency.Inert ingredients: HPMC, PEG shellac, and cetostearyl alcohol.Tegretol-XR tablets [Ciba Geneva]Carbamazepine extended-release tablet.Inert ingredients: Zein, cetostearyl alcohol, PEG, starch, talc, gum tragacanth, and mineral oil.Sinemed CR tablets [Dupont pharma]Contains a combination of carbidopa and levodopa for sustained-release delivery. This is a special erosion polymeric tablet for Parkinson's disease treatment.Pentasa capsules [Hoechst Marion/Roussel]Contains mesalamine for ulcerative colitis in a sustained-release mesalamine coated with ethylcellulose. For local effect mostly, about 20% absorbed versus 80% otherwise.Isoptin SR [Knoll]Verapamil HCl sustained-release tablet.Inert ingredients: PEG, starch, PVP, alginate, talc, HPMC, methylcellulose, and microcrystalline cellulose.Pancrease capsules [McNeil]Enteric-coated microspheres of pancrelipase. Protects the amylase, lipase, and protease from the action of acid in the stomach.Inert ingredients: CAP, diethyl phthalate, sodium starch glycolate, starch, sugar, gelatin, and talc.Cotazym-S [Organon]Enteric-coated microspheres of pancrelipase.Eryc [erythromycin delayed-release capsules] [Warner-Chilcott]Erythromycin enteric-coated tablet that protects the drug from instability and irritation.Dilantin Kapseals [Parke-Davis]Extended-release phenytoin capsule which contains beads of sodium phenytoin, gelatin, sodium lauryl sulfate, glyceryl monooleate, PEG 200, silicon dioxide, and talc.Micro-K Extencaps [Robbins]Ethylcellulose forms semipermeable film surrounding granules by microencapsulation for release over 8–10 h without local irritation.Inert ingredients: Gelatin, and sodium lauryl sulfate.Quinidex Extentabs [Robbins]300-mg dose, 100-mg release immediately in the stomach and is absorbed in the small intestine. The rest is absorbed later over 10–12 h in a slow-dissolving core as it moves down the GI tract.Inert ingredients: White wax, carnauba wax, acacia, acetylated monoglyceride, guar gum, edible ink, calcium sulfate, corn derivative, and shellac.Compazine Spansules [GSK]Initial dose of prochlorperazine release first, then release slowly over several hours.Inert ingredients: Glycerylmonostearate, wax, gelatin, sodium lauryl sulfate.Slo-bid Gyrocaps [Rhone-Poulenc Rorer]A controlled-release 12–24-h theophylline product.Theo-24 capsules [UCB Pharma]A 24-hr sustained-release theophylline product.Inert ingredients: Ethylcellulose, edible ink, talc, starch, sucrose, gelatin, silicon dioxide, and dyes.Sorbitrate SA [Zeneca]The tablet contains isosorbide dinitrate 10 mg in the outer coat and 30 mg in the inner coat.Inert ingredients: Carbomer 934P, ethylcellulose, lactose magnesium stearate, and Yellow No. 10.
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Drug Release from Matrix
++A matrix is an inert solid vehicle in which a drug is uniformly suspended. A matrix may be formed by compressing or fusing the drug and the matrix material together. Generally, the drug is present in a small percentage, so that the matrix protects the drug from rapid dissolution and the drug slowly diffuses out over time. Most matrix materials are water insoluble, although some matrix materials may swell slowly in water. Drug release using a matrix dosage form may be achieved using tablets or small beads, depending on the formulation composition and therapeutic objective. Figure 17-7 shows three common approaches by which matrix mechanisms are employed. In Fig. 17-7A, the drug is coated with a soluble coating, so drug release relies solely on the regulation of drug release by the matrix material. If the matrix is porous, water penetration will be rapid and the drug will diffuse out rapidly. A less porous matrix may give a longer duration of release. Unfortunately, drug release from a simple matrix tablet is not zero order. The Higuchi equation describes the release rate of a matrix tablet:
++where Q = amount of drug release per cm2 of surface at time t, S = solubility of drug in g/cm3 in the dissolution medium, A = content of drug in insoluble matrix, P = porosity of matrix, D = diffusion coefficient of drug, and λ = tortuosity factor.
++Figure 17-7Graphic Jump Location
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Examples of three different types of modified matrix-release mechanisms.
++Figure 17-7B represents a matrix enclosed by an insoluble membrane, so the drug release rate is regulated by the permeability of the membrane as well as the matrix. Fig. 17-7C represents a matrix tablet enclosed with a combined film. The film becomes porous after dissolution of the soluble part of the film. An example of this is the combined film formed by ethylcellulose and methylcellulose. Close to zero-order release has been obtained with this type of release mechanism.
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Gum-Type Matrix Tablets
++Some excipients have a remarkable ability to swell in the presence of water and form a substance with a gel-like consistency. When this happens, the gel provides a natural barrier to drug diffusion from the tablet. Because the gel-like material is quite viscous and may not disperse for hours, this approach provides a means for maintaining the drug for hours until all the drug has been completely dissolved and diffused into the intestinal fluid. Gelatin is a common gelling material. However, gelatin dissolves rapidly after the gel is formed. Drug excipients such as methylcellulose, gum tragacanth, Veegum, and alginic acid form a viscous mass and provide a useful matrix for controlling drug release and dissolution. Drug formulations with these excipients provide extended drug release for hours.
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Polymeric Matrix Tablets
++Various polymeric materials have been used to prolong the rate of drug release. The most important characteristic of this type of preparation is that the prolonged release may last for days or weeks rather than for a shorter duration [as with other techniques]. An early example of an oral polymeric matrix tablet was Gradumet [Abbott Laboratories], which was marketed as an iron preparation. The non-biodegradable plastic matrix provides a rigid geometric surface for drug diffusion, so that a relatively constant rate of drug release is obtained. In the case of the iron preparation, the matrix reduces the exposure of the irritating drug to the GI mucosal tissues. The matrix is usually expelled unchanged in the feces after all the drug has leached out.
++Polymeric matrix tablets for oral use are generally quite safe. However, for certain patients with reduced GI motility caused by disease, polymeric matrix tablets should be avoided, because accumulation or obstruction of the GI tract by matrix tablets has been reported. As an oral sustained-release product, the matrix tablet has not been popular. In contrast, the use of the matrix tablet in implantation has been more popular.
++The use of biodegradable polymeric material for extended release has been the focus of more recent research. One such example is polylactic acid copolymer, which degrades to lactic acid and eliminates the problem of retrieval after implantation.
++Other polymers for drug formulations include polyacrylate, methacrylate, polyester, ethylene—vinyl acetate copolymer [EVA], polyglycolide, polylactide, and silicone. Of these, the hydrophilic polymers, such as polylactic acid and polyglycolic acid, erode in water and release the drug gradually over time. A hydrophobic polymer such as EVA releases the drug over a longer duration time of weeks or months. The rate of release may be controlled by blending two polymers and increasing the proportion of the more hydrophilic polymer, thus increasing the rate of drug release. The addition of a low-molecular-weight polylactide to a polylactide polymer formulation increased the release rate of the drug and enabled the preparation of an extended-release system [Bodmeier et al, 1989]. The type of plasticizer and the degree of cross-linking provide additional means for modifying the release rate of the drug. Many drugs are incorporated into the polymer as the polymer is formed chemically from its monomer. Light, heat, and other agents may affect the polymer chain length, degree of cross-linking, and other properties. This may provide a way to modify the release rate of the polymer matrices prepared. Drugs incorporated into polymers may have release rates that last over days, weeks, or even months. These vehicles have been often recommended for protein and peptide drug administration. For example, EVA is biocompatible and was shown to prolong insulin release in rats.
++Hydrophobic polymers with water-labile linkages are prepared so that partial breakdown of the polymers allows for desired drug release without deforming the matrix during erosion. For oral drug delivery, the problem of incomplete drug release from the matrix is a major hurdle that must be overcome with the polymeric matrix dosage form. Another problem is that drug release rates may be affected by the amount of drug loaded. For implantation and other uses, the environment is more stable compared to oral routes, so a stable drug release from the polymer matrix may be attained for days or weeks.
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Slow-Release Pellets, Beads or Granules
++Pellets or beads are small spherical particles that can be formulated to provide a variety of modified drug release properties. The size of these beads can be very small [microencapsulation] for injections or larger for oral drug delivery. Several approaches have been used to manufacture beaded formulations incuding pan coating, spray drying, fluid bed drying, and extrusion-spheronization.
++An early approach to the manufacture of ER drug products was the use of encapsulated drugs in a beaded or pellet formulation. In general, the beads are prepared by coating the powdered drug onto preformed cores known as nonpareil seeds. The nonpareil seeds are made from a slurry of starch, sucrose, and lactose. The drug-coated beads are then coated by a variety of materials that act as a barrier to drug release. The beads may have a blend of different thicknesses to provide the desired drug release. The beads may be placed in a capsule [eg, amphetamine ER capsules, Adderall XR] or with the addition of other excipients compressed into tablets [eg, metoprolol succinate extended-release tablets, Toprol XL].
++Pan coating is a modified method adopted from candy manufacturing. Cores or nonpareil seeds of a given mesh size are slowly added to known amount of fine drug powder and coating solution and rounded for hours to become coated drug beads. The drug-coated beads are then coated with a polymeric layer which regulates drug release rate by changing either the thickness of the film or the composition of the polymeric material. Coatings may be aqueous or nonaqueous. Aqueous coatings are generally preferred. Nonaqueous coatings may leave residual solvents in the product, and the removal of solvents during manufacture presents danger to workers and the environment. Cores are coated by either sprayed pan coating or by air-suspension coating. Once the drug beads are prepared, they may be further coated with a protective coating to allow a sustained or prolonged release of the drug. Spray dry coating or fluid-bed coating is a more recent approach and has several advantages over pan coating. Drug may be dissolved in a solution that is sprayed or dispersed in small droplets in a chamber. A stream of hot air evaporates the solvent and the drug becomes a dry powder. The powdered material which is aerated may be coated with a variety of excipients to achieve the desired drug release. Several experimental process variables for fluid-bed coating include inlet air temperature, spray rate [g/min], atomizing air pressure, solid content, and curing time. Pelletization may also be obtained by extrusion-spheronization in which the powdered drug and excipients are mixed in a mixer/granulator. The moist mixture is then fed through an extruder at a specified rate and becomes spheronized on exit though small diameter dies. A wide range of extrusion screen sizes and configurations are available for optimization of pellet diameter.
++The use of various amounts of coating solution can provide beads with various coating protection. A careful blending of beads is used to achieve a desired drug release profile. The finished drug product [eg, beads in capsule or beads in tablet] may contain a blend of beads coated with materials of different solubility rates to provide a means of controlling drug release and dissolution.
++Some products take advantage of bead blending to provide two doses of drug in one formulation. For example, a blend of rapid-release beads with some pH-sensitive enteric-coated material may provide a second dose of drug release when the drug reaches the intestine.
++The pellet dosage form can be prepared as a capsule or tablet. When pellets are prepared as tablets, the beads must be compressed lightly so that they do not break. Usually, a disintegrant is included in the tablet, causing the beads to be released rapidly after administration. Formulation of a drug into pellet form may reduce gastric irritation, because the drug is released slowly over a period of time, therefore avoiding high drug concentration in the stomach. Dextroamphetamine sulfate formulated as timed-release pellets in capsules [Dexedrine Spansule] is an early example of a beaded dosage form. Another older product is a pellet-type extended-release product of theophylline [Gyrocap]. Table 17-5 shows the frequency of adverse reactions after theophylline is administered as a solution or as pellets. If theophylline is administered as a solution, a high drug concentration is reached in the body due to rapid drug absorption. Some side effects may be attributed to the high concentration of theophylline. Pellet dosage forms allows drug to be absorbed gradually, therefore reducing the incidence of side effects by preventing a high Cmax.
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Table 17-5 Incidence of Adverse Effects of Sustained-Release Theophylline Pellet versus Theophylline Solutiona
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Table 17-5 Incidence of Adverse Effects of Sustained-Release Theophylline Pellet versus Theophylline SolutionaVolunteers Showing Side EffectsSide EffectsUsing SolutionUsing Sustained-Release PelletsNausea100Headache40Diarrhea30Gastritis20Vertigo50Nervousness31
aAfter 5-day dosing at 600 mg theophylline/24 h, adverse reaction points on fifth day: solution, 135; pellets, 18.
From Breimer and Dauhof [1980], with permission.
++Bitolterol mesylate [Tornalate] is a β2-adrenergic receptor agonist used as a bronchodilator in asthma. A study in dogs indicated that the incidence of tachycardia was reduced using an extended-release bead preparation, whereas the bronchodilation effect was not reduced. Administering the drug as extended-release pellets apparently reduced excessively high drug concentration in the body and avoided stimulating an increase in heart rate. Studies also reported reduced gastrointestinal side effects of the drug potassium chloride in pellet or microparticulate form. Potassium chloride is irritating to the GI tract. Formulation of potassium chloride in pellet form reduces the chance of exposing high concentrations of potassium chloride to the mucosal cells in the GI tract.
++Many extended-release cold products also employ the bead formulation approach. A major advantage of pellet dosage forms is that the pellets are less affected by stomach emptying. Because numerous pellets are within a capsule, some pellets will gradually reach the small intestine each time the stomach empties, whereas a single extended-release tablet may be delayed in the stomach for a long time as a result of erratic stomach emptying. Stomach emptying time is particularly important in the formulation and in vivo behavior of enteric-coated products. Enteric-coated tablets may be delayed for hours by the presence of food in the stomach, whereas enteric-coated pellets are relatively unaffected by the presence of food.
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Prolonged-Action Tablets
++An alternate approach to prolong the action of a drug is to reduce the aqueous solubility of the drug, so that the drug dissolves slowly over a period of several hours. The solubility of a drug is dependent on the salt form used. An examination of the solubility of the various salt forms of the drug is performed in early drug development. In general, the nonionized base or acid form of the drug is usually much less soluble than the corresponding salt. For example, sodium phenobarbital is more water soluble than phenobarbital, the acid form of the drug. Diphenhydramine hydrochloride is more soluble than the base form, diphenhydramine.
++In cases where it is inconvenient to prepare a less soluble form of the drug, the drug may be granulated with an excipient to slow dissolution of the drug. Often, fatty or waxy lipophilic materials are employed in formulations. Stearic acid, castor wax, high-molecular-weight polyethylene glycol [Carbowax], glyceryl monosterate, white wax, and spermaceti oil are useful ingredients in providing an oily barrier to slow water penetration and the dissolution of the tablet. Many of the lubricants used in tableting may also be used as lipophilic agents to slow dissolution. For example, magnesium stearate and hydrogenated vegetable oil [Sterotex] are actually used in high percentages to cause sustained drug release in a preparation. The major disadvantage of this type of preparation is the difficulty in maintaining a reproducible drug release from patient to patient, because oily materials may be subjected to digestion, temperature, and mechanical stress, which may affect the release rate of the drug.
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Ion-Exchange Products
++Ion-exchange preparations usually involve an insoluble resin capable of reacting with either an anionic or cationic drug. An anionic resin is negatively charged so that a positively charged cationic drug may react with the resin to form an insoluble nonabsorbable resin–drug complex. Upon exposure in the GI tract, cations in the gut, such as potassium and sodium, may displace the drug from the resin, releasing the drug, which is absorbed freely. The main disadvantage of ion-exchange preparations is that the amount of cation–anion in the GI tract is not easily controllable and varies among individuals, making it difficult to provide a consistent mechanism or rate of drug release. A further disadvantage is that resins may provide a potential means of interaction with nutrients and other drugs.
++Ion exchange may be used in extended-release liquid preparations. An added advantage is that the technique provides some protection for very bitter or irritating drugs. Ion exchange has been combined with a coating to obtain a more effective sustained-release product. Examples include dextromethorphan polistirex [Delsyn®], an oral suspension formulated as an ion-exchange complex to mask the bitter taste and to prolong the duration of drug action, and Tussionex Pennkinetic®, an oral suspension containing chlorpheniramine polistirex and hydrocodone polistirex.
++A general mechanism for the formulation of cationic drugs is
++For anionic drugs, the corresponding mechanism is
++The insoluble drug complex containing the resin and drug dissociates in the GI tract in the presence of the appropriate counter ions. The released drug dissolves in the fluids of the GI tract and is rapidly absorbed.
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Core Tablets
++A core tablet is a tablet within a tablet. The inner core is usually used for the slow-drug-release component, and the outside shell contains a rapid-release dose of drug. Formulation of a core tablet requires two granulations. The core granulation is usually compressed lightly to form a loose core and then transferred to a second die cavity, where a second granulation containing additional ingredients is compressed further to form the final tablet.
++The core material may be surrounded by hydrophobic excipients so that the drug leaches out over a prolonged period of time. This type of preparation is sometimes called a slow-erosion core tablet, because the core generally contains either no disintegrant or insufficient disintegrant to fragment the tablet. The composition of the core may range from wax to gum or polymeric material. Numerous slow-erosion tablets have been patented and are sold commercially under various trade names.
++The success of core tablets depends very much on the nature of the drug and the excipients used. As a general rule, this preparation is very much hardness dependent in its release rate. Critical control of hardness and processing variables are important in producing a tablet with a consistent release rate.
++Core tablets are occasionally used to avoid incompatibility in preparations containing two physically incompatible ingredients. For example, buffered aspirin has been formulated into a core and shell to avoid a yellowing discoloration of the two ingredients upon aging.
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Microencapsulation
++Microencapsulation is a process of encapsulating microscopic drug particles with a special coating material, therefore making the drug particles more desirable in terms of physical and chemical characteristics. A common drug that has been encapsulated is aspirin. Aspirin has been microencapsulated with ethylcellulose, making the drug superior in its flow characteristics; when compressed into a tablet, the drug releases more gradually compared to a simple compressed tablet.
++Many techniques are used in microencapsulating a drug. One process used in microencapsulating acetaminophen involves suspending the drug in an aqueous solution while stirring. The coating material, ethylcellulose, is dissolved in cyclohexane, and the two liquids are added together with stirring and heating. As the cyclohexane is evaporated by heat, the ethylcellulose coats the microparticles of the acetaminophen. The microencapsulated particles have a slower dissolution rate because the ethylcellulose is not water soluble and provides a barrier for diffusion of drug. The amount of coating material deposited on the acetaminophen determines the rate of drug dissolution. The coating also serves as a means of reducing the bitter taste of the drug. In practice, microencapsulation is not consistent enough to produce a reproducible batch of product, and it may be necessary to blend the microencapsulated material in order to obtain a desired release rate.
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Osmotic Drug Delivery Systems
++Osmotic drug delivery systems have been developed for both oral extended-release products known as gastrointestinal therapeutic systems [GITS] and for parenteral drug delivery as an implantable drug delivery [eg, osmotic minipump]. Drug delivery is controlled by the use of an osmotically controlled device in which a constant amount of water flows into the system causing the dissolving and releasing of a constant amount of drug per unit time. Drug is released via a single laser-drilled hole in the tablet.
++Figure 17-8 describes an osmotic drug delivery system in the form of a tablet which contains an outside semipermeable membrane and an inner core filled with a mixture of drug and osmotic agent [salt solution]. When the tablet is placed in water, osmotic pressure is generated by the osmotic agent within the core. Water moves into the device, forcing the dissolved drug to exit the tablet through an orifice. The rate of drug delivery is relatively constant and unaffected by the pH of the environment.
++Figure 17-8Graphic Jump Location
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Cross section of the extended-release hydromorphone tablet.
[Adapted with permission from Gupta S, Sathyan G. Providing constant analgesia with OROS® hydromorphone. J Pain Symptom Manage. 2007;33[2 suppl]: S19-S24.]++Newer osmotic drug delivery systems are considered “push-pull” systems. Nifedine [Procardia XL] extended-release tablets have the appearance of a conventional tablet. Procardia XL ER tablets have a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert [but osmotically active] components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through a laser-drilled tablet orifice in the active layer. Drug delivery is essentially constant [zero order] as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
++Methylphenidate HCl [Concerta®] extended- release tablets uses osmotic pressure to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. A laser-drilled orifice on the drug-layer end of the tablet allows for exit of the drug. This product is similar to the GITS discussed earlier. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as an insoluble tablet shell.
++The frequency of side effects experienced by patients using GITS was considerably less than that with conventional tablets. When the therapeutic system was compared to the regular 250-mg tablet given twice daily, ocular pressure was effectively controlled by the osmotic system. The blood level of acetazolanine using GITS, however, was considerably below that from the tablet. In fact, the therapeutic index of the drug was measurably increased by using the therapeutic system. The use of extended-release drug products, which release drug consistently, may provide promise for administering many drugs that previously had frequent adverse side effects because of the drug's narrow therapeutic index. The osmotic drug delivery system has become a popular drug vehicle for many products that require an extended period of drug delivery for 12 to 24 hours [Table 17-6].
++Table Graphic Jump Location
Table 17-6 OROS Osmotic Therapeutic Systemsa
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Table 17-6 OROS Osmotic Therapeutic SystemsaTrade NameManufacturerGeneric NameDescriptionAcutrimCibaPhenylpropanolamineOnce-daily, over-the-counter appetite suppressantCovera-HSSearleVerapamilControlled-Onset Extended-Release [COER-24] system for hypertension and angina pectorisDynaCirc CRSandoz PharmaceuticalsIsradipineTreatment of hypertensionEfidac 24Ciba Self-MedicationOver-the-counter, 24-hour extended-release tablets providing relief of allergy and cold symptoms, containing either chlorpheniramine maleate, pseudoephedrine hydrochloride, or a combination of pseudoephedrine hydrochloride/ brompheniramine maleateGlucotrol XLPfizerGlipizideExtended-release tablets indicated as an adjunct to diet for the control of hyperglycemia in patients with non-insulin-dependent diabetesMinipress XLPfizerPrazosinExtended-release tablets for treatment of hypertensionProcardia XLPfizerNifedipineExtended-release tablets for treatment of angina and hypertensionAdalat CRBayer AGNifedipineAn Alza-based OROS system of nifedipine introduced internationallyVolmaxGlaxo-WellcomeAlbuterolExtended-release tablets for the relief of bronchospasm in patients with reversible obstructive airway disease
aAlza's OROS Osmotic Therapeutic Systems use osmosis to deliver drug continuosly at controlled rates for up to 24 h.
++A newer osmotic delivery system is the L-Oros Softcap [Alza], which claims to enhance bioavailability of poorly soluble drug by formulating the drug in a soft gelatin core and then providing extended drug delivery through an orifice drilled into an osmotic driven shell [Fig. 17-9]. The soft gelatin capsule is surrounded by the barrier layer, the expanding osmotic layer, and the release-rate-controlling membrane. A delivery orifice is formed through the three outer layers but not through the gelatin shell. When the system is administered, water permeates through the rate-controlling membrane and activates the osmotic engine. As the engine expands, hydrostatic pressure inside the system builds up, thereby forcing the liquid formulation to break through the hydrated gelatin capsule shell at the delivery orifice and be pumped out of the system. At the end of the operation, liquid drug fill is squeezed out, and the gelatin capsule shell becomes flattened. The osmotic layer, located between the inner layer and the rate-controlling membrane, is the driving force for pumping the liquid formulation out of the system. This layer can gel when it hydrates. In addition, the high osmotic pressure can be sustained to achieve a constant release. This layer should comprise, therefore, a high-molecular-weight hydrophilic polymer and an osmotic agent. It is a challenge to develop a coating solution for a high-molecular-weight hydrophilic polymer. A mixed solvent of water and ethanol was used for this coating composition.
++Figure 17-9Graphic Jump Location
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Configuration of L-Oros Softcap.
[From Dong et al, 2002, with permission.]+++
Gastroretentive System
++The extended-release drug product should release the drug completely within the region in the GI tract in which the drug is optimally absorbed. Due to GI transit, the extended-release drug product continuously moves distally down the GI tract. In some cases, the extended-release drug product containing residual drug may exit from the body. Pharmaceutical formulation developers have used various approaches to retain the dosage form in the desired area of the gastrointestinal tract. One such approach is a gastroretentive system that can remain in the gastric region for several hours and prolong the gastric residence time of drugs [Arora et al, 2005]. These gastroretentive systems are sometimes referred to as floating drug delivery systems. For example, diazepam [Valium] was been formulated using methylcellulose to provide sustained release [Valrelease]. The manufacturer of Valrelease claimed that the hydrocolloid [gel] floated in the stomach to give sustained release diazepam. In other studies, however, materials of various densities were emptied from the stomach without any difference as to whether the drug product was floating on top or sitting at the bottom of the stomach.
++The most important consideration in this type of formulation appears to be the gelling strength of the gum material and the concentration of gummy material. Modification of the release rates of the product may further be achieved with various amounts of talc or other lipophilic lubricant.
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Transdermal Drug Delivery Systems
++A transdermal drug delivery system [patch] is a dosage form intended for delivering drug across the skin for systemic drug absorption [see Chapters 7, 13]. Transdermal drug absorption also avoids presystemic metabolism or “first-pass” effects. The transdermal drug delivery systems deliver the drug through the skin in a controlled rate over an extended period of time [Chapter 14, Table 14-12]. Examples of transdermal drug delivery systems are listed in Tables 17-7 and 17-8. Transdermal delivery drug products vary in patch design [Fig. 17-10]. Generally, the transdermal patch consists of [1] a backing or support layer that protects the patch, [2] a drug layer that might be in the form of a solid gel reservoir or in a matrix, [3] a pressure-sensitive adhesive layer, and [4] a release liner or protective strip that is removed before placing the patch on the skin. In some cases, the adhesive layer may also contain the active drug [Gonzalez and Cleary, 2010].
++Table Graphic Jump Location
Table 17-7 Examples of Transdermal Delivery Systems
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Table 17-7 Examples of Transdermal Delivery SystemsTypeTrade NameRationaleMembrane-controlled systemTransderm-Nitro [Novartis]Drug in reservoir, drug release through a rate-controlling polymeric membraneAdhesive diffusion-controlled systemDeponit system [PharmaSchwartz]Drug dispersed in an adhesive polymer and in a reservoirMatrix-dispersion systemNitro-Dur [Key]Drug dispersed into a rate-controlling hydrophilic or hydrophobic matrix molded into a transdermal systemMicroreservoir systemNitro-Disc [Searle]Combination reservoir and matrix-dispersion system
++Table Graphic Jump Location
Table 17-8 Transdermal Delivery Systems
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Table 17-8 Transdermal Delivery SystemsTrade NameManufacturerGeneric NameDescriptionCatapres-TTSBoehringer IngelheimClonidineOnce-weekly product for the treatment of hypertensionDuragesicJanssen PharmaceuticalFentanylManagement of chronic pain in patients who require continuous opioid analgesia for pain that cannot be managed by lesser meansEstradermCiba-GeigyEstradiolTwice-weekly product for treating certain postmenopausal symptoms and preventing osteoporosisNicoderm CQHoechst MarionNicotineAn aid to smoking cessation for the relief of nicotine-withdrawal symptomsTestodermAlzaTestosteroneReplacement therapy in males for conditions associated with a deficiency or absence of endogenous testosteroneTransderm-NitroNovartisNitroglycerinOnce-daily product for the prevention of angina pectoris due to coronary artery disease; contains nitroglycerin in a proprietary, transdermal therapeutic systemTransderm ScopScopolaminePrevention of nausea and vomiting associated with motion sickness
++Figure 17-10Graphic Jump Location
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The four basic configurations for transdermal drug delivery systems.
++Drug diffusion may be controlled by a semipermeable membrane next to the reservoir layer. In other cases, drug diffusion is controlled by passage through the epidermis layer of the skin. The transdermal delivery system generally contains large drug concentrations to produce the ideal drug delivery with a zero-order rate. The patch may contain residual drug when the patch is removed from the application site.
++Nitroglycerin is commonly administered by transdermal delivery [eg, Nitro-Dur, Transderm-Nitro®]. Transdermal delivery systems of nitroglycerin may provide hours of protection against angina, whereas the duration of nitroglycerin given in a sublingual tablet [Nitrostat®] or sublingual spray [Nitrolingual] may be only a few minutes. The nitroglycerin patch is placed over the chest area and provides up to 12 hours of angina protection. In a study comparing these three dosage forms in patients, no substantial difference was observed among the three preparations. In all cases, the skin was found to be the rate-limiting step in nitroglycerin absorption. There were fewer variations among products than of the same product among different patients.
++The skin is a natural barrier to prevent the influx of foreign chemicals [including water] into the body and the loss of water from the body [Guy, 1996]. To be a suitable candidate for transdermal drug delivery, the drug must possess the right combination of physicochemical and pharmacodynamic properties. The drug must be highly potent so that only a small systemic drug dose is needed and the size of the patch [dose is also related to surface area] need not be exceptionally large, not greater than 50 cm2 [Guy, 1996]. Physicochemical properties of the drug include a small molecular weight [