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22.1
CHAPTER 22
DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY
SYSTEMS
Steve I. Shen, Bhaskara R. Jasti, and Xiaoling LiUniversity of the Pacific, Stockton, California
22.1 PHYSICOCHEMICAL PROPERTIES OF 22.7 BIODEGRADABLE/ERODIBLE
DRUG 22.2 DELIVERY SYSTEMS 22.9
22.2 ROUTES OF DRUG 22.8 OSMOTIC PUMP 22.10
ADMINISTRATION 22.3 22.9 ION EXCHANGE RESINS 22.11
22.3 PHARMACOLOGICAL AND 22.10 NEW MACROMOLECULAR DELIVERY
BIOLOGICAL EFFECTS 22.4 APPROACHES 22.12
22.4 PRODRUG 22.4 22.11 CONCLUSION 22.14
22.5 DIFFUSION-CONTROLLED DELIVERY REFERENCES 22.14
SYSTEMS 22.5
22.6 DISSOLUTION/COATING-
CONTROLLED DELIVERY SYSTEMS 22.9
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, injec-
tions, 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 ofintended 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
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5.2 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
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/sustained-
release 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 dominanceover 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 controlled-
release delivery system, many factors such as physicochemical properties of the drug, route of drug
administration, and pharmacological and biological effects must be considered.
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
FIGURE 22.1 Therapeutic or toxic levels and immediate- versus controlled-release dosage form.
22.1PHYSICOCHEMICAL PROPERTIES OF DRUG
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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.
Various routes of administration pose different challenges for product design. As a result of thedifferent 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 m2). 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 situationsas 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 mult iday
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
22.2ROUTES OF DRUG ADMINISTRATION
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5.4 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
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.
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 re-
quires 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 insensitiv-
ity 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 influencethe 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
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 administrat ion, 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 com-
pound is released to elicit its pharmacological action (Fig. 22.2).
The prodrug approach has been used for one or more of the following reasons:
22.3PHARMACOLOGICAL AND BIOLOGICAL EFFECTS
22.4PRODRUG
FIGURE 22.2 Schematic of prodrug.
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DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.5
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 willnot 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.
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 = kinetic energy
k = Boltzmanns constant
T = temperature
m = massv = velocity
This equation shows that an increase in temperature is exponentially correlated to velocity (v2). 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 as 9:
(22.3)
where J = flux of diffusion
D = diffusivity of drug molecule
= concentration gradient of the drug molecule across diffusional barrier with
thickness dx
22.5DIFFUSION-CONTROLLED DELIVERY SYSTEMS
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5.6 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
According to the diffusion principle, cont rolled-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.
In Fig. 22.3, CR is drug concentration in the reservoir or matrix compartment, CP is solubility of
drug in the polymer phase, CD is the concentration in the diffusion layer, hm is the thickness of the
membrane, hd is thickness of the diffusion layer, and hp + dhp 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).
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.
Analys is of di ffus ion-cont ro ll ed re se rvoi r or ma tr ix drug delive ry syst ems 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
FIGURE 22.3 Schematic illustrations of reservoir versus matrix systems.
FIGURE 22.4 An example of a reservoir-type transdermal drug deliverysystem.
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DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.7
(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-con-
trolled reservoir-type drug delivery device with a unit surface area can be described as follows2:
(22.5)
where Dm
= diffusivity of the drug in a polymer membrane with thickness hm
Dd
= diffusivity of hydrodynamic diffusion layer with thickness hd
Cb
= concentration of drug in reservoir side
t = time
Under a sink condition, where Cb(t) 0 or Cs Cb(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 polymermembrane layer or the hydrodynamic diffusion layer. If the polymer membrane is the rate-control-ling layer, KDdhm Dmhd, the equation can be simplified to:
(22.8)
which shows that the release rate is direct ly proportional to the solubil ity 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 sys tem, oft en described as monoli thic device , is designed to uni formly dis tribute 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 anotherdimension 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 by 2
(22.9)
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5.8 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
where CA is initial amount of drug, CP is solubility of drug in polymer, and hp is a time dependent
variable defined by
(22.10)
where is a constant for relative magnitude of the concentration in the diffusion layer and depletionzone, Dp is the diffusivity of drug in the polymer devices, and other parameters are the same asdescribed for Eqs. (22.4) to (22.9). At a very early stage of the release process, when there is a verythin 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 concentrationdifference between depletion and diffusion layers.
If
where the deple tion 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)
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DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.9
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).
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 = rate of drug dissolu tion
D = diffusion coefficient of drug in diffusion layer
h = thickness of diffusion layer
A = surface area of drug particlesC
0= saturation concentration of the drug in diffusion layer
Ct
= 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 C0 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 coating-
controlled 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.
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
22.6DISSOLUTION/COATING-CONTROLLED DELIVERYSYSTEMS
22.7BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS
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5.10 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
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 deliv-
ery of macromolecules.
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 hydrophil ic 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 two-
compartment 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.
The rate of water diffusing into the osmotic device is expressed as 12
(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 ( P),the equation can be simplified to
(22.18)
22.8OSMOTIC PUMP
FIGURE 22.5 Schematic illustration of an elementary osmotic pump (a) and a push-pullosmotic pump device (b).
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DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.11
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-orderdelivery 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.
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 determinesthe 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 concen-
tration (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. 22.6 b). 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.
22.9ION EXCHANGE RESINS
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5.12 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
The advances in biotechnology have introduced many proteins and other macromolecules that have
potential therapeutic applications. These macromolecules bring new challenges to formulation scien-tists, 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 theparticle 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 22.6 Schematic illustration of first generation (a) and secondgeneration (b) ion exchange drug delivery system.
22.10NEW MACROMOLECULAR DELIVERY APPROACHES
FIGURE 22.7 Illustration of an implantable osmotic pump.
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DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.13
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 ofgas 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
TABLE 22.1 Examples of Various Delivery Approaches
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5.14 DESIGN OF MEDICAL DEVICES AND DIAGNOSTIC INSTRUMENTATION
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.
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 mecha-
nisms, 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.
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.
22.11 CONCLUSION
REFERENCES
D l d d f Di it l E i i Lib @ M G Hill ( di it l i i lib )
DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS