CHAPTER 22 DESIGN OF CONTROLLED- RELEASE ......Physicochemical properties such as solubility,...

22.1

CHAPTER 22

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERYSYSTEMS

Steve I. Shen, Bhaskara R. Jasti, and Xiaoling LiUniversity of the Pacific, Stockton, California

22.1 PHYSICOCHEMICAL PROPERTIES OF 22.7 BIODEGRADABLE/ERODIBLEDRUG 22.2 DELIVERY SYSTEMS 22.9

22.2 ROUTES OF DRUG 22.8 OSMOTIC PUMP 22.10ADMINISTRATION 22.3 22.9 ION EXCHANGE RESINS 22.11

22.3 PHARMACOLOGICAL AND 22.10 NEW MACROMOLECULAR DELIVERYBIOLOGICAL EFFECTS 22.4 APPROACHES 22.12

22.4 PRODRUG 22.4 22.11 CONCLUSION 22.1422.5 DIFFUSION-CONTROLLED DELIVERY REFERENCES 22.14SYSTEMS 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 andtested for medical use. The United States Food and Drug Administration (FDA) approved 22 to 53new molecular entities each year between 1993 and 1999.1 Creation of these active ingredients is onlypart of the arsenal against diseases. Every drug molecule needs a delivery system to carry the drug tothe site of action upon administration to the patient. Delivery of the drugs can be achieved usingvarious 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 provideimmediate release of the drug with little or no control over delivery rate. To achieve and maintaintherapeutically effective plasma concentrations, several doses are needed daily, which may causesignificant fluctuations in plasma levels (Fig. 22.1). Because of these fluctuations in drug plasmalevels, the drug level could fall below the minimum effective concentration (MEC) or exceed theminimum 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 fluctuationsof 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 deliverysystems, although they are often used interchangeably. Sustained-release dosage forms are systems thatprolong 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 justsimply delaying the release rate and are designed to deliver the drug at specific release rates within apredetermined time period. Targeted delivery systems are also considered as a controlled deliverysystem, 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 requiredsite, 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 beoverlooked. Disadvantages of using such delivery systems include possible toxicity of the materialsused, dose dumping, requirement of surgical procedures to implant or remove the system, and highermanufacturing 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 drugproducts that are reaching the end of their patent life. A typical example is modifying an existingdrug 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 releasedosage forms cannot achieve the desired pharmacological action. These include highly water solubledrugs that need slower release and longer duration of action, highly lipophilic drugs that requireenhancement of solubility to achieve therapeutic level, short half-life drugs that require repeatedadministration, 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 rateto achieve a drug level necessary for treatment of the disease. For most drugs that show a clearrelationship between concentration and response, the drug concentration will be maintained withinthe 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 drugadministration, and pharmacological and biological effects must be considered.

Physicochemical properties such as solubility, stability, lipophilicity, and molecular interactions play amajor role in biological effectiveness of a drug. Solubility is a measure of the amount of solute thatcan 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.

22.1 PHYSICOCHEMICAL PROPERTIES OF DRUG



DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 5.3

fluids of the body at a reasonably fast dissolution rate. Drug molecules with very low aqueoussolubility often have lower bioavailability because of the limited amount of dissolved drug at the siteof absorption. In general, drugs with lower than 10 mg/mL in aqueous solutions are expected toexhibit low and erratic oral bioavailability.

Once the drug is administered, biological fluids that are in direct contact with a drug moleculemay influence the stability of the drug. Drugs may be susceptible to both chemical and enzymaticdegradation, which results in a loss of activity of the drug. Drugs with poor acidic stability, whencoated with enteric coating materials, will bypass the acidic stomach and release the drug at a lowerportion of the gastrointestinal (GI) tract. Drugs can also be protected from enzymatic cleavage bymodifying the chemical structure to form prodrugs.

The ability of a drug to partition into a lipid phase can be evaluated by the distribution of drugbetween lipid and water phase at equilibrium. A distribution constant, the partition coefficient K, iscommonly 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 biologicalmembrane and/or the polymer membrane. Commonly, the partition coefficient is determined byequilibrating the drug in a saturated mixture of octanol (lipid phase) and water. Drugs with a highpartition coefficient can easily penetrate biological membranes, as they are made of lipid bilayers, butare unable to proceed further because of a higher affinity to the membrane than the aqueoussurroundings. Drugs with a low partition coefficient can easily move around the aqueous areas of thebody, 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 thepharmacokinetic parameters of a drug. These factors should also be taken into consideration indesigning 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 factorfor design of drug delivery system. For example, the oral route is most widely utilized route becauseof its ease of administration and the large surface area of the GI tract (200 m2). The presence ofmicrovilli makes this the largest absorptive surface of the body (4500 m2).2 The challenges of oraladministration 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 ofa drug in the gastrointestinal tract. A hydrodynamically balanced drug-delivery system (HBS) isdesigned to achieve bulk density of less than 1 when contacted with gastric fluids rendering the drugformulation buoyant. This dosage form is also called floating capsules or tablets because of thischaracteristic.3

Another commonly used route for drug delivery is parenteral administration. The routes used forparenteral 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 digestiveenzymes in the GI tract. The disadvantages of parenteral administrations are difficulty ofadministration, requirement of sterile conditions, and cost of manufacturing.

In addition, skin, with surface area of 2 m2, is a commonly used route for drug delivery.Advantages of the transdermal route include avoidance of the first-pass effect, potential of multidaytherapy with a single application, rapid termination of drug effects, and easy identification ofmedication in an emergency. The limitations are skin irritation and/or sensitization, variation of

22.2 ROUTES OF DRUG ADMINISTRATION





intra- and inter individual percutaneous absorption efficiency, the limited time that the patch canremain affixed, and higher cost.4

Most of the controlled-release delivery systems available in the market for systemic delivery ofdrugs utilize oral, parenteral, and transdermal route for their administration. Advances inbiotechnology produced many gene, peptide, and protein drugs with specific demands on route ofdelivery. Thus, other routes such as buccal, nasal, ocular, pulmonary, rectal, and vaginal are gainingmore attention.

It is important to consider the human dimension in the design of the drug delivery systems. Biologicalfactors, such as age, weight, gender, ethnicity, physiological processes, and disease state, will changethe 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 Blackpatients, while beta blockers work better for Caucasian patients. Pathological changes may influencethe distribution and bioavailability of the drug by altering the physiological process. Decreasedkidney 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 variousapproaches: prodrug approach, diffusion-controlled reservoir and matrix systems, dissolution/coating-controlled systems, osmotically controlled systems, ion-exchange resin systems, andapproaches for macromolecular drug delivery. The aim of this chapter is to introduce the basicconcepts for the designs of various drug delivery systems. Readers c an refer to the references forfurther details.2–9

The molecule with the most potent form does not always have the desired physicochemical propertiesneeded 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 drugdelivery, active ingredients are chemically modified by connecting specialized functional groups thatwill be removed in the body after administration, releasing the parent molecule.8 These latent groupsare used in a transient manner to change the properties of the parent drug to achieve a specificfunction, e.g., alter permeability, solubility, or stability. After the prodrug has achieved its goal, thefunctional 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:

22.3 PHARMACOLOGICAL AND BIOLOGICAL EFFECTS

22.4 PRODRUG

FIGURE 22.2 Schematic of prodrug.





To change half-life. Half-life is defined as the time required by the biological system for removing50 percent of administered drug. Drugs with very short half-life may not be therapeuticallybeneficial unless this characteristic is improved. Attaching the drug to a polymer as part of apendent will enhance its half-life. Modification of the drug to protect the site of degradation ormetabolism 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 theproperties 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 thesite 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 bodyto produce site specific therapeutic action.

Diffusion process has been utilized in design of controlled release drug delivery systems for severaldecades. This process is a consequence of constant thermal motion of molecules, which results in netmovement of molecules from a high concentration region to a low concentration region. The rate ofdiffusion 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 kineticenergy in the system.

(22.2)

where E = kinetic energy k = Boltzmann’s constant T = temperature m = mass v = velocity

This equation shows that an increase in temperature is exponentially correlated to velocity (v2). Sizeand mass are also significant factors in the diffusion process. At a given temperature, the mass ofmolecule is inversely proportional to velocity [Eq. 22.2]. Larger molecules interact more with thesurrounding environment, causing them to have slower velocity. Accordingly, large molecules diffusemuch slower than light and small particles. The viscosity of the environment is another importantparameter in diffusion, since the rate of molecular movement is associated with the viscosity of theenvironment. Diffusion is fastest in the gas phase, slower in the liquid phase, and slowest in the solidphase.

Mathematically, the rate of drug delivery in diffusion-controlled delivery systems can bedescribed by Fick’s laws. Fick’s 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

22.5 DIFFUSION-CONTROLLED DELIVERY SYSTEMS





According to the diffusion principle, controlled-release drug delivery systems can be designed as areservoir system or a matrix system. Drugs released from both reservoir and matrix type devicesfollow 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 ofdrug in the polymer phase, CD is the concentration in the diffusion layer, hm is the thickness of themembrane, hd is thickness of the diffusion layer, and hp + dhp indicates the changing thickness of thedepletion zone of matrix.

In a reservoir system, if the active agent is in a saturated state, the driving force is kept constantuntil it is no longer saturated. For matrix systems, because of the changing thickness of the depletionzone, release kinetics is a function of the square root of time.10 A typical reservoir system fortransdermal delivery consists of a backing layer, a rate-limiting membrane, a protective liner, and areservoir compartment. The drug is enclosed within the reservoir compartment and released througha rate-controlling polymer membrane (Fig. 22.4).

Membranes used to enclose the device can be made from various types of polymers. The rate ofrelease can be varied by selecting the polymer and varying the thickness of the rate-controllingmembrane. 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 fewassumptions:

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 asdefined by

FIGURE 22.3 Schematic illustrations of reservoir versus matrix systems.

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





(22.4)

where K = partition coefficient of the drug molecule from polymer to solution C

s = 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 h

d

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 directly proportional to the solubility of the drug in polymer andinversely proportional to thickness of the polymer membrane.

Delivery systems designed on this principle can be administered by different routes: intrauterinesuch as Progestasert, implants such as Norplant, transdermal such as Transderm-Nitro, and ocularsuch as Ocusert.

A matrix system, often described as monolithic device, is designed to uniformly distribute thedrug within a polymer as a solid block. Matrix devices are favored over other design for theirsimplicity, low manufacturing costs, and lack of accidental dose dumping, which may occur withreservoir systems when the rate controlling membrane ruptures.

The release properties of the device depend highly upon the structure of the matrix: whether it isporous or nonporous. The rate of drug release is controlled by the solubility of the drug in thepolymer and the diffusivity of the drug through the polymer for nonporous system. For a porousmatrix, 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 highloading can complicate the release mechanism because of formation of cavities as the drug is leavingthe 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)





where CA is initial amount of drug, CP is solubility of drug in polymer, and hp is a time dependentvariable 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 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 ofdrug 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 processof a solid drug with relatively low aqueous solubility. The dissolution rate can be quantitativelydescribed by the Noyes-Whitney equation as follows.

(22.16)

where = rate of drug dissolution

D = diffusion coefficient of drug in diffusion layer h = thickness of diffusion layer A = surface area of drug particles C

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 givenamount 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 millingtechnique with stabilizer and other excipients, aggregation can be prevented to make microparticlessmaller 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 thephysical and chemical properties of a drug can be modified to alter the saturation solubility. Forexample, salt forms of a drug are much more soluble in an aqueous environment than the parentdrug. 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 enclosingthe drug in a polymer shell or coating. After the dissolution or erosion of the coating, drug moleculesbecome available for absorption. Release of drug at a predetermined time is accomplished bycontrolling the thickness of coating. In Spansule® systems, drug molecules are enclosed in beads ofvarying thickness to control the time and amount of drug release. The encapsulated particles with thincoatings will dissolve and release the drug first, while a thicker coating will take longer to dissolveand will release the drug at later time. Coating-controlled delivery systems can also be designed toprevent the degradation of the drug in the acidic environment of the stomach, which can reach as lowas pH 1.0. Such systems are generally referred as enteric-coated systems. In addition, enteric coatingalso 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 anddissolution mechanisms may be required to define the drug release from such systems.

Biologically degradable systems contain polymers that degrade into smaller fragments inside the bodyto release the drug in a controlled manner. Zero-order release can be achieved in these systems aslong as the surface area or activity of the labile linkage between the drug and the polymeric backbone

22.6 DISSOLUTION/COATING-CONTROLLED DELIVERYSYSTEMS

22.7 BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS





are kept constant during drug release. Another advantage of biodegradable systems is that, whenformulated for depot injection, surgical removal can be avoided. These new delivery systems canprotect 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 ofwater to diffuse into the core of the device filled with a hydrophilic component.11 A water-sensitivecomponent in the core can either dissolve or expand to create osmotic pressure and push the drugout of the device through a small delivery orifice, which is drilled to a diameter that correlates toa specific rate. In an elementary osmotic pump, the drug molecule is mixed with an osmotic agentin 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 separatedfrom the push compartment (Fig. 22.5b). The main advantage of the osmotic pump system is thatconstant 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 modifiedby 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 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 (�� P),the equation can be simplified to

(22.18)

22.8 OSMOTIC PUMP

FIGURE 22.5 Schematic illustration of an elementary osmotic pump (a) and a push-pullosmotic pump device (b).





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 constantosmotic 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 asdescribed earlier.

The ion exchange resin system can be designed by binding drug to the resin. After the formation ofa drug/resin complex, a drug can be released by an ion exchange reaction with the presence ofcounterions. 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 ofexchanging ions, and nature of nonexchanging ions. Although it is known that ionic strength of GIfluid is maintained at a relatively constant level, first-generation ion-exchange drug delivery systemshad 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 aspolyethylene glycol 4000 to retard the swelling in water (Fig. 22.6b). These particles are then coatedwith a water-permeable polymer such as ethyl cellulose to act as a rate-controlling barrier to regulatethe drug release.

22.9 ION EXCHANGE RESINS





The advances in biotechnology have introduced many proteins and other macromolecules that havepotential therapeutic applications. These macromolecules bring new challenges to formulation scien-tists, since the digestive system is highly effective in metabolizing these molecules, making oraldelivery almost impossible, while parenteral routes are painful and difficult to administer. A potentialcarrier for oral delivery of macromolecules is polymerized liposomes.14 Liposomes are lipid vesiclesthat target the drug to selected tissues by either passive or active mechanisms.15 Advantages ofliposomes include increased efficacy and therapeutic index, reduction in toxicity of the encapsulatedagent, and increased stability via encapsulation. One major weakness of liposomes is the potentialleakage of encapsulated drugs due to the stability of liposome. Unlike traditional liposomes, thepolymerized liposomes are more rigid because of cross-linking and allow the polymerized liposomesto withstand harsh stomach acids and phospholipase. This carrier is currently being tested for oraldelivery of vaccines.

Pulmonary route is also being utilized as route for delivery of macromolecules. The lung’s largeabsorptive surface area of around 100 m2 makes this route a promising alternative route for proteinadministration. 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 usingthis technology, dried powder particles can be designed at an optimum size of 1 to 5 µm for deeplung delivery. Advantages of powder formulation include higher stability of peptide and protein forlonger shelf life, lower risk of microbial growth, and higher drug loading compared to liquidformulation.16 Liquid formulations for accurate and reproducible pulmonary delivery are now madepossible by technology which converts large or small molecules into fine-particle aerosols anddeposits 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.

22.10 NEW MACROMOLECULAR DELIVERY APPROACHES

FIGURE 22.7 Illustration of an implantable osmotic pump.





and upon activation, the pressure will drive the liquid through fine pores creating the microsize mistfor pulmonary delivery.

Transdermal needleless injection devices are another candidate for protein delivery.17 The devicepropels the drug with a supersonic stream of helium gas. When the helium ampule is activated, thegas 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 permeabilitychange of skin at the site of administration. An alternative way to penetrate the skin barrier has beendeveloped utilizing thin titanium screens with precision microprojections to physically createpathways through the skin and allow for transportation of macromolecules. Another example ofmacromolecular delivery is an implantable osmotic pump designed to deliver protein drugs in a

TABLE 22.1 Examples of Various Delivery Approaches





precise manner for up to 1 year (Fig. 22.7). This implantable device uses osmotic pressure to push thedrug formulation out of the device through the delivery orifice.

Controlled-release delivery devices have been developed for more than 30 years. Most of the devicesutilize 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 ofdrugs, and pharmacokinetics. With development in the field of biotechnology, there is an increase inthe number of protein and other macromolecular drugs. These drugs introduce new challenges andopportunities for design of drug delivery systems.

1. CDER 1999 Report to the Nation, Improving Public Health Through Human Drugs. US Department of Human Services, Foodand 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 inControlled-Release Technology,” Drug Dev. Ind. Pharm., 19:1061–1081, 1993.

4. R. O. Potts and G. W. Cleary, “Transdermal Drug Delivery: Useful Paradigms,” J. Drug Target, 3 (4):247–251, 1995.

5. J. R. Robinson and V. H. Lee, (eds.), Controlled Drug Delivery: Fundamentals and Applications, 2d ed., Marcel Dekker, NewYork, 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):163–164, 1977.

11. F. Theeuwes, “Elementary Osmotic Pump,” J. Pharm. Sci., 64:1987–1991, 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):500–503, 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):576–582, 1995.

15. A. D. Bangham, “Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids,” J. Mol. Biol., 13:238–252,1965.

16. J. R. White and R. K. Campbell, “Inhaled Insulin: An Overview,” Clinical Diabetes, 19(1):13–16, 2001.

17. T. L. Brukoth, B. J. Bellhouse, G. Hewson, D. J. Longridge, A. G. Muddle, and D. F. Saphie, “Transdermal and TransmucosalPowdered Drug Delivery,” Crit. Rev. Ther. Drug Carrier Sys., 16(4):331–384, 1999.

22.11 CONCLUSION

REFERENCES




CHAPTER 22 DESIGN OF CONTROLLED- RELEASE ......Physicochemical properties such as solubility,...

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