22 Design of Controlled-Release Drug Delivery Systems

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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



DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS


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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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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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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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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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(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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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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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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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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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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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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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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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.

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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 )


22 Design of Controlled-Release Drug Delivery Systems

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