22 Design of Controlled-Release Drug Delivery Systems

Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN
CHAPTER 22
DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

Steve I. Shen, Bhaskara R. Jasti, and Xiaoling Li
University of the Pacific, Stockton, California
22.1 PHYSICOCHEMICAL PROPERTIES OF DRUG 22.2 22.2 ROUTES OF DRUG ADMINISTRATION 22.3 22.3 PHARMACOLOGICAL AND BIOLOGICAL EFFECTS 22.4 22.4 PRODRUG 22.4 22.5 DIFFUSION-CONTROLLED DELIVERY SYSTEMS 22.5 22.6 DISSOLUTION/COATINGCONTROLLED DELIVERY SYSTEMS 22.9
22.7 BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS 22.9 22.8 OSMOTIC PUMP 22.10 22.9 ION EXCHANGE RESINS 22.11 22.10 NEW MACROMOLECULAR DELIVERY APPROACHES 22.12 22.11 CONCLUSION 22.14 REFERENCES 22.14
With the advances in science and technology, many new chemical molecules are being created and tested for medical use. The United States Food and Drug Administration (FDA) approved 22 to 53 new molecular entities each year between 1993 and 1999.1 Creation of these active ingredients is only part of the arsenal against diseases. Every drug molecule needs a delivery system to carry the drug to the site of action upon administration to the patient. Delivery of the drugs can be achieved using various types of dosage forms including tablets, capsules, creams, ointments, liquids, aerosols, injections, and suppositories. Most of these conventional drug delivery systems are known to provide immediate release of the drug with little or no control over delivery rate. To achieve and maintain therapeutically effective plasma concentrations, several doses are needed daily, which may cause significant fluctuations in plasma levels (Fig. 22.1). Because of these fluctuations in drug plasma levels, the drug level could fall below the minimum effective concentration (MEC) or exceed the minimum toxic concentration (MTC). Such fluctuations result in unwanted side effects or lack of intended therapeutic benefit to the patient. Sustained-release and controlled-release drug delivery systems can reduce the undesired fluctuations of drug levels, thus diminishing side effects while improving the therapeutic outcome of the drug (Fig. 22.1). The terms sustained release and controlled release refer to two different types of drug delivery systems, although they are often used interchangeably. Sustained-release dosage forms are systems that prolong the duration of the action by slowing the release of the drug, usually at the cost of delayed
22.1
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5.2 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
FIGURE 22.1 Therapeutic or toxic levels and immediate- versus controlledrelease dosage form.
onset and its pharmacological action. Controlled-release drug systems are more sophisticated than just simply delaying the release rate and are designed to deliver the drug at specific release rates within a predetermined time period. Targeted delivery systems are also considered as a controlled delivery system, since they provide spatial control of drug release to a specific site of the body. Advantages of controlled release drug delivery systems include delivery of a drug to the required site, maintenance of drug levels within a desired range, reduced side effects, fewer administrations, and improved patient compliance. However, there are potential disadvantages that should not be overlooked. Disadvantages of using such delivery systems include possible toxicity of the materials used, dose dumping, requirement of surgical procedures to implant or remove the system, and higher manufacturing costs. In the pharmaceutical industry, design and development of controlled/sustainedrelease delivery systems have been used as a strategic means to prolong the proprietary status of drug products that are reaching the end of their patent life. A typical example is modifying an existing drug product that requires several doses a day to a single daily dosing to maintain the dominance over generic competition. For some drugs, controlled delivery is necessary, since immediate release dosage forms cannot achieve the desired pharmacological action. These include highly water soluble drugs that need slower release and longer duration of action, highly lipophilic drugs that require enhancement of solubility to achieve therapeutic level, short half-life drugs that require repeated administration, and drugs with nonspecific action that require the delivery to target sites. An ideal drug delivery system should deliver precise amounts of a drug at a preprogrammed rate to achieve a drug level necessary for treatment of the disease. For most drugs that show a clear relationship between concentration and response, the drug concentration will be maintained within the therapeutic range, when the drug is released by zero-order rate. In order to design a controlledrelease delivery system, many factors such as physicochemical properties of the drug, route of drug administration, and pharmacological and biological effects must be considered.
22.1 PHYSICOCHEMICAL PROPERTIES OF DRUG

Physicochemical properties such as solubility, stability, lipophilicity, and molecular interactions play a major role in biological effectiveness of a drug. Solubility is a measure of the amount of solute that can be dissolved in the solvent. For a drug to be absorbed, it must first dissolve in the physio logical
DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.3
fluids of the body at a reasonably fast dissolution rate. Drug molecules with very low aqueous solubility often have lower bioavailability because of the limited amount of dissolved drug at the site of absorption. In general, drugs with lower than 10 mg/mL in aqueous solutions are expected to exhibit low and erratic oral bioavailability. Once the drug is administered, biological fluids that are in direct contact with a drug molecule may influence the stability of the drug. Drugs may be susceptible to both chemical and enzymatic degradation, which results in a loss of activity of the drug. Drugs with poor acidic stability, when coated with enteric coating materials, will bypass the acidic stomach and release the drug at a lower portion of the gastrointestinal (GI) tract. Drugs can also be protected from enzymatic cleavage by modifying the chemical structure to form prodrugs. The ability of a drug to partition into a lipid phase can be evaluated by the distribution of drug between lipid and water phase at equilibrium. A distribution constant, the partition coefficient K, is commonly used to describe the equilibrium of drug concentrations in two phases. (21.1) The partition coefficient of a drug reflects the permeability of the drug through the biological membrane and/or the polymer membrane. Commonly, the partition coefficient is determined by equilibrating the drug in a saturated mixture of octanol (lipid phase) and water. Drugs with a high partition coefficient can easily penetrate biological membranes, as they are made of lipid bilayers, but are unable to proceed further because of a higher affinity to the membrane than the aqueous surroundings. Drugs with a low partition coefficient can easily move around the aqueous areas of the body, but will not cross the biological membranes easily. In addition to the inherent properties of drug molecules, molecular interactions such as drug-drug, drug-protein, and drug-metal ion binding are important factors that can significantly change the pharmacokinetic parameters of a drug. These factors should also be taken into consideration in designing controlled drug delivery systems.
22.2 ROUTES OF DRUG ADMINISTRATION

Various routes of administration pose different challenges for product design. As a result of the different barriers and pathways involved, selection of an administration route is an important factor for design of drug delivery system. For example, the oral route is most widely utilized route because of its ease of administration and the large surface area of the GI tract (200 m 2). The presence of microvilli makes this the largest absorptive surface of the body (4500 m2). 2 The challenges of oral administration are short GI transit time, extreme acidic pH, abundant presence of digestive enzymes, and first-pass metabolism in the liver. Several products were designed to prolong the retention time of a drug in the gastrointestinal tract. A hydrodynamically balanced drug-delivery system (HBS) is designed to achieve bulk density of less than 1 when contacted with gastric fluids rendering the drug formulation buoyant. This dosage form is also called floating capsules or tablets because of this characteristic.3 Another commonly used route for drug delivery is parenteral administration. The routes used for parenteral therapy include intradermal, subcutaneous, intravenous, intracardiac, intramuscular, intraarterial, and intrasynovial. Parenteral administrations offer immediate response, in such situations as cardiac arrest or shock, and good bioavailability for drugs that undergo degradation by digestive enzymes in the GI tract. The disadvantages of parenteral administrations are difficulty of administration, requirement of sterile conditions, and cost of manufacturing. In addition, skin, with surface area of 2 m 2 , is a commonly used route for drug delivery. Advantages of the transdermal route include avoidance of the first-pass effect, potential of multiday therapy with a single application, rapid termination of drug effects, and easy identification of medication in an emergency. The limitations are skin irritation and/or sensitization, variation of
intra- and inter individual percutaneous absorption efficiency, the limited time that the patch can remain affixed, and higher cost. 4 Most of the controlled-release delivery systems available in the market for systemic delivery of drugs utilize oral, parenteral, and transdermal route for their administration. Advances in biotechnology produced many gene, peptide, and protein drugs with specific demands on route of delivery. Thus, other routes such as buccal, nasal, ocular, pulmonary, rectal, and vaginal are gaining more attention.
22.3 PHARMACOLOGICAL AND BIOLOGICAL EFFECTS

It is important to consider the human dimension in the design of the drug delivery systems. Biological factors, such as age, weight, gender, ethnicity, physiological processes, and disease state, will change the pharmacokinetics and pharmacodynamics of a drug. For example, dosing newborn infants requires caution because of their immature hepatic function and higher water content in the body. Geriatric patients may suffer from reduced sensitivity of certain receptors that may lead to insensitivity to certain drugs. It has been found that different ethnic groups respond to drugs differently. Diuretics and calcium channel blockers are recommended as first-line therapy in hypertensive Black patients, while beta blockers work better for Caucasian patients. Pathological changes may influence the distribution and bioavailability of the drug by altering the physiological process. Decreased kidney and/or liver functions will affect the clearance of many drugs. In this chapter, the discussion of the design of drug delivery systems is based on various approaches: prodrug approach, diffusion-controlled reservoir and matrix systems, dissolution/ coating-controlled systems, osmotically controlled systems, ion-exchange resin systems, and approaches for macromolecular drug delivery. The aim of this chapter is to introduce the basic concepts for the designs of various drug delivery systems. Readers c an refer to the references for further details.29
22.4 PRODRUG
The molecule with the most potent form does not always have the desired physicochemical properties needed for drug dissolution and/or absorption. If fact, of all the pharmaceutically active ingredients, 43 percent are sparingly water soluble or insoluble in water. In the prodrug approach for drug delivery, active ingredients are chemically modified by connecting specialized functional groups that will be removed in the body after administration, releasing the parent molecule.8 These latent groups are used in a transient manner to change the properties of the parent drug to achieve a specific function, e.g., alter permeability, solubility, or stability. After the prodrug has achieved its goal, the functional group is removed in the body (enzymatic cleavage or hydrolysis) and the parent compound is released to elicit its pharmacological action (Fig. 22.2). The prodrug approach has been used for one or more of the following reasons:
FIGURE 22.2 Schematic of prodrug.
To change half-life. Half-life is defined as the time required by the biological system for removing 50 percent of administered drug. Drugs with very short half-life may not be therapeutically beneficial unless this characteristic is improved. Attaching the drug to a polymer as part of a pendent will enhance its half-life. Modification of the drug to protect the site of degradation or metabolism is another method to achieve longer half-life. To cross a biological barrier. Drugs with unbalanced hydrophilic or hydrophobic properties will not effectively cross the biological barriers. Attachment of functional groups can change the properties of the parent drug and allow the prodrug to cross the barrier. To increase retention time. When intended for a part of the body with high tissue turnover rate, such as intestinal mucosa, a drug linked to a mucoadhesive polymer can increase adhesion to the site and increase bioavailability of a drug that has low residence time. To target a specific site. Connecting specialized functional groups that have site-specific affinity (peptide, antibody, etc.) can allow the parent drug to be delivered to the targeted area of the body to produce site specific therapeutic action.
22.5 DIFFUSION-CONTROLLED DELIVERY SYSTEMS

Diffusion process has been utilized in design of controlled release drug delivery systems for several decades. This process is a consequence of constant thermal motion of molecules, which results in net movement of molecules from a high concentration region to a low concentration region. The rate of diffusion is dependent on temperature, size, mass, and viscosity of the environment. Molecular motion increases as temperature is raised as a result of the higher average kinetic energy in the system. (22.2) where E k T m v = = = = = kinetic energy Boltzmanns constant temperature mass velocity
This equation shows that an increase in temperature is exponentially correlated to velocity (v 2). Size and mass are also significant factors in the diffusion process. At a given temperature, the mass of molecule is inversely proportional to velocity [Eq. 22.2]. Larger molecules interact more with the surrounding environment, causing them to have slower velocity. Accordingly, large molecules diffuse much slower than light and small particles. The viscosity of the environment is another important parameter in diffusion, since the rate of molecular movement is associated with the viscosity of the environment. Diffusion is fastest in the gas phase, slower in the liquid phase, and slowest in the solid phase. Mathematically, the rate of drug delivery in diffusion-controlled delivery systems can be described by Ficks laws. Ficks first law of diffusion is expressed as9: (22.3) where J = flux of diffusion D = diffusivity of drug molecule = concentration gradient of the drug molecule across diffusional barrier with thickness dx
According to the diffusion principle, controlled-release drug delivery systems can be designed as a reservoir system or a matrix system. Drugs released from both reservoir and matrix type devices follow the principle of diffusion, but they show two different release patterns as shown in Fig. 22.3.
FIGURE 22.3 Schematic illustrations of reservoir versus matrix systems.
In Fig. 22.3, CR is drug concentration in the reservoir or matrix compartment, CP is solubility of drug in the polymer phase, C D is the concentration in the diffusion layer, hm is the thickness of the membrane, hd is thickness of the diffusion layer, and hp + dh p indicates the changing thickness of the depletion zone of matrix. In a reservoir system, if the active agent is in a saturated state, the driving force is kept constant until it is no longer saturated. For matrix systems, because of the changing thickness of the depletion zone, release kinetics is a function of the square root of time. 10 A typical reservoir system for transdermal delivery consists of a backing layer, a rate-limiting membrane, a protective liner, and a reservoir compartment. The drug is enclosed within the reservoir compartment and released through a rate-controlling polymer membrane (Fig. 22.4).
FIGURE 22.4 An example of a reservoir-type transdermal drug delivery system.
Membranes used to enclose the device can be made from various types of polymers. The rate of release can be varied by selecting the polymer and varying the thickness of the rate-controlling membrane. The drug in the reservoir can be in solid, suspension, or liquid form. Analysis of diffusion-controlled reservoir or matrix drug delivery systems requires a few assumptions: 1. The diffusion coefficient of a drug molecule in a medium must be constant. 2. The controlled drug release must have a pseudo-steady state. 3. Dissolution of solid drug must occur prior to the drug release process. 4. The interfacial partitioning of the drug is related to its solubility in polymer and in solution as defined by
(22.4)
where K = partition coefficient of the drug molecule from polymer to solution Cs = solubility of drug in the solution phase Cp = solubility of drug in polymer phase With the above assumptions, the cumulative amount Q of drug released from a diffusion-controlled reservoir-type drug delivery device with a unit surface area can be described as follows2: (22.5) where D m = Dd = Cb = t = diffusivity of the drug in a polymer membrane with thickness h m diffusivity of hydrodynamic diffusion layer with thickness h d concentration of drug in reservoir side time 0 or Cs C b(t), Eq. (22.5) is reduced to (22.6) This relationship shows that release of drug can be a constant, with the rate of drug release being (22.7) In extreme cases, the rate of release may depend mainly on one of the layers, either the polymer membrane layer or the hydrodynamic diffusion layer. If the polymer membrane is the rate-controlDmhd, the equation can be simplified to: ling layer, KD dhm (22.8) which shows that the release rate is directly proportional to the solubility of the drug in polymer and inversely proportional to thickness of the polymer membrane. Delivery systems designed on this principle can be administered by different routes: intrauterine such as Progestasert, implants such as Norplant, transdermal such as Transderm-Nitro, and ocular such as Ocusert. A matrix system, often described as monolithic device, is designed to uniformly distribute the drug within a polymer as a solid block. Matrix devices are favored over other design for their simplicity, low manufacturing costs, and lack of accidental dose dumping, which may occur with reservoir systems when the rate controlling membrane ruptures. The release properties of the device depend highly upon the structure of the matrix: whether it is porous or nonporous. The rate of drug release is controlled by the solubility of the drug in the polymer and the diffusivity of the drug through the polymer for nonporous system. For a porous matrix, the solubility of the drug in the network and the tortuosity of the network add another dimension to affect the rate of release. In addition, drug loading influences the release, since high loading can complicate the release mechanism because of formation of cavities as the drug is leaving the device. These cavities will fill with fluids and increase the rate of release. The cumulative amount released from a matrix-controlled device is described by2 (22.9)
Under a sink condition, where Cb(t)
where C A is initial amount of drug, CP is solubility of drug in polymer, and h p is a time dependent variable defined by
(22.10)
where is a constant for relative magnitude of the concentration in the diffusion layer and depletion zone, D p is the diffusivity of drug in the polymer devices, and other parameters are the same as described for Eqs. (22.4) to (22.9). At a very early stage of the release process, when there is a very thin depletion zone, the following will be true:
Equation (22.10) can be reduced to (22.11) and placing Eq. (22.11) into Eq. (22.9) gives (22.12) Since KCp = Cs, Eq. (22.12) becomes (22.13) The term implies that the matrix system is more sensitive to the magnitude of concentration difference between depletion and diffusion layers. If
where the depletion zone is much larger and the system has a very thin diffusion layer, Eq. (22.10) becomes
(22.14)
and placing Eq. (22.14) into Eq. (22.9) makes
(22.15)
Equation (22.15) indicates that after the depletion zone is large enough, the cumulative amount of drug released (Q) is proportional to the square root of time (t1/2).
22.6 DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS

Controlled release of drug can be achieved by utilizing the rate-limiting step in the dissolution process of a solid drug with relatively low aqueous solubility. The dissolution rate can be quantitatively described by the Noyes-Whitney equation as follows. (22.16) where D h A C0 Ct = rate of drug dissolution = = = = = diffusion coefficient of drug in diffusion layer thickness of diffusion layer surface area of drug particles saturation concentration of the drug in diffusion layer concentration of drug in bulk fluids at time t
The surface area A of the drug particle is directly proportional to the rate of dissolution. For a given amount of drug, reducing the particle size results in a higher surface area and faster dissolution rate. However, small particles tend to agglomerate and form aggregates. Using a specialized milling technique with stabilizer and other excipients, aggregation can be prevented to make microparticles smaller than 400 nm in diameter to improve the dissolution of the drug in the body. The saturation solubility C 0 can also be manipulated to change the rate of dissolution. Both the physical and chemical properties of a drug can be modified to alter the saturation solubility. For example, salt forms of a drug are much more soluble in an aqueous environment than the parent drug. The solubility of a drug can also be modified when the drug forms a complex with excipients, resulting in a complex with solubility different from the drug itself. Controlled or sustained release of drug from delivery systems can also be designed by enclosing the drug in a polymer shell or coating. After the dissolution or erosion of the coating, drug molecules become available for absorption. Release of drug at a predetermined time is accomplished by controlling the thickness of coating. In Spansule systems, drug molecules are enclosed in beads of varying thickness to control the time and amount of drug release. The encapsulated particles with thin coatings will dissolve and release the drug first, while a thicker coating will take longer to dissolve and will release the drug at later time. Coating-controlled delivery systems can also be designed to prevent the degradation of the drug in the acidic environment of the stomach, which can reach as low as pH 1.0. Such systems are generally referred as enteric-coated systems. In addition, enteric coating also protects the stomach from ulceration caused by drug agents. Release of the drug from coatingcontrolled delivery systems may depend upon the polymer used. A combination of diffusion and dissolution mechanisms may be required to define the drug release from such systems.
22.7 BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS

Biologically degradable systems contain polymers that degrade into smaller fragments inside the body to release the drug in a controlled manner. Zero-order release can be achieved in these systems as long as the surface area or activity of the labile linkage between the drug and the polymeric backbone
are kept constant during drug release. Another advantage of biodegradable systems is that, when formulated for depot injection, surgical removal can be avoided. These new delivery systems can protect and stabilize bioactive agents, enable long-term administration, and have potential for delivery of macromolecules.
22.8 OSMOTIC PUMP

This type of delivery device has a semipermeable membrane that allows a controlled amount of water to diffuse into the core of the device filled with a hydrophilic component.11 A water-sensitive component in the core can either dissolve or expand to create osmotic pressure and push the drug out of the device through a small delivery orifice, which is drilled to a diameter that correlates to a specific rate. In an elementary osmotic pump, the drug molecule is mixed with an osmotic agent in the core of the device (Fig. 22.5a). For drugs that are highly or poorly water soluble, a twocompartment push-pull bilayer system has been developed, in which the drug core is separated from the push compartment (Fig. 22.5b). The main advantage of the osmotic pump system is that constant release rate can be achieved, since it relies simply on the passage of water into the system, and the human body is made up of 70 percent water. The release rate of the device can be modified by changing the amount of osmotic agent, surface area and thickness of semipermeable membrane, and/or the size of the hole.
FIGURE 22.5 Schematic illustration of an elementary osmotic pump (a) and a push-pull osmotic pump device (b).
The rate of water diffusing into the osmotic device is expressed as12 (22.17) where = change of volume overchange in time
A, K, h = area, permeability, and thickness of membrane, respectively = difference in osmotic pressure between drug device and release environment = difference in hydrostatic pressure If the osmotic pressure difference is much larger than the hydrostatic pressure difference ( the equation can be simplified to P),
(22.18)
The rate at which the drug is pumped out the device dM/dt, cab be expressed as (22.19) where C is the drug concentration. As long as the osmotically active agent provides the constant osmotic pressure, the delivery system will release the drug at a zero-order rate. The zero-order delivery rate can be expressed as (22.20) where s is osmotic pressure generated by saturated solution and all other symbols are the same as described earlier.
22.9 ION EXCHANGE RESINS

The ion exchange resin system can be designed by binding drug to the resin. After the formation of a drug/resin complex, a drug can be released by an ion exchange reaction with the presence of counterions. In this type of delivery system, the nature of the ionizable groups attached determines the chemical behavior of an ion exchange resin (Fig. 22.6).
An ion exchange reaction can be expressed as
and the selectivity coefficient is defined as (22.21) where [A +] = concentration of free counterion = concentration of drug bound of the resin [B +] = concentration of drug freed from resin = concentration of counterion bound to the resin Factors that affect the selectivity coefficient include type of functional groups, valence and nature of exchanging ions, and nature of nonexchanging ions. Although it is known that ionic strength of GI fluid is maintained at a relatively constant level, first-generation ion-exchange drug delivery systems had difficulty controlling the drug release rate because of a lack of control of exchange ion concentration (Fig. 22.6a). The second-generation ion-exchange drug delivery system (Pennkinetic system) made an improvement by treating the drug-resin complex further with an impregnating agent such as polyethylene glycol 4000 to retard the swelling in water (Fig. 22.6b). These particles are then coated with a water-permeable polymer such as ethyl cellulose to act as a rate-controlling barrier to regulate the drug release.
FIGURE 22.6 Schematic illustration of first generation (a) and second generation (b) ion exchange drug delivery system.
22.10 NEW MACROMOLECULAR DELIVERY APPROACHES

The advances in biotechnology have introduced many proteins and other macromolecules that have potential therapeutic applications. These macromolecules bring new challenges to formulation scientists, since the digestive system is highly effective in metabolizing these molecules, making oral delivery almost impossible, while parenteral routes are painful and difficult to administer. A potential carrier for oral delivery of macromolecules is polymerized liposomes.14 Liposomes are lipid vesicles that target the drug to selected tissues by either passive or active mechanisms. 15 Advantages of liposomes include increased efficacy and therapeutic index, reduction in toxicity of the encapsulated agent, and increased stability via encapsulation. One major weakness of liposomes is the potential leakage of encapsulated drugs due to the stability of liposome. Unlike traditional liposomes, the polymerized liposomes are more rigid because of cross-linking and allow the polymerized liposomes to withstand harsh stomach acids and phospholipase. This carrier is currently being tested for oral delivery of vaccines. Pulmonary route is also being utilized as route for delivery of macromolecules. The lungs large absorptive surface area of around 100 m2 makes this route a promising alternative route for protein administration. Drug particle size is a key parameter to pulmonary drug delivery. To reduce the particle size, a special drying process called glass stabilization technology was developed. By using this technology, dried powder particles can be designed at an optimum size of 1 to 5 m for deep lung delivery. Advantages of powder formulation include higher stability of peptide and protein for longer shelf life, lower risk of microbial growth, and higher drug loading compared to liquid formulation. 16 Liquid formulations for accurate and reproducible pulmonary delivery are now made possible by technology which converts large or small molecules into fine-particle aerosols and deposits them deep into the lungs. The device has a drug chamber that holds the liquid formulation
FIGURE 22.7 Illustration of an implantable osmotic pump.
TABLE 22.1 Examples of Various Delivery Approaches
and upon activation, the pressure will drive the liquid through fine pores creating the microsize mist for pulmonary delivery. Transdermal needleless injection devices are another candidate for protein delivery.17 The device propels the drug with a supersonic stream of helium gas. When the helium ampule is activated, the gas stream breaks the membranes that hold the drug. The drug particles are picked up by a stream of gas and propelled fast enough to penetrate the stratum corneum (the rate-limiting barrier of the skin). This delivery device is ideal for painless delivery of vaccine through the skin to higher drug loading. Limitations to this device are the upper threshold of approximately 3 mg and temporary permeability change of skin at the site of administration. An alternative way to penetrate the skin barrier has been developed utilizing thin titanium screens with precision microprojections to physically create pathways through the skin and allow for transportation of macromolecules. Another example of macromolecular delivery is an implantable osmotic pump designed to deliver protein drugs in a
precise manner for up to 1 year (Fig. 22.7). This implantable device uses osmotic pressure to push the drug formulation out of the device through the delivery orifice.
22.11 CONCLUSION
Controlled-release delivery devices have been developed for more than 30 years. Most of the devices utilize the fundamental principles of diffusion, dissolution, ion exchange, and osmosis (Table 22.1). Optimal design of a drug delivery system will require a detailed understanding of release mechanisms, properties of drugs and carrier materials, barrier characteristics, pharmacological effect of drugs, and pharmacokinetics. With development in the field of biotechnology, there is an increase in the number of protein and other macromolecular drugs. These drugs introduce new challenges and opportunities for design of drug delivery systems.
REFERENCES
1. CDER 1999 Report to the Nation, Improving Public Health Through Human Drugs. US Department of Human Services, Food and Drug Administration and Center for Drug Evaluation and Research. 2. Y. E. Chien, Novel Drug Delivery Systems, 2d ed., Marcel Dekker, New York, 1992. 3. V. S. Gerogiannis, D. M. Rekkas, and P. P. Dallas, Floating and Swelling Characteristics of Various Excipients Used in Controlled-Release Technology, Drug Dev. Ind. Pharm., 19:10611081, 1993. 4. R. O. Potts and G. W. Cleary, Transdermal Drug Delivery: Useful Paradigms, J. Drug Target, 3 (4):247251, 1995. 5. J. R. Robinson and V. H. Lee, (eds.), Controlled Drug Delivery: Fundamentals and Applications, 2d ed., Marcel Dekker, New York, 1987. 6. S. D. Bruck (ed.), Controlled Drug Delivery, vols. 1 and 2, CRC Press, Boca Raton, Florida, 1984. 7. S. Cohen and H. Bernstein (eds.), Microparticulate Systems for Delivery of Proteins and Vaccines, Marcel Dekker, New York, 1996. 8. H. Bundgaard (ed.), Design of Prodrugs, Elsevier Science, New York, 1985. 9. J. Crank, The Mathematics of Diffusion, 2d ed., Oxford Press, New York, 1975. 10. R. A. Lipper and W. I. Higuchi, Analysis of Theoretical Behavior of a Proposed Zero-Order Drug Delivery System, J. Pharm. Sci., 66(2):163164, 1977. 11. F. Theeuwes, Elementary Osmotic Pump, J. Pharm. Sci., 64:19871991, 1975. 12. C. Kim, Controlled Release Dosage Form Design, Technomic, Lancaster, Pa., 2000. 13. S. Motycha and J. G. Naira, Influence of wax coatings on release rate of anions from ion-exchange resin beads, J. Pharm. Sci., 67(4):500503, 1978. 14. J. Okada, S. Cohen, and R. Langer, In vitro Evaluation of Polymerized Liposomes as an Oral Drug Delivery System, Pharm. Res., 12(4):576582, 1995. 15. A. D. Bangham, Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids, J. Mol. Biol., 13:238252, 1965. 16. J. R. White and R. K. Campbell, Inhaled Insulin: An Overview, Clinical Diabetes, 19(1):1316, 2001. 17. T. L. Brukoth, B. J. Bellhouse, G. Hewson, D. J. Longridge, A. G. Muddle, and D. F. Saphie, Transdermal and Transmucosal Powdered Drug Delivery, Crit. Rev. Ther. Drug Carrier Sys., 16(4):331384, 1999.

22 Design of Controlled-Release Drug Delivery Systems

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22 Design of Controlled-Release Drug Delivery Systems

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Source: STANDARD HANDBOOK OF BIOMEDICAL ENGINEERING AND DESIGN

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.2 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

22.1 PHYSICOCHEMICAL PROPERTIES OF DRUG

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.3

22.2 ROUTES OF DRUG ADMINISTRATION

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.4 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

22.3 PHARMACOLOGICAL AND BIOLOGICAL EFFECTS

FIGURE 22.2 Schematic of prodrug.

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.5

22.5 DIFFUSION-CONTROLLED DELIVERY SYSTEMS

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.6 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

FIGURE 22.3 Schematic illustrations of reservoir versus matrix systems.

FIGURE 22.4 An example of a reservoir-type transdermal drug delivery system.

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.7

Under a sink condition, where Cb(t)

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.8 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

and placing Eq. (22.14) into Eq. (22.9) makes

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.9

22.6 DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS

22.7 BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.10 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

22.8 OSMOTIC PUMP

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.11

22.9 ION EXCHANGE RESINS

An ion exchange reaction can be expressed as

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.12 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

22.10 NEW MACROMOLECULAR DELIVERY APPROACHES

FIGURE 22.7 Illustration of an implantable osmotic pump.

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.13

TABLE 22.1 Examples of Various Delivery Approaches

DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

5.14 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION

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